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APPLICATION OF AMMONIA BORANE AND METAL
AMIDOBORANES IN ORGANIC REDUCTION
XU WEILIANG
(B.Sci., Soochow University)
A THESIS SUBMITTED
FOR THE DEGREE OF DOCTOR OF
PHILOSOPHY
DEPARTMENT OF CHEMISTRY
NATIONAL UNIVERSITY OF SINGAPORE
2012
brought to you by COREView metadata, citation and similar papers at core.ac.uk
provided by ScholarBank@NUS
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ACKNOWLEDGEMENTS
I would like to express my sincere gratitude to Prof. Chen Ping. As my Ph.D.
supervisor, Prof. Chen taught me both basic and advanced techniques in chemistry
with great patience. She also led me to the right direction with her experience and
knowledge at every critical point of this thesis. Her assistance and supervision are
great treasures to me and this thesis work.
I also appreciate the help from my co-supervisor, Asst. Prof. Wu Jishan. Dr Wu gave
me great suggestions on my research work and inspired me in every discussion with
him.
In addition, I need to warmly acknowledge Prof. Fan Hongjun and Prof. Zhou
Yonggui from Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
The help from Prof. Fan in theoretical calculation improves the understanding of my
research topic. The discussion with Prof. Zhou on research topic helps me achieve
several additional insights into this topic.
A very special recognition needs to be given to my research group members such as
Prof. Xiong Zhitao and Prof. Wu Guotao for their extensive help and support during
research.
Finally, a special thanks to my family for their uncontional love and support in every
way possible throughout the process of my Ph.D. course.
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THESIS DECLARATION
The work in this thesis is the original work of Xu Weiliang, performed independently
under the supervision of Assoc Prof. Chen Ping, Chemistry Department, National
University of Singapore, between 2007 and 2011. The content of the thesis has been
published in:
1. Xu, W.; Zhou, Y.; Wang, R.; Wu, G.; Chen, P., Lithium amidoborane, highly
chemoselective reagent for reduction of -unsaturated ketones to allylic
alcohols. Organic & Biomolecular Chemistry, 2012,10, 367-371.
2. Xu, W.; Wang, R.; Wu, G.; Chen, P. Calcium amidoborane, a new
chemoselective reagent for reduction of ,-unsaturated aldehydes and ketones to
allylic alcohols. RSC Advances, DOI: 10.1039/C2RA01291J.
3. Xu, W.; Zheng, X; Wu, G.; Chen, P. Reductive amination of aldehydes and
ketones with primary amines by using lithium amidoborane. Chinese Journal of
Chemistry, DOI: 10.1002/cjoc.201200132.
4. Xu, W.; Fan, H.; Wu, G.; Chen, P., Comparative study on reducing aromatic
aldehydes by using ammonia borane and lithium amidoborane as reducing
reagents. New Journal of Chemistry, DOI: 10.1039/c2nj40227k.
Name Signature Date
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Table of contents
Acknowledgements………………………………………………………….. i
Publication list…………………………………………………….................. viii
Summary………………………………………………………………………. ix
List of Tables………………………………………………………………….. xi
List of Figures…………………………………………………………………. xii
Abbreviation List…………………………………………………………….. xiv
Chapter 1. Introduction
1.1 Review on methods for organic reduction……………………………….. 2
1.1.1 Catalytic hydrogenation………………………………………………. 2
1.1.2 Electroreduction and reduction with metals………………………….. 4
1.1.3 Transfer hydrogenation……………………………………………..... 6
1.1.4 Reduction with hydrides and complex hydrides……………………… 9
1.2 Reducing reactivity of some typical borohydride compounds………… 10
1.2.1 Sodium borohydride (NaBH4)……………………………………… 10
1.2.2 Diborane (B2H6), tetrahydrofuran-borane complex (BH3-THF) and dimethyl
sulfide Borane (BMS) ………………………………………………. 13
1.2.3 Amine borane ………………………………………………………… 19
1.2.4 Sodium aminoborohydrides (NaNRR’BH3) ………………………… 25
1.2.5 Lithium aminoborohydrides (LiNRR’BH3, LAB) …………………... 28
1.3 Mechanistic interpretations on borohydride reduction……………………. 31
1.4 Review on ammonia borane and metal amidoboranes for hydrogen
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storage ………………………………………………………………..... 35
1.4.1 Ammonia borane (AB)……………………………………………….. 35
1.4.2 Metal amidoborane (MAB)………………………………………….. 38
1.5 Research gaps and aims…………………………………………………… 39
1.5.1 Research gaps………………………………………………………… 39
1.5.2 Research aims………………………………………………………… 40
Chapter 2. Methodology
2.1 Synthesis of metal amidoboranes…………………………………………. 42
2.1.1 Introduction………………………………………………………….. 42
2.1.2 Synthetic procedure of metal amidoboranes. ……………………… 43
2.2 Synthesis of deuterated ammonia borane and deuterated metal
amidoboranes.......................................................................................... 45
2.2.1 Introduction…………………………………………………………. 46
2.2.2 Synthetic procedure of deuterated ammonia borane and deuterated metal
amidoboranes……………………………………………………….. 46
2.3 Characterization methods………………………………………………. 47
Chapter 3. Reducing aldehydes and ketones by ammonia boranes
3.1 Introduction……………………………………………………………….. 48
3.2 Results and discussion ……………………………………………………. 49
3.2.1 Reaction process and reactivity study………………………………... 49
3.2.2 Kinetic study………………………………………………………….. 53
3.2.3 Theoretical study……………………………………………………. 55
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3.3 Conclusion……………………………………………………………… 58
3.4 Experimental section………………………………………………………. 58
3.4.1 General Remarks…………………………………………………..... 58
3.4.2 General experimental procedure for reducing aldehydes and ketones with
AB........................................................................................................ 59
3.4.3 Products characterization..................................................................... 60
Chapter 4. Reducing aldehydes, ketones and imines by metal amidoboranes
4.1 Introduction………………………………………………………………… 64
4.2 Results and discussion ……………………………………………………. 65
4.2.1 Reducing ketones by MAB………………………………………..... 65
4.2.2 Reducing imines with MAB………………………………………..... 71
4.2.3 Theoretical Study…………………………………………………...... 77
4.2.4 Reducing aromatic aldehydes with MAB…………………………… 79
4.3 Conclusion………………………………………………………………. 82
4.4 Experimental section……………………………………………………….. 83
4.4.1 General Remarks…………………………………………………….. 83
4.4.2 Synthesis of imines............................................................................... 83
4.4.3 General experimental procedure for reducing ketones with LiAB, NaAB or
CaAB................................................................................................... 84
4.4.4 General experimental procedure for reducing imines with LiAB, NaAB or
CaAB.................................................................................................... 84
4.4.5 Products characterization...................................................................... 85
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Chapter 5. Chemoselectively reducing -unsaturated aldehydes and ketones
into allyic alcohols by metal amidoboranes
5.1 Introduction……………………………………………………………….. 92
5.2 Results and discussion …………………………………………………….. 94
5.2.1 Reactivity study………………………………………………............ 94
5.2.2 Mechanism study…………………………………………………...... 97
5.2.3 Reducing -unsaturated aldehydes with MAB…………………..... 98
5.2.4 Explanation on 1,2-reduction property of MAB…………………...... 100
5.3 Conclusion………………………………………………………………… 100
5.4 Experimental section……………………………………………………….. 101
5.4.1 General remarks…………………………………………………... 101
5.4.2 Synthesis of -unsaturated ketones…………………………......... 101
5.4.3 General experimental procedure for reducing -unsaturated ketones or
aldehydes with CaAB………………………………………………………. 102
5.4.4 Products characterization……………………………………….... 103
Chapter 6. Reductive amination of aldehydes and ketones with primary amines
by using lithium amidoborane
6.1 Introduction………………………………………………………………. 109
6.2 Results and discussion ……………………………………………………. 111
6.2.1 Choice of Lewis acid……………………………………………..... 111
6.2.2 Reactivity study………………………………………………….... 112
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6.3 Conclusion………………………………………………………………… 114
6.4 Experimental section………………………………………………………. 115
6.4.1 General remarks…………………………………………………….. 115
6.4.2 General experimental procedure for reducing amination by LiAB.. 115
6.4.3 Products characterization………………………………………....... 116
Chapter 7. Conclusion and Future work
7.1 Conclusion ……………………………………………………………… 121
7.2 Future work……………………………………………………………… 124
Reference……………………………………………………………………… 125
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PUBLICATION LIST
1. Xu, W.; Zhou, Y.; Wang, R.; Wu, G.; Chen, P., Lithium amidoborane, highly
chemoselective reagent for reduction of ,-unsaturated ketones to allylic
alcohols. Organic & Biomolecular Chemistry, 2012,10, 367-371.
2. Xu, W.; Wang, R.; Wu, G.; Chen, P. Calcium amidoborane, a new
chemoselective reagent for reduction of ,-unsaturated aldehydes and ketones to
allylic alcohols. RSC Advances, DOI: 10.1039/C2RA01291J.
3. Xu, W.; Zheng, X.; Wu, G.; Chen, P. Reductive amination of aldehydes and
ketones with primary amines by using lithium amidoborane. Chinese Journal of
Chemistry, DOI: 10.1002/cjoc.201200132.
4. Xu, W.; Fan, H.; Wu, G.; Chen, P., Comparative study on reducing aromatic
aldehydes by using ammonia borane and lithium amidoborane as reducing
reagents. New Journal of Chemistry, DOI: 10.1039/c2nj40227k
5. Xu, W.; Fan, H.; Wu, G.; Wu, J.; Chen, P., Metal Amidoboranes, Superior Double
Hydrogen Transfer Agents in Reducing Ketones and Imines. Chemistry- a
European Journal, under revision.
6. Zheng, X.; Xu, W.; Xiong, Z.; Chua, Y.; Wu, G.; Qin, S.; Chen, H.; Chen, P.,
Ambient temperature hydrogen desorption from LiAlH4-LiNH2 mediated by
HMPA. Journal of Material Chemistry. 2009, 19 (44), 8426-8431.
7. Xiong, Z.; Wu, G.; Chua, Y. S.; Hu, J.; He, T.; Xu, W.; Chen, P., Synthesis of
sodium amidoborane (NaNH2BH3) for hydrogen production. Energy &
Environmental Science 2008, 1 (3), 360-363.
8. Xiong, Z. T.; Chua, Y. S.; Wu, G. T.; Xu, W. L.; Chen, P.; Shaw, W.; Karkamkar,
A.; Linehan, J.; Smurthwaite, T.; Autrey, T., Interaction of lithium hydride and
ammonia borane in THF. Chemical Communications. 2008, (43), 5595-5597.
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SUMMARY
Ammonia borane (NH3BH3, AB) and metal amidoboranes (M(NH2BH3)n, MABs) are
attractive materials for hydrogen storage due to their high hydrogen capacities and
mild dehydrogenation temperature. One of the driving forces for releasing hydrogen
from those materials is the co-existence of protic and hydridic hydrogens in their
structures. On the other hand, although AB and MAB belong to borohydrides, their
applications in organic reductions have not yet been extensively explored. Moreover,
few investigations were given to the participation of protic hydrogens of amine
boranes in organic reductions. The objectives of this study were to explore AB and
MABs as reducing agents in organic reduction and to study the reduction mechanism
involved.
Our experimental results show that AB possesses high reactivity in reducing
aldehydes at ambient temperature and in reducing ketones at 65oC. Based on the
in-situ FT-IR and NMR characterizations, we found that not only the hydridic
hydrogens of AB transfer to carbonyl groups, but the protic hydrogens of AB also
participate in reaction. Furthermore, kinetic study and density functional theory (DFT)
calculations indicate that the reaction between AB and carbonyl obeys a second-order
rate law, being first order of each reactant. In addition, concerted double hydrogen
transfer pathway is the dominant path in the reduction.
In another part of this study, MABs were utilized to reduce unsaturated functional
groups. Interestingly, MABs has higher reducibility towards unsaturated functional
groups than AB. Moreover, the protic hydrogens of MABs are also proved to
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participate in the reduction and transfer to the unsaturated functional groups. In
addition, kinetic study and DFT calculations reveal that the reaction between MAB
and carbonyl or imines obeys a first-order rate law, being first order of MAB. The
rate-determining step of reduction is the elimination of MH from MAB followed by
the transfer of H(M) to C site of unsaturated bond.
MABs are also found to be highly chemoselective reagents for the reduction of
-unsaturated ketones to allylic alcohols and reducing agents for reductive
amination. These two applications provide strong evidences that MABs are promising
candidates for organic reduction.
In conclusion, this study has achieved a ready entry to investigate the reducing
capabilities of AB and MABs in organic reaction. The results of this thesis may
provide guidelines for utilizing AB and MABs not only as hydrogen storage materials
but also as reducing reagents in organic reduction.
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LIST OF TABLES
Table 1.1. Optimized reaction conditions for the catalytic hydrogenation of selected
types of compounds …………………………………………………………... 3
Table 3.1.Reactions of AB and carbonyl compounds in THF……………….. 51
Table 4.1. Reducing ketones by LiAB, NaAB CaAB or AB………………….. 66
Table 4.2. Reducing imines by LiAB, NaAB, CaAB or AB………………… 72
Table 4.4.Reactions of LiAB and aldehydes in THF………………………….. 81
Table 5.1. Reducing 1a in different solvents…………………………………. 95
Table 5.2. Reducing-unsaturated ketones by LiAB or CaAB……………. 96
Table 5.3. Reducing-unsaturated aldehydes by CaAB and LiAB………… 99
Table 6.1. Reductive amination using LiAB in the presence of different Lewis
acids……………………………………………………………………………. 112
Table 6.2. Reductive amination of carbonyl compounds and primary amines by using
AB in the presence of AlCl3…………………………………………………… 113
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LIST OF FIGURES
Figure 2.1. 11B NMR spectrum of LiAB…………………………………........ 44
Figure 2.2. 11B NMR spectrum of NaAB……................................................. 44
Figure 2.3. 11B NMR spectrum of CaAB……………….................................... 45
Figure 3.1. in-situ FT-IR measurement of the reaction between 0.005M AB and
0.005M benzaldehyde………………………………………………………… 49
Figure 3.2. (a) 1H NMR characterization of AB(D)-benzaldehyde in THF-d8. (b) 2H
NMR characterization for A(D)B-benzaldehyde in THF……….................. 50
Figure 3.3. in situ 11B NMR characterization of reacting AB with one equiv.
benzaldehyde at room temperature...................................................................... 51
Figure 3.4. Three curves stand for formation of [OH] under different concentrations
of AB and benzaldehyde...................................................................................... 54
Figure 3.5. 1/ [benzaldehyde] versus time plots for 0.005M benzaldehyde reacting
with 0.005M AB, 0.005M AB(D), 0.005M A(D)B respectively………………. 55
Figure 3.6. The proposed mechanism for the reaction of AB and
benzaldehyde……………………………………………………………………56
Figure 4.1. in situ FT-IR measurements of the reaction of 0.02M LiAB and 0.02M
benzophenone………………………………………………………………….. 68
Figure 4.2. 2H NMR result for LiND2BH3 reacting with benzophenone in
THF………………………………………………………………………….... 68
Figure 4.3. Different concentrations of LiAB reacting with different concentration
of benzophenone ………………………………………………………………. 70
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Figure 4.4. ln C(LiAB) vs. t plot…………….................................................... 70
Figure 4.5. ln C(LiA(D)B) versus t plot is shown as a. ln C(LiAB(D)) versus t plot is
shown as b…………………………………………………………………….. 71
Figure 4.6. in situ FT-IR measurements of the reaction of 0.033M LiAB and 0.033M
N-benzylideneaniline............................................................……………….. 74
Figure 4.7. 2H NMR result for LiND2BH3 reacting with N-benzylideneaniline in
THF………………………………………………………………………… 74
Figure 4.8. Different concentrations of LiAB reacting with different concentration
of N-benzylideneaniline……………………………………………………….. 75
Figure 4.9. ln C (LiAB) vs. t plot....................................................................... 76
Figure 4.10. kLiA(D)B is 0.018 based on the slope of (o); kLiAB(D) is 0.011 with respect to
the slope value of (p)……………………………………………………………76
Figure 4.11. The proposed mechanism for the reaction of LiAB and
N-benzylideneaniline…………………………………………………………. 77
Figure 4.12. The structures of the transition state TS1 and TS2……………..... 78
Figure 4.13. (a) Raman spectra for LiAB and white precipitate; b) 11B solid NMR
spectrum for white precipitate……………………………………………… 80
Figure 5.1. 2H NMR result for LiND2BH3 (LiA(D)B)reacting chalcone in THF..98
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ABBREVIATION LIST
AB: ammonia borane, NH3BH3
AB(D): NH3BD3
A(D)B: ND3BH3
BMS: dimethyl sulfide borane, Me2S·BH3
CaAB: calcium amidoborane, Ca(NH2BH3)2
CBS catalyst: Corey-Bakshi-Shibata catalyst
DCM: dichloromethane, CH2Cl2
DKIE: deuterium kinetic isotopic effect
DFT: density functional theory
DSC: differential scanning calorimetry
EtOAc: ethyl acetate
FTIR: Fourier transform infrared spectroscopy
GC: gas chromatography
INT: intermediate
KAB: potassium amidoborane, KNH2BH3
LAB: lithium aminoborohydrides, LiNRR’BH3
LiAB: lithium amidoborane, LiNH2BH3
LiA(D)B: LiND2BH3
LiAB(D): LiNH2BD3
LC: liquid chromatography
MAB: metal amidoborane, M(NH2BH3)n
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MPV reduction: Meerwein-Ponndorf-Verley reduction
MS: mass spectroscopy
NaAB: sodium amidoborane, NaNH2BH3
NaDMAB: sodium dimethylaminoborohydrides, Na(CH3)2N·BH3
NMR: nuclear magnetic resonance
NaTBAB: sodium tert-butylaminoborohydride, Na t-C4H9NH·BH3
PAB: polyaminoborane, (NH2BH2)n
PIB: polyiminoborane (NHBH)n
SrAB: Strontium amidoborane, Sr(NH2BH3)2
THF: tetrahydrofuran
TS: transition state
XRD: X-ray diffraction
YAB: yttrium amidoborane, Y(NH2BH3)3
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Chapter 1. Introduction
The reduction of organic compounds is one of the most important reactions in organic
synthesis. Generally, there are four common reducing methods: catalytic
hydrogenation, electron transfer, transfer hydrogenation and hydride transfer. Among
these methods, hydride transfer process is the easiest to handle and the friendliest to
researchers. Borohydrides are the most commonly used reagents in hydride transfer.
In 1939, Brown and his co-workers reported the first application of borohydride for
the reduction of organic functional groups.[1] Since then, various borohydride reagents
have evolved for reducing typical organic functional groups such as aldehydes,
ketones, carboxylic acids, olefins, nitriles, epoxides and esters in different
conditions.[2] Due to the convenient operation procedure, high reactivity and high
selectivity, hydroboration – the addition of a boron-hydrogen bond across an
unsaturated moiety – is widely employed in organic reduction.
Amine boranes are attractive borohydride reagents due to their high solubility in a
series of organic solvents and low sensitivity to acid.[3] Therefore, amine boranes are
widely utilized in reducing reaction. Related works have been systematically
reviewed by Hutchins and his co-workers in 1984.[4] In addition, with the recent rapid
development of hydrogen storage research, many researchers show their keen
interests in amine boranes, such as ammonia borane (NH3BH3, or AB for short)[5], and
cationic modified amine boranes, such as metal amidoborane (M(NH2BH3)n, or MAB
for short) due to their high hydrogen capacities and low hydrogen releasing
temperatures.[6] However, the research on AB and MABs is somehow limited in
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hydrogen storage field. Therefore, it would be an interesting topic to investigate the
properities of AB and MAB in reducing organic compounds, which may provide the
basis for the application of new borohydrides in organic reductions.
In the following sections of this chapter, the traditional methods in organic reduction ,
the applications of various typical borohydrides in reducing reactions and its
corresponding reaction mechanisms, and the developments & applications of AB and
MABs in hydrogen storage research will be reviewed .
1.1 Review on methods for organic reduction
1.1.1 Catalytic hydrogenation
Generally, molecular hydrogen does not react with organic compounds at
temperatures below 480 oC. Therefore, the reaction between hydrogen and organic
compounds has to take place in the presence of a catalyst which interacts both
hydrogen and organic molecule.[7-8] The commonly used catalysts are usually based
on transition metals such as platinum, palladium, rhodium, ruthenium and nickel.
Many functional groups can be reduced by catalytic hydrogenation. Among these,
olefins, nitro compounds and nitriles show higher reactivity than others, such as
ketones, aldehydes and esters.[9] Catalytic hydrogenation is seldom used in reducing
amides due to extreme condition needed.[10] There are four factors affecting catalytic
hydrogenation, i. e., the ratio of catalyst to compound,[11-12] solvent, temperature[11]
and the pressure of hydrogen[13]. Generally, reduction is more favored under larger
amount of catalyst, higher temperature and higher pressure. The frequently used
solvents are methanol and ethanol though more hydrogens dissolve in pentane and
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hexane.[14] Furthermore, the pH value also plays an important role in the steric
outcome of reaction. syn-addition is favored in acidic conditions. On the other hand,
basic conditions results in anti-addition of hydrogen[15]. In addition, another important
effect, i. e., mixing, should be considered.[16] It is because that catalytic hydrogenation
including homogeneous hydrogenation and heterogeneous hydrogenation is a reaction
of at least 2 phases. Therefore, good contact is needed between gas and liquid or
between hydrogen and catalyst in heterogeneous hydrogenation case. Shaking and fast
magnetic stirring are, therefore, preferred. In catalytic hydrogenation, special
precautions should be taken to prevent potential explosion because of the use of
molecular hydrogen. Therefore, all the metal or glass connections must be
leakage-free. Guidelines for use and dosage of catalysts are given in Table 1.1.[16]
Table 1.1 Optimized reaction conditions for the catalytic hydrogenation of selected types of compounds, adapted from ref.[16].
Starting compound
Product Catalyst Cat./Comp.
Ratio (wt %) Temp (oC)
Pressure (atm)
Alkene Alkane
5% Pd (C) 5-10% 25 1-3 PtO2 0.5-3% 25 1-3
Raney Ni30-200% 25 1
10% 25 50
Carbocyclic aromatic
Hydroaromatic
PtO2 6-20%, AcOH 25 1-3 5%
Rh(Al2O3)40-60% 25 1-3
Raney Ni 10% 75-100 70-100
Heterocyclic aromatic
Hydroaromatic
PtO2 4-7%, AcOH
or HCl/MeOH25 1-4
5% Rh(C)20%,
HCl/MeOH 25 1-4
Raney Ni 2% 65-200 130
Aldehyde, ketone
Alcohol PtO2 2-4% 25 1
5% Pd (C) 3-5% 25 1-4 Raney Ni 30-100% 25 1
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Halide hydrocarbon
5% Pd (C) 1-15%, KOH 25 1 5% Pd
(BaSO4) 30-100%,KOH 25 1
Raney Ni 10-20%, KOH 25 1
1.1.2 Dissolving Metal Reduction
Dissolving metal reductions is one of the first reductions of organic compounds
discovered hundred years ago.[17-19] This reduction is defined as acceptance of
electrons. The reaction of reducing carbonyl is illustrated in scheme 1.1 as an example
to explain the mechanism[20-21]: when a metal is dissolved in a solvent such as liquid
ammonia, it gives away electrons and becomes a cation; subsequently, the organic
substrate in the system accepts an electron to form anion A, or two electrons to form
dianion B which is relatively difficult to form because the encounter of two negative
species is required and two negative sites are close to each other; if protons is absent
in the system, two anion A may combine together to form a dianion of a dimertic
nature C; on the other hand, in the presence of proton, radical anion A is protonated to
a radical D which can couple with another D to form a pinacol E, or accept another
electron to form an alcohol after another protonation. Furthermore, pinacol E and
alcohol F may also result from double protonation of C and B, respectively.
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C O1e
C O
A
C O
C O
C O
B
1e
C OHH+
D
C OH
C OH
2 H+
C E
C OH1e
H+
CHOH
F
2 H+
dimerization
dimerization
Scheme 1.1. Mechanism of reducing carbonyl by dissolving metal, adapted from ref. [16]
The “dissolving metal reduction” is effective in reducing polar multiple bonds such as
C=O.[22] It can also successfully reduce conjugated dienes, aromatic rings[23-26] and
carbon-carbon double bond conjugated with a polar group[27-28]. However, this method
is extremely difficult to reduce an isolated carbon-carbon double bond and has little
practical application.
The reducing ability of metal parallels with its relative electrode potential, i. e., Li
(-2.9V)≈ K (-2.9V) > Na (-2.7V) > Al (-1.34V) > Zn (-0.76V) > Fe (-0.44V) > Sn
(-0.14V).[16] Metal with higher negative potentials, such as alkali metals, are capable
of reducing most unsaturated compounds. However, metals with lower potentials,
such as iron and tin, are able to only reduce strongly polarized bonds such as nitro
groups. In addition, most dissolving metal reductions are carried out in the presence
of proton donor, such as methanol, ethanol and tert-butyl alcohol. The function of
these proton donors is to protonate the intermediate anion radicals and prevents
undesirable side reactions, such as dimerization and polymerization.[16] In dissolving
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metal reduction, attentions should be carefully paid in the following aspects: firstly
alkali metal should have high purity since trace metals, such as iron, may catalyze the
reaction between alkali metal and liquid ammonia to form alkali amide and hydrogen;
secondly, work-up process after reaction requires particular safety attentions since
ammonia is highly toxic; thirdly, metal used in the reaction should be cut into meal
sheets or small particles, therefore, a specific safety rule should be obeyed because
some alkali is easily explosive and on fire; lastly, unreacted metal after reaction
should be decomposed by addition of ammonium chloride or sodium benzoate, water
is forbidden to add in the system in order to avoid explosions and fires.
1.1.3 Transfer hydrogenation
Reducing unsaturated organic compounds by transfer hydrogenation was first
reported in 1903.[29] However, this kind of reaction was not established as useful
synthetic method until the development of Meerwein-Ponndorf-Verley (MPV)
reduction.[30] The next milestone was the discovery that transition metal complexes
can catalyze transfer hydrogenation process.[31] Nowadays, substantial research has
concerned the application of chiral transition metal catalysts for asymmetric transfer
hydrogenation.[31]
The main difference between catalytic hydrogenation and transfer hydrogenation is
the source of hydrogen i. e., the former needs molecular hydrogen gas, however, the
later needs hydrogen donor, DH2, which can transfer two Hs to an unsaturated
functional group under the influence of a suitable promoter. In most cases, the two
hydrogens leave hydrogen donor nonequivalently, i. e., one as formal hydride and the
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other as formal proton. At the same time, the hydrogen donor is converted to its
dehydrogenated counterpart D. Generally speaking, any chemical compounds which
have two mobilized hydrogen under certain conditions can be used as hydrogen
donors. However, 2-propanol[32-33], formic acid and its salts[34], and Hantzsch ester[35]
are three compounds that are wildly used as hydrogen donors in transition metal
catalyzed transfer hydrogenation. Primary alcohols are seldom used as hydrogen
donor because aldehydes, the dehydrogenated counterpart of primary alcohols, may
be toxic to catalysts.[36]
The transfer of hydrogen from donor to acceptor can process at different manners
depending on the catalysts used. There are two kinds of mechanisms that have been
proposed for the metal-catalyzed process, i.e., direct hydrogen transfer and hydridic
route, respectively. The direct hydrogen transfer mechanism[37-39] requires that the
substrate and hydrogen donor interact with catalyst simultaneously to form an
intermediate where the hydrogen is delivered as a formal hydride from the donor to
the acceptor in a concerted process as shown in scheme 1. 2. MPV reduction is typical
in this kind of mechanism.
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R1 R2
OH+
R3 R4
OAl O
R2
R1
3
R1 R2
O+
R3 R4
OH
MPV reduction
AlOO
O
R1
R2
R2
R1
R1R2
R3 R4
O
AlOO
O
R2
R1
R1R2
O
H
R2R1 R4R3
AlOO
O
R2
R1
R1R2
OR2R1 R4R3
H
AlOO
O
R3
R4
R2
R1
R1R2
R2 R1
O
R2HO
R1
OHR4
R3
1
2
3
4
Scheme 1.2. Mechanism of MPV reduction, adapted from ref [36]
In the MPV reduction, firstly the catalyst, aluminum alkoxide 1, combines with
carbonyl oxygen to achieve a tetra coordinated aluminum intermediate 2. Then
hydride is transferred to the carbonyl from the alkoxy ligand via a pericyclic
mechanism to form intermediate 3. At the next step, the new carbonyl dissociates
from 3 and tricoordinated aluminum species 4 is formed. Finally, an alcohol from
solution displaces the newly reduced carbonyl to regenerate the catalyst 1. However,
this mechanism is typically observed under electropositive metal-catalyzed cases,
such as Al and lanthanides. In the cases of transition metal derivatives as catalysts,
hydridic route[40-41] is the typical mechanism for transfer hydrogenation as shown in
scheme 1. 3.
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9
R1 R2
OH+
R3 R4
O
R1 R2
O+
R3 R4
OHLxM
OR1
R2HLxM
(H)
OR1
R2
LxM
(H)
H
OR4
R3
LxM
(H)
H
OR4
R3
LxM
(H)
H
R3 R4
O
R1 R2
O
R1 R2
OH
R3 R4
OH
5
6
7
8
Scheme 1.3. Mechanism of hydridic route, adapted from ref. [36]
In the hydridic route, firstly one molecule of alcohol solvent coordinates with
transition metal catalyst LxM to form alkoxy complex 5. Then the metal-hydride
intermediate 6 and ketone which is derivative from alcohol solvent are produced after
intramolecular -hydrogen extraction procedure. In the next step, substrate ketone
displaces the coordinated acetone to give 7. Through inner sphere mechanism, a new
alkoxy derivative 8 is formed after hydride transfer. Finally, a new molecule of
alcohol solvent displaces the alkoxy ligand to produce the reduced product.
In general, low-aggregation aluminum alkoxides are able to induce the reaction to
follow the direct hydrogen transfer process., while Ru,[40, 42-44] Ir,[45-46] and Rh[47-48]
complexes are effective catalysts for hydridic route.
1.1.4 Reduction with hydrides
Lithium aluminum hydride and sodium borohydride were synthesized and firstly used
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10
as reducing reagents in 1947[2, 49] and 1953[50], respectively. Since then, various
hydrides compounds such as diborane, metal borohydrides and metal aluminum
hydrides are synthesized based on these two compounds. The reactions of complex
hydrides with unsaturated compounds involve a hydridic hydrogen transfer from the
nucleophile hydride to the electrophile site of unsaturated bond. Those complex
hydrides are capable of reducing almost all kinds of unsaturated functional groups.
For example, LiAlH4[51] is a powerful hydride-donor reagent. It can rapidly reduce
esters, acid, nitriles, amides, ketones and aldehydes.
The advantage of complex hydrides reduction over catalytic hydrogenation is that the
reduction can be carried out under normal atmosphere and no pressurized hydrogen is
needed. Therefore, the operations are safer and friendlier to researchers. Among these
complex hydrides, borohydride compounds are rapidly developed in these years. In
the following introduction, applications of some typical borohydride compounds will
be reviewed in detail. Moreover, the mechanism for these reactions will also be
reviewed.
1.2 Reducing reactivity of some typical borohydride compounds
1.2.1 Sodium borohydride (NaBH4)
NaBH4 is a mild reducing reagent. In hydroxylic solvents, aldehydes and ketones are
rapidly reduced at ambient temperature.[52] However, NaBH4 is inert to other
functional groups such as nitro and nitrile. The relative reactivity of a number of
representative groups toward NaBH4 is of the order of acid chlorides > ketones >
epoxides > esters>> nitriles > carboxylic acids.[53] Although NaBH4 has low reducing
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11
ability, some efforts have been taken to enhance the application of NaBH4 in organic
synthesis such as solvent choice and the introduction of addictives. The reaction
characteristics of NaBH4 are summarized in the following sections.
1.2.1.1 Reducing aldehydes and ketones to alcohols
In most cases ,the reduction of aldehydes or ketones by NaBH4 occurs rapidly at room
temperature though heating is required when reducing some aromatic ketones.[52]
NaBH4 is soluble in diglyme and triglyme. However, these solvents appear to
decrease its reducing power. Ketones cannot be reduced in diglyme at room
temperature.[54] Comparatively, aldehydes are reducible by NaBH4 in diglyme.
Therefore, diglyme or triglyme is an effective solvent for the selective reduction of
aldehydes in the presence of ketones.
1.2.1.2 Reducing esters to alcohols
NaBH4 is soluble in various alcohol solvents, such as ethanol and isopropyl alcohol.
Although it reacts rapidly with methanol liberating hydrogen, NaBH4/Methanol
system is quite effective in reducing ester. Mandal and his workers[55] reported that
esters having N-alkyl-N-aryl functionality at the -position are easily reduced with
NaBH4/MeOH at 0-5°C in high yield up to 98%. One example is shown in scheme
1.4.
NO
C6H5HN
CO2CH3
C6H5
NaBH4/ MeOH
15minNO
C6H5HN
CH2OH
C6H5
96%
Scheme 1.4. One example for reducing ester in NaBH4/ MeOH system
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12
Melancthon and his workers studied the reactions between NaBH4/Methanol and
esters.[56] They found that esters of simple heterocyclic, aromatic, and aliphatic acids
are reduced under an excess of sodium borohydride (up to 10-fold excess) in
methanol. Although these two methods provide high reactivities in reducing ester and
keep other functional groups such as amides and C=C intact, the amount of NaBH4 is
up to 5-10 fold excess. Therefore, it increases the cost of reaction and the risk of
explosion in dealing with the excess NaBH4.
1.2.1.3 Reducing carboxylic acids to alcohols
Periasamy and his co-workers reported that carboxylic acids can be reduced directly
to alcohols by successive addition of NaBH4 and I2.[57] The reaction procedure can be
summarized in scheme 1.5. This system is important due to its effectiveness in
reducing an acid group without affecting ester group even if the ester group is nearby.
NaBH4 + RCOOH RCOOBH3Na + H2
0.5I2
RCOOBH2 + 0.5 NaI + 0.5H2RCH2OBORCH2OHH3O+
Scheme 1.5. The reaction procedure for reducing carboxylic acid by NaBH4/I2 system.
1.2.1.4 Reducing nitriles or nitros to amines
Herbert and his co-workers found that the addition of AlCl3 to NaBH4 in diglyme
gave a clear solution which is a more powerful reducing agent than NaBH4 itself.[58]
Nitriles can be reduced to primary amines by this reducing agent system. One
example is given in scheme 1.6. Moreover, aldehydes, ketones, esters, carboxylic
acids and epoxides are reduced to alcohols by this method. However, sodium salts of
Page 29
13
the carboxylic acids and nitro cannot be reduced. Therefore, the reagent permits the
selective reduction of an ester group in the presence of the carboxylate or nitro group.
CN1.AlCl3, NaBH4
diglymeCH2NH2
85%2. H3O+
Scheme 1.6. One example for reducing nitrile by AlCl3/ NaBH4 system.
Yoo and his co-workers found that NaBH4/CuSO4 system has higher reducibility than
NaBH4 alone.[59] Nitriles and aliphatic and aromatic nitro groups besides ketones,
aliphatic esters and olefins, can be reduced by this method. However, amides,
aliphatic and aromatic carboxylic acids are inert.
1.2.2 Diborane (B2H6), tetrahydrofuran-borane complex (BH3-THF) and
dimethyl sulfide Borane (BMS)
B2H6 is an acidic-type reducing agent which shows different selectivity with the
basic-type reducing agents such as NaBH4. Diborane tends to attack on electro-rich
center of functional group due to its electro-deficiency.[60] However, NaBH4 reacts
with functional group by nucleophilically attacking on an electron-deficient center.[1]
The high reactivity of diborane is due to its ready dissociation into borane. The borane
molecule serves as a strong Lewis acid forming coordination complex with Lewis
base. Many reactions involving borane complexes have low activation energy.[60]
Schaeffer and coworkers found that a new compound formed when B2H6 dissolved in
THF.[61] Raman spectroscopic investigation together with 11B and 1H NMR studies
revealed that this new compound was tetrahydrofuran-borane complex
(BH3-THF).[62-63] BH3-THF is a convenient reducing agent due to its high stability.
However, there are still some characteristics which limit its application:[60] (1)
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14
BH3-THF can only be sold as a dilute solution in THF (1M);(2) THF is slowly
cleaved by BH3 at room temperature; (3) NaBH4 (< 5mol%) has to be added to
BH3-THF to inhibit the cleavage of THF.
Like BH3-THF, dimethyl sulfide borane (BMS) is also one of the borane-Lewis base
complexes. The preparation of BMS was first reported by Burg and Wagner.[64] BMS
has been found to overcome all the disadvantages of BH3-THF[60, 65]: 1) BMS has a
molar concentration of BH3 ten times of that of BH3-THF. The commercial
concentration of BMS is 10M; 2) BMS can be stored for months at room temperature
without loss of hydride activity. However, it reacts with atmospheric moisture upon
exposure to air resulting in a decrease in purity. 3) BMS is soluble in various aprotic
solvents such as ethyl ether, THF, hexane, toluene and glyme. Due to its remarkable
stability and high reactivity, BMS is a very useful reagent for the reduction of organic
functional groups.
The relative reactivity of a number of representative functional groups toward
diborane, BH3-THF and BMS indicates the following order of reactivity: carboxylic
acids > olefins > ketones > nitriles > epoxides > esters. The reaction characteristics of
diborane, BH3-THF, and BMS are summarized in the following sections.
1.2.2.1 Hydroboration of olefins
Unsaturated compounds with carbon-carbon double bonds or triple bonds are
converted into organoboranes via hydroboration with diborane, BH3-THF or BMS.
Herbert and coworkers found that the reaction of olefin and diborane is essentially
quantitative and involves a cis regioselective addition.[53, 66]
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15
Organoboranes are susceptible to react with carboxylic acids. A detailed
investigation[67] revealed that carbon-carbon single bond product is obtained after
reacting organoborane with excess glacial acetic acid in diglyme at refluxing
temperature for 2-3 hrs (scheme 1.7). This hydroboration-protonolysis procedure
provides a convenient non-catalytic method for hydrogenating carbon-carbon double
bonds.
3 CH3SCH2CH=CH2
BH3
CH3SCH2CH2-CH2
BCH3SH2CH2C CH2CH2SCH3
RCOOH3 CH3SCH2CH2CH3
Scheme 1.7. Hydroboration-protonolysis procedure for reducing olefin by diborane.
On the other hand, organoboranes react with hydrogen peroxide to produce alcohols.
(scheme 1.8).[68] This method is also commonly used in synthesizing alcohols from
alkenes.
1) BMS, hexane
2) H2O2, OH-
OH86%
Scheme 1.8. One example for olefin reacting with BMS and follow-up hydrogen peroxide to produce
alcohol.
1.2.2.2 Reducing aldehydes or ketones into alcohols
Aliphatic and aromatic aldehydes and ketones are rapidly reduced to alcohols at room
temperature by diborane, BH3-THF, or BMS. The first step in this reduction is the
formation of corresponding dialkoxy derivatives of borane (scheme 1.9).[1] All
attempts to isolate the mono-alkoxy derivative were unsuccessful.[69] Trialkyl borate
is formed when an excess of aldehyde or ketone is used as shown in scheme 1.10.
After hydrolysis with acid aqueous solution, alcohol product is obtained. BH3-THF
has similar features as to diborane.
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16
CO
R'R+ B2H6 2(RR'CHO)2BH4
H3O+
CHO
R'R
H4
Scheme 1.9. The reaction procedures for reacting carbonyl compound with diborane.
CO
R'R+ B2H6 3(RR'CHO)3B9
H3O+
CHO
R'R
H
Scheme 1.10 The reaction procedures for reacting an excess of carbonyl compound with diborane.
Comparatively, kinetic studies showed that reducing ketone by BMS is slower by a
factor of four compared to BH3-THF.[70] BMS is also one of several effective borane
sources for asymmetric ketone reduction using Corey-Bakshi-Shibata catalyst (CBS
catalyst).[71] The rate determining step is nucleophilic substitution of methyl sulfide in
BMS by ketone (scheme 1.11).
ON
HNO2SMe
H
CN
O
NB
O
H PhPh
BH3
BMS
ON
HNO2SMe
H
CN
OH
90%, 98.5% ee Scheme 1.11. One example for reducing ketone by BMS in the presence of CBS catalyst.
1.2.2.3 Reducing epoxides into alcohols
In the study of the reactivity of NaBH4 and BF3 in diglyme where BH3-THF is in situ
formed, Brown and coworker[72] found that the reduction of epoxides was fast.
However, when pure BH3-THF was applied, the reaction rate was slow at room
temperature[73] and some byproducts resulted from the use of BH3-THF were derived.
Therefore, Brown and Yoon demonstrated[74-75] that either NaBH4 or BF3 was acting
as catalyst to promote the reaction of diborane with epoxides (scheme 1.12).
Therefore, BH3-THF is much milder reducing agent toward epoxides than the reagent
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17
prepared in situ from NaBH4 and BF3.
OBH3-THF
BF3 cat.
OH
Scheme 1.12. One example for reducing epoxide to alcohol by BH3-THF.
1.2.2.4 Reducing esters to alcohols
Aliphatic acid esters are reduced relatively slowly by BH3-THF at 0 oC.[76] The time
required for complete conversion to the corresponding alcohol is 12 to 24 hrs. Phenyl
acetate is reduced even more slowly, and the aromatic acid esters are almost inert at 0
oC. The lower reactivity of the ester group is due to the electron-withdrawing
inductive effect of oxygen on the carbonyl group. Therefore, the reduction of simple
esters to alcohol using BH3-THF has limitation in organic synthesis. Scheme 1.13 is a
specific example for ester reduction by BH3-THF.
N
C(CH2)2COCH3
O O
BH3-THF
25 oC N
CH2(CH2)2CH2OH
Scheme 1.13. One example for reducing ester by BH3-THF.
On the other hand, esters can be reduced with BMS at elevated temperatures.[77]
Aliphatic esters are rapidly reduced in refluxing THF.[78-80] Aromatic esters react at a
slower rate.
1.2.2.5 Reducing imines to amines
The reduction of simple alkyl-substituted imines with BH3-THF under mild
conditions gives excellent yields of the corresponding amines.[81] A specific example
is shown in scheme 1.14. BH3-THF also exhibits superior selectivity and reactivity in
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18
reducing isoquinoline.[82] Isoquinoline reacts with BH3-THF giving an intermediate ,
dihydroisoquinoline–borane adduct, which is further reduced to
tetrahydroisoquinoline upon treatment with dilute aqueous HCl in ethanol (scheme
1.15).
O2N CH
NC6H5
BH3-THF
0-5 oCO2N CH2NHC6H5
Scheme 1.14. One example for reducing imine by BH3-THF.
N
BH3-THF
NBH3
5% HCl-H2O
EtOH NH Scheme 1.15. One example for reducing isoquinoline by BH3-THF.
1.2.2.6 Reducing nitriles to amines
The BH3-THF reagent reacts slowly with both aliphatic and aromatic nitriles at 0 oC
(scheme 1.16).51 However, by using an excess of borane reagent and a higher
temperature, high isolated yields of amines are obtained upon hydrolysis of the
intermediate borazine in acid.
O2N CN1. BH3-THF
2. EtOH/ HClO2N CH2NH2 HCl
Scheme 1.16. Reducing nitrile by BH3-THF.
One other hand, BH3-THF and diborane cannot achieve primary amines in the case of
reducing aliphatic nitriles. For example, acetonitrile reacts with diborane at low
temperatures to form a borane adduct.[11] At 20 oC, this adduct decomposes giving ca.
50% yield of N,N,N-triethylborazine (scheme 1.17).
3CH3CN:BH3HB
NBH
NBH
NC2H5
C2H5C2H5
20 oC
Scheme 1.17. Acetonitrile reacts with diborane to form a six-member ring compound.
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19
BMS is a useful reagent for the preparation of amines via reduction of nitriles.[77]
Both aliphatic and aromatic nitriles undergo fast reduction if a theoretical amount of
BMS is used in refluxing toluene (scheme 1.18). Therefore, BMS is an ideal
alternative for diborane or BH3-THF in reducing nitriles.
Cl ClCH2CN
Cl Cl
CH2CH2NH2
BMS
C6H5CH3, refluxing64%
Scheme 1.18. Reducing nitrile by BMS.
1.2.2.7 Reducing carboxylic acids to alcohols
Both aliphatic and aromatic carboxylic acids can be reduced by BH3-THF to the
corresponding primary alcohols rapidly and quantitatively under mild condition. [76, 83]
Borane reagent also shows high selectivity in reducing carboxylic acid group in the
presence of other reactive functional groups. Two specific examples are shown in
scheme 1.19[84-85].
COOHNO2
1.BH3-THFCH2OH
NO2
2. hydrolysis
C6H5C COOH
O
C6H5C CH2OH
O1.BH3-THF
2. hydrolysis
Scheme 1.19. Two examples of reducing carboxylic acids by BH3-THF.
Comparing with BH3-THF, BMS is another borane reagent that shows particular
promise to reduce carboxylic acid.[77] Aliphatic carboxylic acids react readily at 25 oC
with BMS in a variety of solvents. Aromatic carboxylic acids react very slowly with
BMS, but reduction occurs rapidly in the presence of trimethyl borate.[86]
1.2.3 Amine borane
In 1937, the first amine borane, Me3N-BH3, was reported by Schlesinger and his
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20
co-workers[87]. This complex was formed by the direct reaction of trimethylamine and
diborane (scheme 1.20). This initial discovery paved an innovative way to synthesize
numerous amine boranes by treating primary, secondary, and tertiary amine with
diborane.[88] In general, stable amine borane complexes will form if the pKa of the
amine is above 5.0-5.5.[4] This means that ammonia and nearly all aliphatic amines
form stable complexes with BH3. The major exceptions are branched chain tertiary
amines, such as tri-isobutylamine, where steric hindrance of the alkyl groups prevents
stable bonding.[4] Amine boranes are capable of reducing various functional groups.
They are advantageous to borohydride reagents because of their high solubility in
organic solvents and reduced sensitivity to acid.[89-90] Furthermore, the reducing
ability of amine borane is greatly dependent on the base strength of the amine moiety:
the lower the pKa of the amine, the stronger the reducing agent.[91] For example, in
aliphatic amine boranes, the reducing capabilities decrease in the order of NH3BH3>
RNH2BH3> R2NHBH3> R3NBH3.[3] In addition, the activity of amine borane is
always enhanced under acidic conditions.[3] Applications of amine boranes in
reducing various functional group are discussed below.
2 Me3N + B2H6 2 Me3N BH3
Scheme 1.20. Formation of Me3N-BH3 by the direct reaction of trimethylamine and diborane.
1.2.3.1 Reducing olefins to organoboranes
The use of amine borane has attracted considerable attention because the complexes
are relatively stable. Hydroboration of olefins with triethylamine and terminal olefins
in diglyme with pyridine borane were reported by Koster et al[92] in 1957 and
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21
Hawthorne et al[93] in 1958, respectively. These works indicate that the higher the
stability of amine boranes the lower the capability of borane to reduce alkenes, which
is due to that hydroboration must occur via a free, dissociated borane. According to
this reason, most amine boranes hydroborate simple alkenes only at elevated
temperatures, see above 100oC.[93] However, these conditions always result in
extensive thermal isomerization.[94] Such a drawback limits its application in
hydroborating functionally substituted olefin. In order to increase the reactivity of
amine borane, three methods are utilized, i. e., modifying the electronic effects to
lower the Lewis basicity of the amine, increasing the steric effect and adding
addictives. The functions of the first two methods are to increase the rate of
dissociation of the amine borane complex and thereby increase the rate of
hydroboration. One example on electronic effect is exhibited by the N-arylamine
borane complex which is capable of hydroborating terminal olefins at 25oC in THF or
benzene[95] (scheme 1.21). Another example of steric effect is about 2,6-lutidine
borane hydroborating 1-octene. In refluxing THF after 2 hrs, the hydroboration with
2,6-lutidine borane is quantitative while only 25% of 1-octene are completed with
pyridine borane as hydroboration reagent (scheme 1.22).[95] Consequently,
N-phenylmorpholine and N,N-diethylaniline show great promise as convenient, stable,
hydroboration agents. The third method is found in the paper published by Pelter et al
in 1981.[96] In their work, hydroboration of 1-octene in the presence of methyl iodide
was completed in 6 hr in refluxing THF or in 2 hr in refluxing glyme. The function of
methyl iodide is to convert the amine which dissociates from amine borane complex
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22
into methiodide salt. Therefore, more borane molecules are free after the equilibrium
is broken.
N + CH2=CH(CH2)5CH3
THF
69oC/ 2hrB(CH2CH2(CH2)5CH3)3 N+BH3
Scheme 1.21. Hydroborating terminal olefin by N-arylamine borane complex.
+ CH2=CH(CH2)5CH3
THF
25oC/ 1hrB(CH2CH2(CH2)5CH3)3 +BH3O NC6H5 O NC6H5
100%
Scheme 1.22. Hydroborating 1-octene by 2,6-lutidine borane.
1.2.3.2 Reducing aldehydes or ketones to alcohols
In 1958, Barnes and his co-workers[97] reported that pyridine borane gives no
detectable reduction of carbonyl compounds after 38 hrs at 25oC. Under more
vigorous conditions like refluxing benzene or toluene, aldehydes and ketones are
reduced into corresponding alcohols. However, only one of the three available
hydrides of pyridine borane is active. Noth et al also reported similar reaction results
on reducing aldehydes and ketones with ethyl-, i-propyl-, t-butyl-, and dimethylamine
boranes in refluxing ether or benzene in 1960.[98] These experimental results show
that the reduction of carbonyl compounds with amine boranes in neutral and
non-aqueous solvents is slow and unsatisfactory (scheme 1.23).
O
+ (CH3)3N BH3
HO H
diglyme
100oC/ 3 days55%
Scheme 1.23. Reducing ketone by amine borane in diglyme.
In 1959, Jones found an interesting phenomenon of which amine boranes exhibited
stronger reducing capability in acid medium.[99] He reported the reduction of
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23
4-t-butylcyclohexanone with trimethylamine borane in the presence of Lewis acid
BF3-Et2O. With BF3-Et2O, the ketone dissolved in diglyme is reduced quantitatively
in 2 min at 0oC (scheme 1.24). Without Lewis acid, the reduction is incomplete even
after heating at 100oC for 3 days.
O
+ (CH3)3N BH3
HO H
diglyme
25oC/ 2min100%+ BF3 Et2O
Scheme 1.24. Reducing ketone by amine borane in the presence of BH3-Et2O
The reaction rates of amine boranes with aldehydes and ketons were found to increase
with increasing acidity of the medium[100]. The reaction with acid catalyst involves a
slow formation of a ketone-borane complex followed by a rapid intramolecular
hydride transfer. As mentioned before, the dissociation of BH3 from amine-borane
complexes is extremely slow at room temperature. Comparatively, the acid catalyzed
reduction proceeds via an initial complex of acid with carbonyl groups followed by an
intermolecular hydride transfer from the amine borane (scheme 1.25). Therefore, the
latter has lower kinetic barrier to allow fast reaction rate.
O
+ (CH3)3N BH3
OBH3
very slow intramolecular H tranf er
OBH2
H
O OH
intermolecular H tranf er
OH
H+ H+
BH3(CH3)3N
Scheme 1.25. Reaction process for reducing ketone by amine borane.
In contrast, ammonia borane (AB) is a mild reducing agent in reducing aldehydes and
ketones without the assistance of acid. It is capable of transferring all three hydride
equivalents to aliphatic and aromatic ketones or aldehydes. After hydrolysis with
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24
diluted HCl, the corresponding alcohols in 65%-97% isolated yields can be
achieved.[101-102] Furthermore, AB exhibits high chemoselectivity in reducing
aldehyde in the presence of ketone. [103] For example, the reduction of a 1:1:0.33
molar mixture of benzaldehyde, acetophenone and AB gives a 97: 3 ratio of
phenylmethanol and phenylethanol as shown in scheme 1.26. The relative reduction
rates decrease in the order: aldehyde > aliphatic ketone > aromatic ketone > -
unsaturated ketone.
OH
1-phenylethanol
CHO+
O0.33 equi. AB
CH3OH/H2O 0oC
OH
phenylmethanol
97 : 3
+
Scheme 1.26. Chemoselectively reducing aldehyde by AB in the presence of ketone.
1.2.3.3 Reducing imines to amines
Billman and McDowell in 1961 reported that dimethylamine borane in glacial acetic
acid reduces aryl imines to the corresponding secondary amines in high yields
(scheme 1.27).[104-105] The advantage of this method is that various functional groups,
such as chloro, nitro, ester and carboxyl, are not affected by the reagent. Furthermore,
amine boranes are better than NaBH4 or LiAlH4 in imines reduction due to the ease of
operation and fast rate of reaction. The importance of carrying out imines reduction in
a mild acid medium is due to the fact that some imines are unstable in an alkaline
medium. However, this method also has a drawback where reduction of imines with
trimethylamine borane in refluxing acetic acid also gives the acetyl derivative of the
corresponding amines.
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25
CH=N + (CH3)3N CH2NH
CH3COOH84%BH3
Scheme 1.27. Reducing imine by amine borane.
AB was also reported to reduce 4-substituted cyclohexyl imines, iminium salts and
enamines in 1983.[106] This work is noteworthy in that equatorial attack of hydride
from AB is favored in the reduction. Therefore, AB shows stereoselectivity in
reducing imines.
1.2.3.4 Reducing indoles to indolines
Pyridine borane in ethanolic acetic acid reduces indoles into indolines at room
temperature without affecting other functional groups such as amide, ester, and
nitrile.[107] One example is shown in scheme 1.28. In the absence of acid medium,
pyridine borane is unable to affect the indole ring. Moreover, pyridine borane in acetic
acid is also a good reagent in reducing quinoline, isoquinoline and other heterocyclic
compounds at room temperature.[108] This kind of method provides a powerful tool for
reducing heterocyclic compounds which are important materials in fine chemistry
manufactories.
NH
+ N BH3
10% HCl/ethanol
10min RTNH
93 %
(CH2)3CO2C2H5 (CH2)3CO2C2H5
Scheme 1.28. Reducing indole by amine borane.
1.2.4 Sodium aminoborohydrides (NaNRR’BH3)
In 1961, Aftandilian and his co-workers first reported the discovery of sodium
aminoborohyrides.[109] In 1984, Hutchins and his co-workers reported the application
of sodium aminoborohydrides in organic reduction.[110] In this paper, two sodium
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26
aminoborohydrides were synthesized, i. e., sodium dimethylaminoborohydrides
(NaDMAB) and sodium tert-butylaminoborohydride (NaTBAB) by treating
corresponding amine boranes with NaH in dry THF followed by filtration or
centrifugation under argon atomsphere to remove excess NaH (Scheme 1.29).
(CH3)2NH BH3 Na(CH3)2NBH3+ NaHTHF
+ H2
NaDMAB
t-C4H9NH2 BH3 Na t-C4H9NHBH3+ NaHTHF
+ H2
NaTBAB
Scheme 1.29. Rreactions for the syntheses of NaDMAB and NaTBAB
The authors found that these reagents are moisture sensitive and should be stored
under anhydrous solvent such as THF. Meanwhile, they also found that sodium
aminoborohydrides are effective and selective agents for the reduction of various
functional groups. However, no further work was reported then after. The reduction
results are described in the following sections.
1.2.4.1 Reducing aldehydes or ketones to alcohols
NaDMAB rapidly reduces aliphatic and aromatic aldehydes and ketones into alcohols
at room temperature.[110] Although all three hydrides from BH3 moiety are available
for the reduction, higher concentration of NaDMAB gives higher yields in shorter
period of time as shown in scheme 1.30. In contrast to amine boranes, acid is
unnecessary in the sodium amidoborohydride reduction.
+ NaDMAB1)11.5 hr, RT
2) hydrolysis80%
O
3
OH
+ 3NaDMAB1) 2.5 hr, RT
2) hydrolysis89%
O OH
Scheme 1.30. Reducing ketone by NaDMAB. Excess NaDMAB achieves higher reaction rate
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27
1.2.4.2 Reducing esters to alcohols
Sodium aminoborohydrides are superior to NaBH4 or diborane in reducing aliphatic
and aromatic esters into primary alcohols.[110] Higher yields and shorter reaction time
are achieved upon reacting esters with excess sodium aminoborohydride at 66oC
(Scheme 1.31).
(CH2)8CH3
O
O + NaDMAB1) 13 hr, 25oC
(CH2)8CH3HO 71%2) hydrolysis
(CH2)8CH3
O
O + 1.4NaDMAB1) 1 hr, 66oC, THF
(CH2)8CH3HO 77%2) hydrolysis
Scheme 1.31. Reducing ester by NaDMAB
1.2.4.3 Reducing amides to amines or alcohols
Reduction of amides gives either amines or alcohols via different processes depending
on reducing reagents or reaction conditions applied (Scheme 1.32).[111]
RCNR1R2MH RCHNR1R2
OMO reductive removal of C=O
RCH2NR1R2
explus ion of amineRCHO RCH2OH
[H]
Scheme 1.32. Two different pathways for reducing amide: one is to achieve amine and the other is to
achieve alcohol.
When sodium aminoboranes are used as reducing reagents, the products vary
depending on the type of amide.[110] Primary amides are reduced to afford moderate
isolated yields of primary amines without alcohols. Secondary amides are inert to
reduction in refluxing THF. Tertiary amides, on the other hand, afford good yield of
either alcohols or amines. The product ratio of alcohols and amines depends mainly
on the N-substituents. For example, N,N-dimethylamide affords high yield of its
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28
corresponding alcohol with minor amine formation. However, in the case of reducing
N,N-diisopropyldecanamide, corresponding amine is the predominate product
(scheme 1.33). Therefore, it is concluded that with the increasing size of the N group,
the amount of alcohol decreases while the amine yield enhances. Moreover, the
relative order of reducing reactivity is as following: N,N-dimethyl > N,N-diethyl >
N,N-diisopropyl > primary amides > secondary amides. This work paved the way for
studying the reducibility of metal aminoborohydrides in amide reduction.
O
N + NaDMAB66oC, 5 hr
N
>99%
+ OH
trace
+ NaDMAB101oC, 67 hrO N
(CH2)8CH3
N
(CH2)8CH3
95%
+ CH3(CH2)8CH2OH
5% Scheme 1.33. Two examples for reducing amides by NaDMAB. The product ratio of alcohols
and amines depends mainly on the N-substituents.
1.2.5 Lithium aminoborohydrides (LiNRR’BH3, LAB)
Singaram and his co-workers found that quantitative yield of LAB was obtained after
reacting n-butyllithium or methyllithium with amine boranes (NHR2BH3)[112]. One
example is given in scheme 1.34. Based on their studies, they concluded that LABs
are powerful reducing reagent comparing with LiAlH4 and LiEt3BH.[112-114] In
addition, LABs are regarded as stable and non-air sensitive reducing reagents due to
the facts that 1) LABs are stable in THF solutions (1-2M) and can be stored under
nitrogen at room temperature for at least 9 months without the loss of hydride activity;
2) LABs reductions can be performed without excluding air.
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29
NH + BH3-THF25 oC
1hrNHBH3
n-BuLi
0 oCNBH3Li
Scheme 1.34. One example for synthesizing LAB
The reduction results of LiAB on unsaturated bonds are described below.
1.2.5.1 Reducing aldehydes or ketones to alcohols
Compared to amine borane and sodium amidoborohydrides, LABs easily reduce
aldehydes and ketones to corresponding alcohols in shorter time, i.e.,15-30 min at 0
oC.[115] Only one equivalent of LAB was required in these reductions (scheme
1.35).[116]
O
+ Li NBH31) THF, 0oC,0.5hr
2) hydrolysis
OH
Scheme 1.35. One example for reducing ketone by LAB
1.2.5.2 Reducing esters to alcohols
LABs rapidly reduce both aliphatic and aromatic esters to corresponding alcohols in
dry air[115, 117]. In contrast, other borane reagents such as amine borane and diborane
need long reaction time and higher temperatures; LiAlH4 needs the exclusion of air
(scheme 1.36).
+ Li NBH31) THF, 0oC,0.5hr
2) hydrolysisCH3(CH)6C
O
OEt CH3(CH)6CH2
OH92%
Scheme 1.36. Reducing ester by LAB.
1.2.5.3 Reducing tertiary amides to amines.
Primary and secondary amides are inert to LABs reduction. However, various
aromatic and aliphatic tertiary amides can be reduced by LAB in good yield.[113, 115]
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These results are different from those of sodium aminoboranes which are mentioned
previously. The product ratio of alcohols and amines depends mainly on the steric
environment of the amine moiety of LAB, not on the N substituents of amide. For
example, lithium pyrrolidinoborohydride (LiPyrrBH3) affords high yield of alcohols
in reacting with tertiary amides. However, when lithium
diisopropylaminoborohydride (Li(i-Pr)2NBH3) is utilized in the reaction,
corresponding amine products predominate. It seems that the size of the N groups of
amide has little effect on the reaction results (scheme 1.37).
N (CH2)6CH3
OTHF, 25oC, 3hr
Li(i-Pr)2NBH3N (CH2)7CH3 95%
CH3(CH2)7OH 77%LiPyrrBH3
THF, 25oC, 3hr
N
OTHF, 25oC, 3hr
Li(i-Pr)2NBH3
95%
LiPyrrBH3
THF, 25oC, 3hr
N
HO 99%
N
OTHF, 25oC, 3hr
Li(i-Pr)2NBH3
98%
LiPyrrBH3
THF, 25oC, 2hr
N
HO 99%
Scheme 1.37. Examples for reducing amides by LAB.
Myers and his co-workers reported that lithium amidoborane (LiNH2BH3, LiAB for
short) is also a powerful reagent in reducing tertiary amides.[118] The reaction products
are alcohols (scheme 1.38). Therefore, the reaction is followed the rule summarized
by Singaram, i. e., alcohol is achieved when the amine moiety of LAB is of less steric
hindrance.
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31
N
OH
O
CH2C6H5
1) 4LiAB, 2.5hr25 oC
CH2C6H5
HO 92%2) H3O+
Scheme 1.38. Reducing amide by LiAB.
1.2.5.4 Nitriles—amines
Aliphatic nitriles cannot be reduced by LAB. Only aromatic nitriles can react with
LAB.[117, 119] However, the compounds containing -hydrogen on the nitrile group are
recovered in high yield after hydrolysis step (scheme 1.39). The reason is that LABs
trend to first react with this -hydrogen. Benzylnitrile and
2-methyl-2-phenylpropionitrile, the compounds without -hydrogen to nitrile, react
with LABs to afford corresponding amines in refluxing THF for a relatively long
period of time (scheme 1.40).[113]
CCN
H
H
1.5 LiMe2NBH3
THF, 65oC, 22hr
1. D2O
2. HClCCN
D
H
81%
Scheme 1.39. LAB reacts with -hydrogen of phenylacetonitrile.
1) 1.5 LiMe2NBH3
THF, 65oC, 12hrCH2NH2 57%CN
2) H3O+
CCN
1) 1.5 LiMe2NBH3
THF, 65oC, 17hrCCH2NH2 57%
2) H3O+
Scheme 1.40. Two examples for reducing aromatic nitriles without -hydrogen by LAB.
1.3 Mechanistic interpretations on borohydride reduction
In this part, a brief introduction on the mechanism of reducing functional groups by
borohydrides is given. Ketones, aldehydes and NaBH4 are chosen as representatives
to illustrate the mechanism involved. Most ketones and aldehydes can be reduced by
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32
NaBH4 under 4:1 stoichiometry.[52, 73] The question of how the presumably sequential
transfer of four hydrogens occurs was first addressed by Garrett and Lyttle.[120] In
their research, the kinetic data were consistent with a simple second order rate law
with a 4:1 stoichiometry.
dx/dt= k(A-x)(B-4x)
where A is the initial concentration of NaBH4, B is the initial concentration of ketone
and x is the amount of sodium borohydride consumed at time t.
A process involving four successive hydride transfers with comparable rate constants
generally gives rise to a complex kinetics. Therefore, Garret and Lyttle gave two
possible interpretations, i. e., the first one is sequential transfer of hydrides with a rate
determining first step to conform to the observed kinetics (scheme 1.41).[121]
BH4 + Ok1 H3B O H
H3B O H + Ok2
H2B O H2
H2B O H2
Ok3
+ HB O H3
HB O H3
Ok4
+ B O H4
rate determining
Scheme 1.41. Sequential transfer of hydrides with a rate determining first step.
An alternative suggestion involves the same initial rate-determining first step,
followed by hydrolysis of the intermediate alkoxyborohydride (scheme 1.42).
H3B O H H3BOH + HO HH2O
Scheme 1.42. hydrolysis of the intermediate alkoxyborohydride
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33
The subsequent reduction steps are effected by H3BOH, H2B(OH)2, and HB(OH)3.
This suggestion avoids the necessity of proposing intermediates with several large
steroid molecules attached to boron. However, this sequential mechanism has
drawbacks,[121] i. e., firstly, the proposal made by Garrett and Lyttle is postulate
lacking of experimental evidence; secondly, the mechanism includes a obstacle for
stereochemical rationalization because it postulates not only a single reducing agent,
but four different ones, thereby, each must be responsible for a quarter of the product
molecules if the condition is k2, k3, k4 >>k1. Therefore it is impossible that all of these
four reducing agents have the same stereoselectivity.
Comparing to the sequential mechanism, the alternative mechanism is the complete or
partial disproportionation of the alkoxyborohydride intermediates. The procedure is
shown in scheme 1.43.
BH4 + (RO)2BH2
BH4 + (RO)3BH
BH4 + (RO)4B
(RO)BH3
(RO)3BH
(RO)2BH2
Scheme 1.43. Disproportionation of the alkoxyborohydride intermediates
The disproportionation of alkoxyborohydrides was described by Brown et al.[53, 66, 122]
In their research, reactions of diborane and sodium methoxide did not yield sodium
methoxyborohydride, but the complete disproportionation products instead (scheme
1.44). Therefore, in the disproportionation mechanism, NaBH4 is the only reducing
reagent. The intermediate alkoxyborohydrides disproportionates back to NaBH4 rather
than acting as a reducing reagent. This mechanism significantly simplifies the
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34
understanding of stereochemistry. However, there is still no existing evidence to
distinct between the sequential and the disproportionation mechanisms.
B2H6+ 2NaOCH3 X 2NaBH3(OCH3)
2B2H6 + 3NaOCH3 2NaBH4 + B(OCH3)3
Scheme 1.44. Reactions of diborane and sodium methoxide
Three different geometries for the transfer of hydride to substrate are given in scheme
1.45: linear (mechanism A)[123], four-center (mechanism B)[124] and six-center
mechanism (mechanism C)[125-126]. The role of solvent in mechanism A is 1) to
protonate the carboxyl oxygen or 2) to bond to the potentially electron-deficient boron.
On the other hand, solvent is unnecessary in mechanism B. Comparatively,
mechanism C should be incorporated with one molecule of hydroxylic solvent.
R C R
O
BH3
H
Mechanism A
C O
BH3H
Mechanism B
O
CH
BH3
OH
Pri
Mechanism C
Scheme 1.45. Three geometries for transferring hydride to substrate
Pre-hydrolysis products are indicative to distinguish Mechanism B and C, i. e., in the
mechanism B, the newly formed alcohol attaches to boron site as an alkoxy group.
However, in Mechanism C, the alcoholic solvent attached to boron as an alkoxy group.
Wigfield and his co-workers found that tetraalkoxyborohydride, the pre-hydrolysis
product, has alkoxy groups exclusively derived from solvent attached to boron.[125]
Therefore, in hydroxylic solution, Mechanism B is excluded.
Another evidence to support such a mechanistic interpretation is the kinetic role of
hydroxylic solvent. By performing reduction of ketone in dry diglyme with
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35
2-propanol which was the third reagent rather than solvent, the rate law appears of an
order of 1.5 with respect to 2-propanol. This evidence is not compatible with the
Mechanism C where the reaction order of 2-propanol should be 1. Therefore, the
acyclic Mechanism A may be the main process.[125] The best mechanism in
accordance with the available experimental evidence is shown in scheme 1.46.
PriO H3B H O OPriH
Scheme 1.46. The mechanism for reducing ketone by borane in the presence of 2-propanol
Based on these results, the reaction procedure including the participation of alcoholic
solvent is shown in scheme 1.47.[121]
BH4 + Ok1
+ ROH + OHH3B(OR)
H3B(OR) O + ROH+k2
+ OHH2B(OR)2
H2B(OR)2 O + ROH+k3
+ OHHB(OR)3
HB(OR)3 O + ROH+k4
+ OHB(OR)4
Scheme 1.47. The reaction procedure including the participation of alcoholic solvent
Inspection of such a mechanism reveals that intermediate alkoxyborohdrides of
different hydride contents are formed. The final boron species is
tetraalkoxyborohydride.
1.4 Review on ammonia borane (AB) and metal amidoboranes (MAB)
for hydrogen storage
1.4.1 Ammonia borane (AB)
AB has equivalent protic H(N) and hydridic H(B) and has been intensively
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36
investigated as a promising solid-state hydrogen storage material in the past few
years.[5, 127-128] It possesses a hydrogen content of 19.6 wt %. AB decomposes in a
three-step process with one equivalent of H2 being released in each step as shown in
scheme 1.48.[129] In the first step, AB decomposes to release one equiv. H2 giving rise
to a white amorphous product polyaminoborane ((NH2BH2)n, PAB) at temperatures
lower than 130 C. In the second step, PAB further decomposes to release another
equivalent H2 at temperatures above 150 C, giving an amorphous polymeric product,
polyiminoborane ((NHBH)n, PIB). Releasing the last equiv. of H2, however, can only
be achieved at temperatures above 500 C and thus, only the first two steps are
considered for producing usable hydrogen. However, undesirable side
product-borazine is formed at high temperatures. In order to avoid this toxic product,
additives or catalysts are added in the system so that the dehydrogenation can occur at
lower temperatures. Transition metals such as Ir[130], Ni[131], Pd[132], Co[131] and Rh[133],
have been reported as effective catalysts in the thermolysis of AB. SBA-15[134], ionic
liquid[135-136] can also significantly improve the kinetics of thermolysis of AB.
nNH3BH3 (NH2BH2)n + nH2
(NH2BH2)n (NHBH)n + nH2
(NHBH)n nBN + nH2
Scheme 1.48. Dehydrogenation procedure of AB
Besides thermolysis, AB also undergoes hydrolysis to release H2 as shown in scheme
1.49. Without catalyst, the hydrolysis of AB is a slow process at ambient
temperature. However, by introducing catalytic amount of Pt, Rh, Pd or other
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37
transition metals[137-139], dissociation and hydrolysis of AB can be achieved at ambient
temperature rapidly. Particularly, the release of 3 equiv. of H2 can be achieved in less
than 2 minutes from the AB hydrolysis process by using 20 wt.% of Pt/C catalyst.[138]
Xu et al also reported that non-noble metal catalysts, i.e. Co, Cu and Ni possessed
high catalytic activities in the hydrolysis of AB at ambient temperature.[137]
NH3BH3 + 2H2O NH4+ + BO2
- + 3H2
Scheme 1.49. Hydrolysis process of AB
1.4.2 Metal amidoborane (MAB)
Chemical compositional modification is another effective way to alter the
dehydrogenation thermodynamics of AB.[6] Cationic substitution on AB was first
proposed by Xiong et al.[140] In their study, chemical compositional alteration on AB
was achieved by reacting LiH or NaH with AB. In this reaction, alkali metal hydride
acts as the hydride source whereas NH3 in AB acts as proton source. Cationic
substitution of H+ on AB with an electron donating metal (Li+ and Na+) gives rise to
new compounds, namely lithium amidoborane (LiAB) and sodium amidoborane
(NaAB) (Scheme 1.50)
LiH + NH3BH3 LiNH2BH3 + H2
NaH + NH3BH3 NaNH2BH3 + H2
Scheme 1.50. Synthesis of LiAB and NaAB
Isothermal decomposition of LiAB and NaAB at 91C allows 10.9 wt% and 7.5 wt%
of H2 to be detached, respectively, without borazine formation.[141-143]
Alkaline earth metal amidoborane, namely calcium amidobrane (Ca(NH2BH3)2,
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CaAB), was first synthesized by Diyabalanage and coworkers[144] through the
reaction of CaH2 and AB in THF solution (scheme 1.51). However, THF was
found to coordinate to CaAB strongly and difficult to be removed completely. Wu
et al.[145] directly ball milled CaH2 and AB and synthesized solvent-free CaAB.
CaAB was also found to have improved dehydrogenation properties than AB.
Interestingly, CaAB prepared by different methods exhibit different
dehydrogenation features.[144, 146-147] CaAB derived from the reaction of CaH2 and
2 equiv. of AB in THF solution (where some THF was presented in the product)
decomposed to H2 mainly in the temperature range of 120 to 245 C.
CaH2 + 2NH3BH3-THF Ca(NH2BH3)2-THF + 2H2,
Scheme 1.51. Synthesis of CaAB-THF complex
The solvent free CaAB made from ball milling CaH2 and AB, on the other hand,
releases H2 in a two-step manner having peaks at 100 and 140 C, respectively.
Although significant differences in dehydrogenation profiles were detected, both
CaABs dehydrogenate to release 4 equiv. of H2 (~8 wt%) and give rise to an
amorphous product with a chemical composition of Ca(NBH)2.
Potassium amidoborane (KNH2BH3, KAB) was firstly reported by Diyabalanage
and his co-workers[148]. It was obtained by treating AB with 1 equiv of KH for 4 hr in
THF. According to the DSC measurement, KAB melts prior to its exothermic
decomposition and releases 6.5 wt% H2 at a temperature as low as 80 oC.
Zhang and his co-workers[149] synthesized Sr(NH2BH3)2 (SrAB) by reacting SrH2 with
2 equiv of AB under stringent condition. The thermal decomposition of Sr AB starts
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39
at 80oC under isothermal condition. With the release of H2, NH3 and B2H6 are also
formed due to the decomposition of Sr(NBH)2.
Yttrium amidoborane (YAB) was synthesized by the methathesis of YCl3 and 3 equiv.
of LiAB.[150] However, YAB is unstable at room temperature and releases H2 and NH3
upon heated to elevated temperatures.
1.5 Research gaps and aims
1.5.1 Research gaps
AB and MAB are two kinds of novel hydrogen storage materials which attract
considerable interests in recent years. Most research on these materials focus on their
hydrogen releasing properties. Research gaps for the current study of AB and MAB
are summarized below.
1. AB has been reported to reduce ketones, aldehydes and enones, affording
corresponding alcohols in high isolated yields. It is found that AB is capable of
transferring all three hydride equivalents and the alcohols are easily obtained by
quenching the system to dilute HCl. However, the function of the protic
hydrogens from NH3 group in AB has not been explored and understood yet.
Therefore, the application of AB as double hydrogen transfer reagent is a subject
worthy of detailed research.
2. Although NaAB and LiAB were first synthesized in 1938 and 1996, respectively,
the applications of these two compounds in organic reduction are seldom reported.
For other MAB, such as CaAB, no literatures on their reducing capability were
published so far. Similar to AB, hydridic and protic hydrogens also co-exist in
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MABs. Therefore, whether MABs are double hydrogen transfer reagents and
whether MAB and AB differ in reducing capability are unknown.
1.5.2 Research aims
The motivation of this project is to explore AB and MABs in organic reduction. More
specifically, the objectives of this thesis are:
1. To monitor the reactions of AB with ketones or aldehydes and to prove the
participation of protic hydrogens of AB in the reaction by NMR and FT-IR.
2. To monitor the reactions between MABs and unsaturated polarized organic
functional groups and to prove the participation of protic hydrogenes of MABs in
the reaction by NMR and FT-IR.
3. To study the double hydrogen transfer mechanisms of reducing reactions
involving AB and MABs through kinetics studies and computational simulations.
4. To investigate the application of MABs in other organic reductions such as
chemoselectively reducing -unsaturated carbonyl compounds and reductive
amination.
The results of this thesis may provide guidelines for utilizing AB and MABs not only
as hydrogen storage materials but as powerful double hydrogen transfer reagents in
organic reductions. Meanwhile, the mechanistic studies presented here indicate
interesting correlations between the hydrogen releasing properties/mechanism and
reduction capabilities of AB and MABs.
Although the objective of the thesis is to investigate the reactions between unsaturated
organic compounds and AB or MABs, there is no intention to study all unsaturated
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organic compounds. Only ketones, aldehydes and imines are discussed as substrates to
react with AB and MABs. Other unsaturated compounds such as olefins, esters, amides
and nitriles are beyond the scope of this study. It should be noted that this is not a
critical issue since the results of reducing other unsaturated functional groups can be
deduced from the results of reducing aldehydes and ketones. In addition, the MABs
studied in this thesis are restricted to LiAB, NaAB and CaAB. Other MABs, such as
KAB and YAB, are excluded from this study as well. It should also be noted that this is
also not a critical issue as well because LiAB, NaAB and CaAB are three
representatives MABs in hydrogen storage research and they are relatively stable than
others.
In order to achieve the objectives of this thesis, the successful synthesis of high quality
MABs is important. Therefore, the following chapter will describe the methods of
synthesizing MABs in detail. Meanwhile, brief introductions to the instruments used to
monitor reaction process and characterize final products will be presented.
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Chapter 2 Methodology
2.1 Synthesis of metal amidoboranes
2.1.1 Introduction
In General, there are two methods to synthesize MAB:
The first straightforward method in synthesizing MAB is via reacting AB with
corresponding metal hydride following the equations (1) to (3) [140, 143-144, 147]:
LiH + NH3BH3 LiNH2BH3 + H2 (1)
NaH + NH3BH3 NaNH2BH3 + H2 (2)
CaH2 + 2NH3BH3 Ca(NH2BH3)2 + 2H2 (3)
An alternative way for preparing MAB is by reacting corresponding metal amide with
AB following the equations (4) to (6)[142, 146]:
LiNH2 + NH3BH3 LiNH2BH3 + NH3 (4)
NaNH2 + NH3BH3 NaNH2BH3 + NH3 (5)
Ca(NH2)2 +2NH3BH3 Ca(NH2BH3)2 + 2NH3 (6)
Compared with metal amides, metal hydrides are cheaper and only generate hydrogen
during the preparation of MAB. Metal amides, however, produce NH3 that can further
react with MAB to release hydrogen. Graham and coworker mixed LiNH2 and AB in
the molar ratio of 1 to 1 and proposed the formation of a new hybrid material,
LiNH2BH3NH3 (LiAB·NH3).[151] Chua et al also reported that after reacting calcium
amide with AB through solid state ball milling approach, NH3 formed does not detach
from the solid product but adducts to CaAB to form a novel and high hydrogen
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content complex, namely calcium amidoborane ammoniate (Ca(NH2BH3)2·2NH3 or
CaAB·2NH3).[146]
Additionally, there are two synthetic approaches which have been reported so far for
the preparation of various metal amidoboranes: solid-state mechanical milling[140], [152],
[145] and wet-chemistry synthesis[144], [143]. In a solid reaction where kinetic barrier is
mainly attributed to interfacial reaction and mass transport, energetic mechanical
milling can efficiently reduce the particle size of starting materials and produce more
active surface for reaction. In a liquid reaction which is usually carried out in THF
solution, improved mass transport allows MAB to be formed more easily.
Comparatively wet-chemistry method has advantages over the mechanical milling in
the following aspects, i. e., 1) lower cost; 2) easier operation; 3) higher purity and
lower possibility of self-decomposition of MAB.
Based on the discussion above, the synthesis of MAB in this work is through
reacting metal hydride with AB by wet-chemistry method.
2.1.2 Synthetic procedure of metal amidoboranes.
2.1.2.1 Synthesis of LiAB
1.0 mmol NH3BH3 was firstly dissolved in 10 ml THF in a metal jar in glove box.
Then, 1.0 mmol LiH was quickly added into the solution and the jar cap was
closed. The system was stirred at room temperature until one equivalent of H2 was
released detected by pressure gauge. A clear 1M LiAB solution was thus obtained.
11B NMR characterization (Figure 2.1) showed that the solution has a –BH3
species at -21.90ppm, which is identical to LiAB in THF. The solution can be
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44
directly used in reducing reactions without further purification.
0 -5 -10 -15 -20 -25 -30ppm
Figure 2.1 11B NMR spectrum of LiAB
2.1.2.2 Synthesis of NaAB
1.0 mmol NH3BH3 was firstly dissolved in 10 ml THF in a metal jar in glove box.
Then, 1.0 mmol NaH was quickly added into the solution and the jar cap was
closed. The system was stirred at room temperature until one equivalent of H2 was
released detected by pressure gauge. A clear 1M NaAB solution was thus obtained.
11B NMR characterization (Figure 2.2) showed that the solution has a –BH3
species at -21.70ppm, which is identical to NaAB in THF. The solution can be
directly used in reducing reactions without further purification.
20 15 10 5 0 -5 -10 -15 -20 -25 -30
ppm
Figure 2.2 11B NMR spectrum of NaAB
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45
2.1.2.3 Synthesis of CaAB
1.0 mmol NH3BH3 was firstly dissolved in 10 ml THF in a metal jar in glove box.
Then, 0.5 mmol CaH2 was quickly added into the solution and the jar cap was
closed. The system was stirred at room temperature until one equivalent of H2 was
released detected by pressure gauge. A clear 0.5M CaAB solution was thus
obtained. 11B NMR characterization (Figure 2.3) showed that the solution has a
–BH3 species at -21.80ppm, which is identical to CaAB in THF. The solution can
be directly used in reducing reactions without further purification.
10 5 0 -5 -10 -15 -20 -25 -30
ppm
Figure 2.3 11B NMR spectrum of CaAB
2.2 Synthesis of deuterated ammonia borane and deuterated metal
amidoboranes
2.2.1 introduction
In order to study the mechanisms of organic reductions involving AB and MAB,
isotopic labeling and kinetic isotope effects experiments are necessary.[153-154]
Therefore, deuterated ABs (ND3BH3 and NH3BD3) and deuterated MAB
(M(ND2BH3)n and M(NH2BD3)n) are important reagents needed in this work.
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46
However, those reagents are commercially unavailable. The synthetic procedures
are referred to the works by Penner et al.[155]
2.2.2 Synthetic procedure of deuterated ammonia borane and deuterated
metal amidoboranes
2.2.2.1 Deuterated A(D)B, ND3BH3
0.5 g AB was first dissolved in 10 ml of D2O. The solution was stirred at room
temperature for 40 min. Subsequently, D2O was stripped off under vacuum. This
procedure was repeated for three times. Finally, the solid residue was dried over
vacuum for one day.
2.2.2.2 Deuterated AB(D), NH3BD3
10 mmol of NaBD4, 5.0 mmol of (NH4)2CO3 and 30 ml of THF were added to a
closed metal jar. The mixture was then heated under stirring at 40 °C for 24 h. The
resulting mixture was diluted with additional 20 ml THF and filtered. The filtrate was
evaporated under vacuum. Finally, the solid residue was dried under vacuum
overnight.
2.2.2.3 Deuterated LiA(D)B, LiND2BH3
1.0 mmol ND3BH3 was firstly dissolved in 10 ml THF in a metal jar in glove box.
Then, 1.0 mmol LiH was quickly added into the solution and the jar cap was
closed. The system was stirred at room temperature until one equivalent of HD
was released detected by pressure gauge. A clear 1M LiA(D)B solution was thus
obtained. The solution can be directly used in reducing reactions without further
purification.
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47
2.2.2.4 Deuterated LiAB(D), LiNH2BD3
1.0 mmol NH3BD3 was firstly dissolved in 10 ml THF in a metal jar in glove box.
Then, 1.0 mmol LiH was quickly added into the solution and the jar cap was
closed. The system was stirred at room temperature until one equivalent of H2 was
released detected by pressure gauge. A clear 1M LiAB(D) solution was thus
obtained. The solution can be directly used in reducing reactions without further
purification.
2.3 Characterization methods
Nuclear magnetic resonance (NMR) spectra were recorded on Bruker DRX-500
instrument. Chemical shifts, quoted in ppm, are relative to the internal or external
standard (only for 2H NMR): singlet δ = 0 ppm of TMS for 1H NMR; the middle of
CDCl3 triplet δ = 77 ppm for 13C NMR; singlet δ = 7.26 ppm of CDCl3 for 2H NMR,
singlet δ = 0 ppm of BF3·Et2O for 11B NMR.
Fourier transform infrared spectroscopy (FTIR) spectra were obtained by Varian 3100
FTIR spectrophotometer using Resolution Pro program.
Gas chromatography (GC) results were obtained by Ramin 2060 ( HP-5 column, ).
Mass spectrometry (MS) analyses were performed on Agilent 6890-5973 GC-MS.
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Chapter 3. Reducing aldehydes and ketones by ammonia borane
3.1 Introduction
As introduced in Chapter 1, AB has equivalent protic H(N) and hydridic H(B) and has
been intensively investigated as a promising solid-state hydrogen storage material in
the past few years.[5, 127] AB releases the first equiv. H2 at ca. 110 C through the
dissociation of both B-H and N-H bonds and combination of the opposite charged H
atoms into molecular H2. With the assistances of additives or catalysts, the
dehydrogenation can occur at lower temperatures.[131, 135-137, 139, 156-157] In addition, AB
was reported to be a reducing agent in converting carbonyl group to hydroxyl in protic
or aprotic solvents in 1980’s.[101-103] Hutchins and co-workers also reported that AB is
able to reduce 4-substitituted cyclohexyl imines, iminium salts and enamines.[106]
However, such a reduction was via a two-step process including the hydroboration
and the follow-up hydrolysis (or solvolysis) (scheme 3.1). Similar procedure was also
applied when using other amineboranes, such as trimethylamineborane, as reducing
agents.[99-100] The direct addition of hydridic H(B) and protic H(N) of AB to carbonyl
group was not observed nor reported. It is of interest to figure out whether the
dissociation of N-H of AB and transfer of that H to carbonyl can be involved in the
reduction so that it can correlate with the direct dehydrogenation of AB.
CO
R1 R2
H
BH2NH3
C
OBH2NH3
R2R1 H
H3O+COH
R2R1 Hhydroboration hydrolysis
Scheme 3.1. Process of converting carbonyl compounds to alcohols by using AB as reducing agent.
Two steps are involved: the hydroboration and the follow-up hydrolysis (or solvolysis).
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49
3.2 Results and Discussion
3.2.1 Reaction process and reactivity study
in-situ FT-IR and NMR techniques were employed to monitor the reduction of AB
and benzaldehyde in anhydrous THF. It is interesting to find that the intensity of C=O
stretch (at 1705cm-1) decreases while the intensity of O-H stretch (at 3438 cm-1)
increases with the progression of reduction from the in situ FT-IR measurement
shown in Figure 3.1. This finding indicates that H previously bonds with N in AB
transferred to O of carbonyl group since THF is aprotic solvent and was dried by NaH
prior to the reduction. To confirm this, NH3BD3(AB(D)) was employed to react with
benzaldehyde in THF-d8. From the 1H NMR characterization (shown in Figure
3.2.(a) ), a broad peak at 2.8 ppm attributed to O-H is observed. This finding confirms
that the participation of N-H in the reduction and the formation of O-H. Moreover, a
deuterated product at the carbon end of the C=O was obtained, which evidences the
transfer of deuterium on B of AB(D) to the carbon end of carbonyl group in the
reduction. In the related experiment of reacting ND3BH3 and benzaldehyde in THF, a
singlet at δ = 3.4 ppm attributed to O-D was observed by 2H NMR (spectrum can be
seen in Figure 3.2.(b)). All these isotopic labeling experimental results together with
high yield of phenylmethanol (entry 1, Table 3.1) confirm that the main path for the
reduction is via double hydrogen transfer process, in which both H(N) and H(B) of
AB participate in the reaction and transfer to the O and C sites of carbonyl group,
respectively.
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0 5 10 15 20 25 30 35 40 45 50 55 60
0.0
0.2
0.4
0.6
0.8
1.0
inte
nsi
ty
time/ min
a
b
Figure 3.1. in-situ FT-IR measurement of the reaction between 0.005M AB and 0.005M benzaldehyde.
The changes of intensities of OH stretch vibration at 3438cm-1 (a) and C=O stretch vibration at 1705
cm-1 (b) were monitored with time.
4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0ppm
1H NMR
OHNH
3BD
3
THFa
b
4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0ppm
2H NMRND
3BH
3OD
Figure 3.2. (a) 1H NMR characterization of AB(D)-benzaldehyde in THF-d8. Singlet at 2.9 ppm
attributed to O-H was observed; (b) 2H NMR characterization for A(D)B-benzaldehyde in THF. Singlet
at 3.4 ppm attributed to O-D was observed.
From in situ 11B NMR characterization shown in Figure 3.3, there are two kinds of
boron species which can be observed: AB at -22.5 ppm and borate ester at 18.9ppm.
However, based on this figure, borate ester is just a minor by-product which is too
little to be isolated from the solution for quantification. The majority of B species is,
on the other hand, precipitated from the reacting solution upon reduction forming a
white amorphous substance. The solute is, however, mainly composed of alcohol
product and un-reacted AB or benzaldehyde. We, therefore, tentatively ascribe the
formation of minor borate ester to the alcoholysis between ammonia borane and
phenylmethanol .
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51
30 20 10 0 -10 -20 -30 -40-5
0
5
10
15
20
25
30
35
40
inte
nsity
chemical shift / ppm
0min
10 min
30min
40min
60 min
18.98 ppm
Figure 3.3. in situ 11B NMR characterization of reacting AB with one equiv. benzaldehyde at room
temperature. The small board peak at 18.98 ppm which belongs to borate ester was observed. Quartet at
-22.0 ppm is attributed to un-reacted AB.
Based on the results shown above, various aldehydes and ketones were chosen to
react with AB. The results are shown in Table 3.1. The ratio of substrate and AB was
1 to 1. All the reactions involving aldehydes were carried out in 15 min at room
temperature (detected by GC). Except aldehydes, the reactions involving ketones were
carried out at 65°C. High to excellent isolated yield of secondary alcohols or
primary alcohols were directly achieved at the end of reaction without hydrolysis.
Table 3.1.Reactions of AB and carbonyl compounds in THF [a]
O
R2R1
OH
R2R1
AB
THF Entry Substrate t/min Temp/ oC Conv. %[b] Yield %[c]
1 CHO
15 R. T. >99 76[d]
2 CHO
15 R. T. >99 87
3 CHO
O 15 R. T. >99 80
4 CHO
Cl 15 R. T. >99 80
5 CHO
O2N
15 R. T. >99 89
6 CHO
O
O
15 R.T >99 94
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52
7 CHO
15 R.T. >99 92
8 O
60 [e] 65 >99 80
9 O
60 65 >99 88
10 O
O
240 65 >99 97
11 O
Cl
30 65 >99 90
12 O
O2N
30 R.T. >99 90
13 O
15 R. T. >99 83
14 O
40 65 >99 92
15 O
60 65 >99 88
16 O
60 65 >99 95
[a] The ratio of substrate and AB was 1 to 1 and the concentration of AB (or substrate) was 0.2 M. [b]
Conversion rate was determined by HPLC measurements. [c] Isolated overall yields. [d] The relatively
lower yield was partially due to the side reaction between alcohol formed and borohydride
(alcoholysis) and/or the loss of alcohol in the purification process. [e] The reaction time was 12 hrs
when performed at room temperature.
The direct reduction of aldehydes and ketones to alcohols by AB should be the
consequence of dissociation of both B-H and N-H bonds followed by the addition of
Hs to C=O, which resembles to the double hydrogen transfer (DHT) hydrogenation of
carbonyl compounds, which is via dihydride route catalyzed by transitional metals[41]
or Meerwein-Ponndorf-Verley (MPV) reduction.[33] Ru,[40, 42-44] Ir,[45-46] Rh[47-48] and
aluminum alkoxides complexes[158-159] are effective catalysts for this process.
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53
3.2.2 Kinetics Study
In order to further understand the reaction mechanism, detailed kinetics studies and
computational simulations were carried out by using benzaldehyde as a representative.
Kinetics study of the reaction of AB and benzaldehyde was investigated in THF at
room temperature by employing kinetic and quantitative FT-IR measurement.[160-162]
Determination of reaction order is based on the initial rate of formation of [OH] under
different concentrations of AB and benzaldehyde. As shown in Figure 3.4, the slope
of c curve which stands for 0.017 M AB and 0.025 M benzaldehye reaction is close to
be twice as large as the slope of a curve which refers to 0.0083 M AB and 0.025 M
benzaldehyde reaction. Meanwhile, the slope of the b curve which represents 0.0083
M AB and 0.050 M benzaldehye reaction is approximate to be twice as great as the
slope of a curve as well. These indicate that the phenylmethanol formation between
AB and benzaldehyde obeys second-order rate law, being first order of AB and
benzaldehyde, respectively.
According to the plot of 1/[benzaldehyde] versus time (Figure 3.5a), the rate law at
room temperature can be expressed in the Equation 3.1.
ν=5.62[AB][benzaldehyde] (3.1)
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54
Figure 3.4. Three curves stand for formation of [OH] under different concentrations of AB and
benzaldehyde: a refers to 0.0083 M AB and 0.025 M benzaldehyde reaction; b refers to 0.0083 M AB
and 0.050 M benzaldehye reaction; c refers to 0.017 M AB and 0.025 M benzaldehye reaction.
Deuterium kinetic isotopic effects (DKIE) were analyzed to further understand the
reaction process.[154] When bond breaking is more or less than half complete at the
transition state, the isotopic effect is smaller and can be close to 1 if the transition
state is very reactant-like or very product-like. On the other hand, if the isotopic effect
is large enough, i.e., kH/ kD > 2, it evidences that the bond to that particular hydrogen
is being broken in the rate determining step. Plots of 1/[benzaldehyde] versus t based
on the results of kinetic in-situ FT-IR measurements of the reactions of benzaldehyde
with AB, A(D)B or AB(D) are shown in Figure 3.5, respectively. The DKIE value is
3.47 (kAB/kA(D)B) for A(D)B-benzaldehyde and 2.85 (kAB/kAB(D)) for
AB(D)-benzaldehyde. Because those DKIE values are greater than 2 and closed to
each other, the dissociation of both N-H and B-H bonds are likely to be involved in
the rate determining step.[163]
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55
0 5 10 15 20 25 30
200
250
300
350
400
1/ [
benz
ald
ehy
de
]/ M
-1
time/ min
a, k = 5.62
b, k = 1.97
c, k = 1.62
Figure 3.5. 1/ [benzaldehyde] versus time plots for 0.005M benzaldehyde reacting with 0.005M AB (a) ,
0.005M AB(D) (b), 0.005M A(D)B (c), respectively.
3.2.3 Theoretical study
This theoretical study was derived from collaboration with Prof. Hongjun Fan from
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, China.
Density functional theory (DFT) calculations at B3LYP/cc-PVTZ(-f) level were
carried out to elucidate the reaction details, using benzaldehyde as model substrate.
As shown in Figure 6, the concerted double-H-transfer pathway is thermodynamically
and kinetically feasible. The key feature of this pathway is the six-membered cyclic
transition state (TS2) which associates the two hydrogen bonds adducts (INT1 and
INT2). The formation of INT1 and dissociation of INT2 shall have small barriers on
free energy surface. The transition states of TS1 and TS3 cannot be located with the
current theoretical methodology since in general there is no barrier on electronic
energy surface for such process. However, these steps are not expected to be the
rate-determining step. Additionally, the barrier of another double-H-transfer pathway
where AB has reverse orientation with respect to C=O bond is much higher.
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56
Figure 3.6. The proposed mechanism for the reaction of AB and benzaldehyde. The bond lengths are
given in Å. The H (in parenthesis) and G values (kcal/mol) in THF at 298 K and 1 atm were
corrected with gas-phase harmonic frequencies
We also investigated the step-wise hydrogenation pathway. The pathway with the
lowest energy barrier starts with the formation of C6H5CHOBH3 and NH3, followed
by the B-H bond addition to achieve C6H5CH2(OBH2). After this procedure, NH3 then
bonds back to the unsaturated borane center, and finally undergoes N-H addition to
achieve the final product. The rate-determining step of this step-wise pathway is the
B-H addition, with the barrier of 33.2 kcal/mol which is 3.1 kcal/mol higher than that
of the double-H-transfer pathway. As the concerted double-H-transfer pathway is
more favourable in activation energy and agrees with the DKIE results and the
second-order kinetics, it should be the dominant path in the reduction. However, due
to the relatively small energy difference between the double-H-transfer pathway and
the step-wise pathway, the latter may also contribute to the overall reduction process
(scheme 3.2).
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57
O
CH
BH2
NH2
H
R
H
HC
H
OHR + [NH2BH2]
concerted double-H-transfer process
O
CH
BH2
NH3
R
H
NH2
H
BH2
OCH
R
HC
H
OHR + [NH2BH2]
+
step-wise double-H-transfer process
H
Scheme 3.2. Proposed reaction mechanism: concerted and step-wise double-H-transfer processes.
Coincidently, a research group of Heinz Berke from University of Zürich also studies
the double hydrogen transfer ability of AB at the same time as we do. They reported
that AB can reduce imines[164] through concerted double hydrogen transfer process
because the energy barrier of stepwise reaction pathway is 16.9 kcal/mol higher than
that of concerted reaction pathway (scheme 3.3(a)). Subsequently, a step-wise double
hydrogen transfer mechanism was identified by this research group in the reaction of
AB and polarized olefins.[165] This conclusion is mostly based on the DKIE results:
kAB/kAB(D)=1 and kAB/kA(D)B=1.55. It means that only the protic H(N) transfers get
involved in the rate determining step (scheme 3.3 (b)).
N
CH
BH2
NH2
HR2
R1
C N
R1 R2+ NH3BH3 C N
R1 R2
H H
+ [NH2BH2]
(a) AB reducing imines: concerted double hydrogen transfer process
CN
CNR1
R2
+ NH3BH3
R2
R1
H
CN
CN
BH2NH3CN
CNR1
R2
HH
R3 R3
R3
(b) AB reducing polarized olef ins: step-wise double hydrogen transfer process
+ [NH2BH2]
Scheme 3.3. Proposed mechanisms of reducing (a) imines, (b) polarized olefins by AB.[164-165]
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Moreover, Stephan et al[166] reported that AB reduces CO2 to methanol with the
assistance of Al-based frustrated Lewis pair. Theoretical investigations from
Musgrave et al[167] showed that AB could reduce CO2 through two-hydrogen transfer
process. It seems that there will be more research on the double hydrogen transfer
ability of AB in the future.
3.3 Conclusion
In conclusion, AB is an efficient agent in reducing aldehydes or ketones to
corresponding alcohols with high yields. in situ FTIR and deuterium labelling studies
prove that AB transfers two different charged hydrogen to carbonyl groups during the
reaction process. This double hydrogen transfer process is different from the
hydroboration process reported previously. Mechanistic investigations confirm that
protic H(N) and hydridic H(B) of ammonia borane participate in the reduction, in
which the dissociations of both B-H and N-H bonds are likely to be involved in the
rate-determining step. Theoretical calculations show that the energy barrier for a
concerted double-H-transfer process is lower than that of step-wise process. However,
due to the relatively small energy difference between these two pathways, the
step-wise process may also contribute to the overall reduction.
3.4 Experimental Section
3.4.1General remarks
Solvents and most of reagents were purchased commercially and used without further
purification: THF (J&K, HPLC, dried over NaH), benzaldehyde (Sigma-Aldrich, 99%,
Table 3.1, entry 1), 4-methylbenzaldehyde (Alfa Aesar, 98%, Table 3.1, entry 2),
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59
4-methoxybenzaldehyde (J&K, 99%, Table 3.1, entry 3), 4-chlorobenzaldehyde
(Acros, 99%, Table 3.1, entry 4), 4-nitrobenzaldehyde (J&K, 99%, Table 3.1, entry
5), 4-formylphenyl acetate (Alfa, 98%, Table 3.1, entry 6), cinnamaldehyde (Aladin,
98%, Table 3.1, entry 7), acetophenone (Sigma-Aldrich, 99%, Table 3.1, entry 8),
4-methylacetophenone (Alfa Aesar, 96%, Table 3.1, entry 9),
4-methoxyacetophenone (Alfa Aesar, 99%, Table 3.1, entry 10),
4-chloroacetophenone (TCI, 97%, Table 3.1, entry 11), 4-nitroacetophenone (J&K,
99%, Table 3.1, entry 12), benzylacetone (TCI, 95%, Table 3.1, entry 13),
4-phenyl-3-buten-2-one (Sigma Aldrich, 99%, Table 3.1, entry 14), chalcone (Alfa
Aesar, 97%, Table 3.1, entry 15), benzophenone (Sigma Aldrich, 99%, Table 3.1,
entry 16).
3.4.2 General experimental procedure for reducing aldehydes and ketones with
AB
4 ml 0.25M AB THF solution was added into 1ml 1M aldehyde or ketone solution in
THF at room temperature or reflux temperature in a closed glass bottle. FTIR
spectrometer was employed to monitor the consumption of carbonyl group and
formation of OH group. After the reaction, THF was evaporated, and then, 10 ml
hexane was added in the glass bottle to extract alcohol product for three times. Then,
clear hexane solution was collected after centrifugation. Next, hexane was evaporated
and a transparent liquid residue was left. In the end, further column chromatography
(silica gel, 200-300 mesh, elution by EtOAc/ hexane = 1: 10 solution) was utilized to
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purify alcohol product. Alcohol was characterized by 1H NMR, 13C NMR , FT-IR and
MS.
3.4.3 Products characterization
D
HOH
α-Deuterobenzenemethanol 1H NMR (500 MHz, CDCl3, 25 oC; TMS):
δ = 2.25 (s, 1H; O-H), 4.65 (d, 3JHH = 9.90Hz 2H; CH2), 7.30-7.36 ppm (m, 5H; ArH);
13C NMR (126 MHz, CDCl3, 25oC; CDCl3): δ = 64.93(t, JCD=21.84 Hz), 127.01,
127.63, 128.54, 140.83 ppm; FT-IR (film): νmax = 3338, 3087, 3064, 3030, 2915, 2135,
1496, 1453, 1208, 1201, 734, 697 cm-1; MS (EI): m/z (%) 109 [M]+ (80), 79 (100), 92
(20).
phenylmethanol (entry 1, Table 3.1): 1H NMR (500 MHz, CDCl3, 25 oC; CHCl3): δ
= 2.80 (s, 1H; O-H), 4.64 (s, 2H; CH2), 7.30-7.40 ppm (m, 5H; ArH); 13C NMR (126
MHz, CDCl3, 25oC; CDCl3): δ = 65.00, 126.94, 127.49, 128.44, 140.86 ppm; FT-IR
(film): νmax = 3335 (O-H), 3087, 3064, 3030, 2931, 2873, 1496, 1453, 1208, 1201,
734, 697 cm-1; MS (EI): m/z (%) 108 [M]+ (94), 79 (100), 51 (19), 91 (16).
4-methylphenylmethanol (entry 2, Table 3.1): 1H NMR (500 MHz, CDCl3, 25 oC;
CHCl3): δ = 1.95 (s, 1H; O-H), 2.38 (s, 3H; CH3), 4.65 (s, 2H; CH2), 7.19 (d, 3JHH =
7.89Hz, 2H; ArH), 7.27 ppm (d, 3JHH = 8.08Hz, 2H; ArH); 13C NMR (126 MHz,
CDCl3, 25oC; CDCl3): δ = 21.17, 65.22, 127.14, 129.25, 137.37, 137.40 ppm ; FT-IR
(film) : νmax = 3334, 3048, 3021, 2950, 2919, 1518, 1445, 1032, and 802 cm-1; MS
(EI): m/z (%) 122 [M]+ (92), 107 (100), 91 (69), 79 (65).
4-methoxylphenylmethanol (entry 3, Table 3.1): 1H NMR (500 MHz, CDCl3, 25 oC;
CHCl3): δ = 2.21 (s, 1H; O-H), 3.81 (s, 3H; CH3), 4.59 (s, 2H; CH2), 6.89-6.90 (m,
2H; ArH), 7.27-7.29 ppm (m, 2H; ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) :
δ = 55.33, 64.91, 113.98, 128.65, 133.24, 159.19 ppm; FT-IR(film): νmax = 3354,
3032, 3001, 2935, 2836, 1612, 1514, 1247, 1033, 816cm-1; MS (EI): m/z (%) 138[M]+
(100), 109 (73), 121 (52), 77 (50), 94 (33).
4-chlorophenylmethanol (entry 4, Table 3.1): 1H NMR (500 MHz, CDCl3, 25 oC;
CHCl3): δ = 2.14 (s, 1H; O-H), 4.65 (s, 2H; CH2), 7.23-7.34 ppm (m, 4H; ArH); 13C
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61
NMR (126 MHz, CDCl3, 25oC; CHCl3): δ = 64.50, 128.29, 128.68, 133.36, 139.34
ppm; FT-IR (film): νmax = 3342, 2953, 2920, 2855, 2731, 1597, 1491, 1450, 1405,
1086, 1012, 708 cm-1 ; MS (EI): m/z (%) 142 [M]+ (60), 77 (100), 107 (68), 113 (18).
4-nitrophenylmethanol (entry 5, Table 3.1): 1H NMR (500 MHz, CDCl3, 25 oC;
CHCl3): δ = 2.24 (s, 1H; O-H), 4.84 (s, 2H; CH2), 7.54 (d, 3JHH = 8.86Hz, 2H; ArH ),
8.22 ppm (d, 3JHH = 8.76Hz, 2H; ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) :
δ = 64.00, 123.75, 127.04, 147.34, 148.30 ppm; FT-IR(film): νmax = 3521, 3112, 2924,
2884, 1602, 1511, 1344, 1196, 1057, 736 cm-1; MS (EI): m/z (%) 153 [M]+ (34), 77
(100), 107 (50), 89 (41), 51 (28), 136 (22).
methyl 4-(hydroxymethyl)benzoate (entry 6, Table 3.1): 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 2.08 (s, 1H; O-H), 3.91 (s, 3H; CH3), 4.76 (s, 2H; CH2),
7.41-7.43 (m, , 2H; ArH ), 8.00-8.02 ppm (m, 2H; ArH); 13C NMR (126 MHz, CDCl3,
25oC; CDCl3) : δ = 52.04, 64.67, 126.44, 129.35, 129.82, 145.96, 166.94 ppm;
FT-IR(film): νmax = 3384, 3032, 3001, 2935, 2836, 1710, 1612, 816 cm-1; MS (EI):
m/z (%) 166 [M]+ (40), 77 (100), 107 (60), 136 (30).
cinnamyl alcohol (entry 7, Table 3.1): 1H NMR (500 MHz, CDCl3, 25 oC; CHCl3):
δ = 1.61 (s, 1H; O-H), 4.31 (d, 3JHH = 5.72 Hz, 2H; CH2), 6.33-6.39 (m, 1H; CH),
6.62 ppm (d, 3JHH = 15.9 Hz, 1H; CH), 7.22-7.25 (m, 3H; ArH), 7.31 ppm (t, 3JHH =
7.57 Hz, 2H; ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 63.71, 126.47,
127.69, 128.53, 128.59, 131.16, 136.70 ppm; FT-IR(film): νmax = 3322, 3081, 3026,
2920, 2861, 1494, 1449, 1091, 966, 732, 690 cm-1; MS (EI): m/z (%) 134 [M]+ (75),
92 (100), 77 (76).
α-methylbenzenemethanol (entry 8, Table 3.1): 1H NMR (500 MHz, CDCl3, 25 oC;
CHCl3): δ = 1.40 (d, 3JHH = 6.45Hz, 3H; CH3), 1.96 (s, 1H; O-H), 4.77-4.82 (m, 1H;
CH), 7.17-7.20 (m, 1H; ArH), 7.25-7.30 ppm (m, 4H; ArH); 13C NMR (126 MHz,
CDCl3, 25oC; CDCl3) : δ = 25.16, 70.42, 125.40, 127.47, 128.51, 145.84 ppm;
FT-IR(film): νmax = 3359, 3085, 3062, 3028, 2972, 2873, 1492, 1451, 1368, 1203,
1077, 898 cm-1; MS (EI): m/z (%): 122 [M]+ (36), 107 (100), 79 (90), 43 (23), 51
(20).
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62
4-methyl-α-methylbenzenemethanol (entry 9, Table 3.1): 1H NMR (500 MHz,
CDCl3, 25 oC; CHCl3): δ = 1.48 (d, 3JHH = 6.46 Hz, 3H; CH3), 1.96 (s, 1H; O-H), 2.36
(s, 3H; CH3), 4.86 (q, 3JHH = 6.14Hz, 1H; CH), 7.17 (d, 3JHH = 7.84 Hz, 2H; ArH),
7.27 ppm (d, 3JHH = 8.06 Hz, 2H; ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) :
δ = 21.04, 25.03, 70.18, 125.31, 129.11, 137.07, 142.86 ppm; FT-IR(film): νmax =
3368, 3021, 2972, 2924, 2868, 1513, 1088, 1009, 898, 817 cm-1; MS (EI): m/z (%)
136 [M]+ (36), 121 (100), 93 (68), 77 (32), 43 (25) .
4-methoxyl-α-methylbenzenemethanol (entry 10, Table 3.1): 1H NMR (500 MHz,
CDCl3, 25 oC; CHCl3): δ = 1.47 (d, 3JHH = 6.44 Hz, 3H; CH3), 1.89 (s, 1H; O-H), 3.80
(s, 3H; CH3), 4.85 (q, 3JHH = 6.38 Hz, 1H; CH), 6.87-6.89 (m, 2H; ArH), 7.28-7.30
ppm (m, 2H, ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 24.98, 55.27,
69.94, 113.86, 126.63, 138.03, 159.00 ppm; FT-IR (film) : νmax =3377, 2063, 2970,
2931, 2836, 1611, 1583, 1511, 1301, 1245, 1176, 1087, 897, 832 cm-1; MS (EI): m/z
(%) 152 [M]+ (28), 137 (100), 135 (82), 91 (43), 109 (38), 119 (40).
4-chloro-α-methylbenzenemethanol (entry 11, Table 3.1): 1H NMR (500 MHz,
CDCl3, 25 oC; CHCl3): δ = 1.45 (d, 3JHH= 6.45 Hz, 3H; CH3), 2.25 (s, 1H; O-H), 4.84
(q, 3JHH = 6.39Hz, 1H; CH), 7.27-7.31 ppm (m, 4H; ArH); 13C NMR (126 MHz,
CDCl3, 25oC; CDCl3) : δ = 25.23, 69.67, 126.80, 128.57, 133.03, 144.30 ppm; FT-IR
(film) : νmax = 3349, 2974, 2928, 2888, 1597, 1492, 1406, 1370, 1089, 1013, 897, 828
cm-1 ; MS (EI): m/z (%) 156 [M]+ (23), 141 (100), 77 (81), 113 (31).
4-nitro-α-methylbenzenemethanol (entry 12, Table 3.1): 1H NMR (500 MHz,
CDCl3, 25 oC; CHCl3): δ = 1.49 (d, 3JHH=1.53 Hz, 2H; CH2), 2.50 (s, 1H; O-H), 4.98
(q, 3JHH=6.14 Hz, 1H; CH), 7.50-7.53 (m, 2H; ArH), 8.15-8.17 ppm (m, 2H; ArH);
13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 25.44, 69.41, 123.71, 126.12, 147.15,
153.22 ppm; FT-IR (film) : νmax = 3521, 3112, 2924, 2884, 1602, 1511, 1458, 1344,
1196, 1057, 736 cm-1; MS (EI): m/z (%) 166 [M-H]+ (1), 152 (100), 107 (45), 77 (42),
43 (24).
methylbenzenepropanol (entry 13, Table 3.1): 1H NMR (500 MHz, CDCl3, 25 oC;
CHCl3): δ = 1.24 (d, 3JHH = 6.20 Hz, 3H; CH3), 1.62 (s, 1H; O-H), 1.73-1.84 (m, 2H;
Page 79
63
CH2), 2.65-2.8 (m, 2H; CH2), 3.82-3.86 (m, 1H; CH), 7.19-7.23 (m, 3H; ArH ),
7.28-7.31 ppm (m. 2H; ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 23.58,
32.15, 40.82, 67.37, 67.38, 125.83, 128.42, 142.09 ppm; FT-IR (film) : νmax = 3351,
3082, 3062, 3026, 2965, 2927, 2860, 1603, 1495, 1454, 1129, 745, 698 cm-1; MS
(EI): m/z (%) 150 [M]+ (1), 117 (100), 91 (83), 132 (48), 78 (20).
4-phenyl-3-buten-2-ol (entry 14, Table 3.1): 1H NMR (500 MHz, CDCl3, 25 oC;
CHCl3): δ = 1.25 (d, 3JHH = 6.39 Hz, 3H; CH3), 1.56 (s, 1H; O-H), 4.35-4.40 (m, 1H;
CH), 6.13-6.17 (m,1H, CH), 6.45 (d, 3JHH = 15.93 Hz, 1H; CH), 7.11-7.27 ppm (m,
5H; ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 23.42, 68.94, 126.46,
127.64, 128.59, 129.41, 133.58, 136.72 ppm; FT-IR (film): νmax = 3342, 3078, 3058,
3026, 2972, 2926, 2871, 1493, 1449, 1141, 1059, 967, 748, 693 cm-1; MS (EI): m/z
(%) 148 [M]+ (50), 129 (100), 105 (67), 115 (50), 132 (25), 77 (25), 91 (33).
chalcol (entry 15, Table 3.1): 1H NMR (500 MHz, CDCl3, 25 oC; CHCl3): δ = 2.17
(d, 3JHH = 3.13 Hz, 1H; CH), 5.36 (d, 3JHH = 3.13 Hz, 1H; O-H), 6.35-6.40 (m, 1H;
CH), 6.67 (d, 3JHH = 15.84 Hz, 1H; CH), 7.21-7.34 ppm (m, 10H; ArH); 13C NMR
(126 MHz, CDCl3, 25oC; CDCl3) : δ = 75.13, 126.38, 126.64, 127.81, 127.82, 128.58,
128.64, 130.57, 131.60, 136.58, 142.84 ppm ; FT-IR (film): νmax = 3342, 3077, 3059,
3027, 1599, 1449, 1493, 1092, 1067, 1009, 966, 744, 695 cm-1; MS (EI): m/z (%) 209
[M-H]+ (47), 105 (100), 191 (67), 178 (27), 77 (33), 115 (30).
α-phenylbenzenemethanol (entry 16, Table 3.1): 1H NMR (500 MHz, CDCl3, 25 oC;
CHCl3): δ = 2.22 (d, 3JHH = 3.58 Hz, 1H; O-H), 5.73 (d, 3JHH = 3.42 Hz, 1H; CH),
7.15-7.30 ppm (m, 10H; ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ =
76.29, 126.55, 127.58, 128.50, 143.82 ppm; FT-IR (film) : νmax = 3259, 3086,
3059, 3027, 2906, 1596, 1492, 1446, 1273, 1197, 1175, 1017, 761, 739, 701 cm-1; MS
(EI): m/z (%) 184 [M]+ (48), 105 (100), 77 (43).
Page 80
64
Chapter 4. Reducing ketones, imines and aldehydes by metal
amidoboranes
4.1 Introduction
As introduced in Chapter 1, lithium aminoborohydrides (LiNRR’BH3) have been
investigated as powerful, selective, air-stable reducing agents for almost two decades.
Significant amount of research from Singaram’s group in this field show that reducing
unsaturated functional groups by lithium aminoborohydrides can be carried out under
mild condition via a two-step process including hydroboration and the follow-up
hydrolysis (or solvolysis)[113-114] (see scheme 4.1). In comparison with lithium
aminoborohydrides, LiAB has two Hs bonding with N and thus may exhibit special
features in the reaction with unsaturated bonds. LiAB was first synthesized in liquid
in 1996 and was regarded as nucleophilic hydride to reduce tertiary amide into
primary alcohol.[118] In 2002, the solid structure of LiAB was resolved and its thermal
dehydrogenation was investigated.[140] Due to high hydrogen content and mild
dehydrogenation temperature, LiAB has been investigated intensively for hydrogen
storage.[143] Theoretical calculations show that hydrogen desorption from LiAB is via
the combination of protic H(N) and hydridic H(B) of LiAB, in which the hydridic H
firstly transfers to the Li side and then binds with H(N) to form molecular H2.[168]
Amidoboranes of other elements, such as Ca,[144, 147] Na,[142] K,[148] Y[150] and Sr[149] et
al, were also synthesized recently, and have been probed for hydrogen storage. It is of
interest to figure out whether the dissociation of B-H and N-H of MAB such as LiAB,
NaAB or CaAB and transfer of those Hs to unsaturated functional groups can be
Page 81
65
realized so that it can correlate with the direct dehydrogenation of LiAB, NaAB or
CaAB.
With the partial substitution of protic H in AB by alkali or alkaline earth element, the
nature of B-H, N-H and B-N bondings in amidoborane change significantly.
Structural analyses on the solid state LiAB and AB showed that the B-H bond length
in LiAB was increased in comparison to that in AB indicating weakened B-H
bonding.[169] Moreover, the metal assisted H transfer mechanism of hydrogen release
from amidoborane is different from the ion initiated dehydrogenation of AB.[168, 170]
Thus, it is very interesting to figure out the different chemistry of reducing
unsaturated bonds by MAB and AB.
CX
R1 R2
H
BH2NRR'Li
CXBH2NRR'Li
R2R1
H
H3O+CH
XH
R1
Hhydroboration hydrolysis
X= O, N-R''
Scheme 4.1. Process of converting ketones or imines to alcohols or amines by using lithium
aminoborohydrides as reducing agent. Two steps are involved: the hydroboration and the follow-up
hydrolysis (or solvolysis).
4.2 Results and Discussion
4.2.1 Reducing ketones by MAB
4.2.1.1 Reactivity and reaction procedure study
Experimental results of the reactions between LiAB, NaAB or CaAB and ketones are
listed in the Table 4.1. The corresponding results of using AB to reduce ketones are
also included in the table. The molar ratio of ketone and MAB was 2: 1 for LiAB or
NaAB and 4:1 for CaAB, respectively. The time of reduction was in-between 30 and
Page 82
66
60 minutes. The reductions were carried out at room temperature (RT) for LiAB,
NaAB and CaAB. In all the cases, conversion rates of ketones were all above 99%
measured by GC. AB, in general, exhibits lower reactivity in comparison to MAB. As
shown in the Table 4.1, higher reaction temperature (65 oC) and longer reaction time
were needed for AB in most cases in order to complete the reduction. It should be
noted that the differences between MAB and AB in reducing active carbonyl groups (i.
e., 4-nitroacetophenone (entry 5, Table 4.1) and benzylacetone (entry 6, Table 4.1))
are not pronounced under the current conditions.[171] Lower temperatures may need to
be applied to differentiate their reactivities.
Table 4.1. Reducing ketones by LiAB, NaAB CaAB or AB [a]
R1 R2
O MAB
THF, RT R1 R2
OH
Entry Ketone MAB T/ oC t/hr Yield % [b]
1 O
LiAB NaAB CaAB
AB
RT RT RT 65
1 1 1 1
75 71 77 80
2 O
LiAB NaAB CaAB
AB
RT RT RT 65
1 1 1 1
90 78 81 88
3 O
O
LiAB NaAB CaAB
AB
RT RT RT 65
1 1 1 4
81 82 85 97
4 O
Cl
LiAB NaAB CaAB
AB
RT RT RT 65
0.5 0.5 0.5 0.5
89 78 80 90
5 O
O2N
LiAB NaAB CaAB
RT RT RT
0.5 0.5 0.5
90 71 79
Page 83
67
[a] The ratio of substrate and LiAB or NaAB was 2 to 1 and the concentration of LiAB or NaAB
was 0.083 M or 0.1 M respectively; the ratio of substrate and CaAB was 4 to 1 and the
concentration of CaAB was 0.05 M; the ratio of substrate and AB was 1:1 and the concentration of
AB was 0.2 M. [b] Isolated overall yields.
In order to understand the reaction mechanism, benzophenone (entry 7, Table 4.1)
was selected as the reference compound to react with LiAB. in situ FT-IR and NMR
were employed to monitor the reduction processes.
The intensity of carbonyl group stretch vibration at 1663cm-1 decreased while the
intensity of OH stretch vibration at 3402cm-1 increased with time as evidenced by the
in situ FT-IR characterization (see Figure 4.1), indicating that H previously bonded
with N in LiAB transferred to O of ketone. To confirm such a hydrogen transfer,
LiND2BH3 (LiA(D)B) was employed to react with benzophenone in THF: a singlet at
δ = -1.0 ppm attributed to O-D was observed in 2H NMR spectrum shown in Figure
4.2. In another related experiment, LiNH2BD3 (LiAB(D)) was also applied to react
with benzophenone. A deuterated product at the carbon end of the C=O was obtained,
which shows the transfer of the deuterium on B of LiAB(D) to the C of carbonyl in
the reduction. These experimental results confirm that both N-H and B-H in MAB
participate directly in the reduction and transfer Hs to ketones (see scheme 4.2).
AB RT 0.5 90 6 O
LiAB NaAB CaAB
AB
RT RT RT RT
0.5 0.5 0.5 0.5
86 80 80 83
7 O
LiAB NaAB CaAB
AB
RT RT RT 65
1 1 1 1
94 70 90 95
Page 84
68
NB
Hb
HaM
CO
R R'
OHa
CR R'
HbH
H
H
Scheme 4.2. MAB transfers not only protic Ha to the oxygen end of carbonyl or the nitrogen end of
imine group, but also hydridic Hb to the carbon end of carbonyl group.
0 1 2 3 4 5 6in
tens
ity (
a.u.
)time/ min
a
0 1 2 3 4 5 6
inte
nsity
(a.
u.)
time/ min
b
Figure 4.1. in situ FT-IR measurements of the reaction of 0.02M LiAB and 0.02M benzophenone. The
time-dependences of (a) intensity of OH stretch vibration at 3402 cm-1, (b) intensity of the C=O
stretch vibration at 1663 cm-1.
5 4 3 2 1 0 -1 -2 -3ppm
-1.0 ppm
Figure 4.2. 2H NMR result for LiND2BH3 reacting with benzophenone in THF. A singlet at δ = -1.0
ppm attributed to OD was observed.
4.2.1.2 Kinetic study
Kinetic studies of the reactions of LiAB with benzophenone were carried out in THF
at room temperature by employing kinetic and quantitative FT-IR measurements
respectively. Determination of reaction order was based on initial increasing rate of
[OH]. The curves of alcohol concentration versus time at different molar
concentration ratios are shown in Figure 4.3. Initial increasing rates of alcohol
concentration can be obtained from the slope of each curve: the slope of a curve
Page 85
69
which stands for 0.01 M LiAB and 0.01 M benzophenone reaction is close to be twice
as large as the slope of c curve which refers to 0.005 M LiAB and 0.01M
benzophenone reaction. Meanwhile, the slope of the b curve which represents 0.01 M
LiAB and 0.005 M benzaldehye reaction is approximate to be twice as great as the
slope of d curve which refers to 0.005M LiAB and 0.005 M benzophenone reaction.
as well. Meantime, the slope of a curve is the same as that of b curve. The slope of c
curve shares the same value with that of d curve. Based on these experimental results,
the reaction of LiAB and benzophenone appears to obey a first-order rate law, being
first order of LiAB concentration. Derived from the plot of ln cLiAB versus time as
shown in Figure 4.4, the rate law for LiAB-benzophenone at room temperature can be
expressed in the Eq. (4.1)
ν = 0.039 [LiAB] (4.1)
0.25 0.50 0.750.00132
0.00136
0.00140
0.00144
0.00148
C(O
H)/
M
time/ min
slope= 0.00020
0.15 0.30 0.45 0.60
0.00048
0.00052
0.00056
0.00060
C(O
H)/
M
time/ min
slope= 0.00020
(a) (b)
Page 86
70
0.2 0.4 0.6 0.8
0.00080
0.00085
0.00090
0.00095
C(O
H)/
M
time/ min
slope= 0.00011
0.25 0.50 0.75 1.00
0.00080
0.00084
0.00088
C(O
H)/
M
time/ min
slope= 0.00010
(c) (d)
Figure 4.3. (a) refers to 0.01 M LiAB and 0.01 M benzophenone reaction, the slope is 0.00020; (b)
stands for 0.01 M LiAB and 0.005 M benzophenone reaction, slope equals to 0.00020; (c) is 0.005
M LiAB and 0.01 M benzophenone reaction, slope is 0.00011; (d) is 0.005 M LiAB and 0.005 M
benzophenone reaction, slope is 0.00010.
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0-5.65
-5.60
-5.55
ln C
(LiA
B)
t i m e / m i n
slope= -0.0386
Figure 4.4 ln C(LiAB) vs. t plot for 0.0066M LiAB reacting with 0.0066M benzophenone
Deuterium kinetic isotopic effects (DKIE) were investigated to further study the
reaction mechanism. Through the kinetic in situ FT-IR measurement, the rate
constants of reactions between benzophenone with LiA(D)B or with LiAB(D), were
determined from the rate law equation. The results are shown in Figure 4.5. The DKIE
value is 1.26 (kLiAB/ kLiA(D)B) for LiA(D)B-benzophenone and 1.89 (kLiAB/ kLiAB(D)) for
LiAB(D)-benzophenone. Because the DKIE values of LiA(D)B-ketone is close to 1
and that of LiAB(D)-ketone is close to 2, we tentatively propose that the dissociation
of B-H bonds in LiAB is involved in the rate determining step of the reduction.
Page 87
71
0.4 0.6 0.8 1.0 1.2 1.4
-5.34
-5.32
-5.30
-5.28
ln C
(LiA
(D)B
)
t i m e / m i n
slope= -0.031
0.5 1.0 1.5 2.0 2.5 3.0 3.5
-5.44
-5.42
-5.40
-5.38
-5.36
ln C
(LiA
B(D
))
t i m e / m i n
slope= -0.020
a b
Figure 4.5. ln C(LiA(D)B) versus t plot for 0.0066M LiA(D)B reacting with 0.0066M benzophenone
is shown as a.From the slope, kLiA(D)B is 0.031; ln C(LiAB(D)) versus t plot for 0.0066M LiAB(D)
reacting with 0.0066M benzophenone is shown as b. kLiAB(D) is 0.00825 concerning to the slope
value.
4.2.2 Reducing imines with MAB
4.2.2.1 Reactivity and reaction procedure study
Table 4.2 gives the experimental results of the reactions of MAB or AB with imines.
The molar ratio of imine and reducing agent was 1: 1 for LiAB or NaAB or AB and
1.5:1 for CaAB, respectively. The time for near complete conversion of imines varied
from 1 to 6 hrs. CaAB is somehow less reactive than LiAB and NaAB. Comparatively,
LiAB, NaAB and CaAB show much higher reactivity than AB in reducing imines. As
an example, the time for reducing N-benzylideneaniline (entry 1, Table 4.2) with
equivalent AB was ca. 4 hrs at 65 oC. However, it was within 3 hrs at ambient
temperature if equivalent LiAB or NaAB, or 0.67 equivalent CaAB was applied.
Page 88
72
Table 4.2. Reducing imines by LiAB, NaAB, CaAB or AB [a]
R3
CH
NR4
MAB
THF, RT
R3
CH2
HN
R4
[a] The ratio of substrate and LiAB or NaAB was 1 to 1 and the concentration of LiAB or NaAB was
0.083 M or 0.1 M respectively; the ratio of CaAB and substrate was 1 to 1.5 and the concentration of
Entry Imine MAB T/ oC t/ hr Yield % [b]
1
N
LiAB[c] NaAB CaAB AB [d]
RT RT RT 65
2 2 3 4
93 74 79 98
2
N
LiAB NaAB CaAB
AB
RT RT RT 65
2 2 5 4
94 70 85 94
3 N
O
LiAB NaAB CaAB
AB
RT RT RT 65
3 3 6 6
90 68 85 97
4
N
Cl
LiAB NaAB CaAB
AB
RT RT RT 65
1 1 2 3
94 77 75 93
5
N
O2N
LiAB NaAB CaAB
AB
RT RT RT 65
1 1 2 2
88 80 79 96
6
N
LiAB NaAB CaAB
AB
RT RT RT 65
2 2 5 4
95 82 82 98
7
N
O
LiAB NaAB CaAB
AB
RT RT RT 65
3 3 6 6
91 82 82 95
8
N
Cl
LiAB NaAB CaAB
AB
RT RT RT 65
1 1 2 3
95 79 91 96
Page 89
73
CaAB (or substrate) was 0.05 M; the ratio of substrate and AB was 1 to 1 and the concentration of AB
(or substrate) was 0.10 M. [b] Isolated overall yields. [c]. When N-benzylideneaniline was treated with
0.5 equivalent of LiAB, the conversion rate was only 50% after 1 day detected by GC. [d] The reported
reaction condition for AB-N-benzylideneaniline was 7 hrs at 60 oC.[12]
In order to understand the reaction mechanism, N-benzylideneaniline (entry 1, Table
4.2) was selected as the reference compound to react with LiAB. in situ FT-IR and
NMR were employed to monitor the reduction processes. It was observed in
N-benzylideneaniline-LiAB system through in situ FTIR as shown in Figure 4.6 that
the intensity of C=N stretch at 1631cm-1 decreases while the N-H stretch at 3369 cm-1
increases with the progression of reduction, indicating that H previously bonded with
N in LiAB transferred to N end of imine group. To confirm such a hydrogen transfer
process, LiA(D)B was employed to react with N-benzylideneaniline in THF, a singlet
at δ = 5.6 ppm attributed to ND was observed in the 2H NMR spectrum as shown in
Figure 4.7. In addition, LiAB(D) was also applied to react with N-benzylideneaniline.
A deuterated product at the carbon end of C=N bond was obtained , which shows
the transfer of the deuterium on B of LiAB(D) to the C of imine group in the
reduction. These experimental results confirm that both N-H and B-H in MAB
participate directly in the reduction and transfer Hs to imines. (see scheme 4.3).
N
BHb
HaM
C
N
R R'
N
CR R'
Hb
R" R"H
HH
Ha
Scheme 4.3. MAB transfers both protic Ha and hydridic Hb to imine in the reduction.
Page 90
74
0 1 2 3 4 5 6
inte
nsity
(a.
u.)
time/ min
d
0 1 2 3 4 5 6
Inst
ensi
ty (
a.u.
)
time/ min
c
Figure 4.6. in situ FT-IR measurements of the reaction of 0.033M LiAB and 0.033M
N-benzylideneaniline. The time-dependences of (c) intensity of NH stretch vibration at 3369 cm-1,
and (d) intensity of the C=N stretch vibration at 1631 cm-1 are plotted in the figure.
8 7 6 5 4 3 2 1
5.6 ppm
ppm
Figure 4.7. 2H NMR result for LiND2BH3 reacting with N-benzylideneaniline in THF. A singlet at δ =
5.6 ppm attributed to ND was observed.
4.2.2.2 Kinetic study
Kinetic studies of the reaction between LiAB and N-benzylideneaniline were carried
out in THF at room temperature by employing kinetic and quantitative FT-IR
measurements.[160-161] Determination of reaction order was based on initial increasing
rate of [NH]. The curves of NH concentration versus time at different molar
concentration ratios are shown in Figure 4.8. Initial decreasing rates of [NH] can be
obtained from the slope of each curve: The slope of e which stands for 0.05M LiAB
and 0.05 M N-benzylideneaniline reaction is close to be twice as large as the slope of
g which refers to 0.025 M LiAB and 0.05 M N-benzylideneaniline reaction.
Page 91
75
Meanwhile, the slope of the e is approximate to be the same as the slope of f which
represents to 0.05M LiAB and 0.025M N-benzylideneaniline reaction. The slope of
the g is also close to be the same as the slope of h which represents to 0.025M LiAB
and 0.025M N-benzylideneaniline reaction. These indicate that the reaction between
LiAB and N-benzylideneaniline obeys first-order rate law, being first order of LiAB.
Derived from the plot of ln cLiAB versus time (Figure 4.9), the rate law for
LiAB-N-benzylideneaniline at room temperature can be expressed in the Equation.
(4.2)
νC=N = 0.023[LiAB] (4.2)
0.0 0.2 0.4 0.6 0.8 1.0 1.20.009
0.010
0.011
0.012
0.013
C(a
min
e) /
M
t i m e / m i n
slope= 0.0021
0.3 0.4 0.5 0.6 0.7 0.8 0.90.0130
0.0135
0.0140
0.0145
0.0150
C(a
min
e) /
M
t i m e / m i n
slope= 0.0020
(e) (f)
0.4 0.6 0.8 1.00.0025
0.0030
0.0035
0.0040
0.0045
C (
amin
e) /
M
t i m e / m i n
slope= 0.0011
0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
0.0088
0.0092
0.0096
0.0100
0.0104
C (
am
ine
) / M
t i m e / m i n
slope= 0.0012
(g) (h)
Figure 4.8. (e) refers to 0.050 M LiAB and 0.050M N-benzylideneaniline reaction, the slope is 0.0021;
(f) stands for 0.050 M LiAB and 0.025 M N-benzylideneaniline reaction, slope equals to 0.0020; (g) is
0.025 M LiAB and 0.050 M N-benzylideneaniline reaction, slope is 0.0011; (h) is 0.025 M LiAB and
0.025 M N-benzylideneaniline reaction, slope is 0.0012.
Page 92
76
0 2 4 6 8 10 12 14 16 18 20
-3.90
-3.75
-3.60
-3.45
-3.30
ln C
(Li
AB
)
time /min
R2=0.99677 slope = -0.023
Figure 4.9. ln C (LiAB) vs. t plot for 0.033M LiAB reacting with 0.033M N-benzylideneaniline
Deuterium kinetic isotopic effects (DKIE) were investigated to further study the
reaction mechanism. Through the kinetic in situ FT-IR measurement the rate
constants of reactions between N-benzylideneaniline with LiA(D)B or with LiAB(D),
respectively, were determined from the respective rate law equations. The results are
shown in Figure 4.10. The DKIE value is 1.26 (kLiAB/ kLiA(D)B) for
LiA(D)B-N-benzylideneaniline and 2.12 (kLiAB/ kLiAB(D)) for
LiAB(D)-N-benzylideneaniline. Because the DKIE values of LiA(D)B-imine is close
to 1 and that of LiAB(D)-imine reactions is close to 2, we tentatively propose that the
dissociation of B-H bonds in LiAB is involved in the rate determining step of the
reduction.
0 2 4 6 8 10
-4.2
-4.1
-4.0
ln C
(LiA
(D)B
) / M
t i m e / m i n
slope= -0.018
0 2 4 6 8 10
-3.85
-3.80
-3.75
-3.70
-3.65
ln C
(LiA
B(D
)) /
M
t i m e / m i n
slope= -0.011
(o) (p)
Figure 4.10. kLiA(D)B is 0.018 based on the slope of (o) for 0.033M LiA(D)B reacting with 0.033M
N-benzylideneaniline; kLiAB(D) is 0.011 with respect to the slope value of (p) for 0.033M LiAB(D)
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reacting with 0.033M N-benzylideneaniline.
Based on the experimental results above, the reactions of LiAB with benzophenone
and LiAB with N-benzylideneaniline are similar to each other. Both two obey first
order rate law and the dissociation of B-H bonds in LiAB is involved in the rate
determining step of both reductions. Therefore, LiAB and N-benzylideneaniline
system is used as an example in theoretical investigation to discuss the double
hydrogen transfer process in detail.
4.2.3 Theoretical Study
This theoretical study was derived from collaboration with Prof. Hongjun Fan from
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, China.
Theoretical studies were carried out to elucidate the details of LiAB hydrogenation
reactions, using N-benzylideneaniline as model substrate. Geometry optimizations and
frequencies calculations have been done on DFT B3LYP/cc-PVTZ(-f) level.
Solvation energies were evaluated by self-consistent reaction field (SCRF) approach
at the optimized gas-phase geometry employing the dielectric constant of 7.6 for THF.
All reported energies were free energies in solvation at 298.15K.
Figure 4.11 The proposed mechanism for the reaction of LiAB and N-benzylideneaniline. G values
(kcal/mol) in THF at 298 K and 1 atm were corrected with gas-phase harmonic frequencies.
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Previous studies have shown that the hydrogenation of ketones and imines[164] by AB
undergo concerted double hydrogen transfer mechanism, and a stepwise mechanism
could be in competition. However, both mechanisms were found to bear barriers of
over 40 kcal/mol for the LiAB hydrogenation reaction of N-benzylideneaniline,
therefore, are not feasible under the present reaction condition. Therefore, we propose
a completely different pathway for this reaction. As shown in Figure 4.11, LiAB
undergoes transition state-1 (TS1) to eliminate LiH, with the barrier of 17.2 kcal/mol.
The direct addition of LiH to C=N bond was found not feasible. On the other hand, if
LiH firstly dissociates to Li+ and H-, then N-benzylideneaniline traps the H- to forms
[PhCH2NPh]-, the dissociation and trapping steps do not have noticeable barriers on
the electronic energy surface. The next step is the proton transfer (TS2, +14.0
kcal/mol) from NH2BH2 to [PhCH2NPh]-, following by the ion pair formation
between Li+ and [NHBH2]-. [PhCH2NPh]- can also form ion pair with Li+ first, but in
that case the following proton transfer have much higher barrier (+23.4 kcal/mol).
Figure 4.12 The structures of the transition state TS1 and TS2. The bond lengths are given in Å.
The structures of TS1 and TS2 are shown in Figure 4.12. The rate-determining step of
this mechanism is the first step where LiAB eliminates LiH. This is in good
agreement with the observed first-order kinetics for LiAB and zero order kinetics for
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N-benzylideneaniline. Furthermore, this step is featured by the B-H bond breaking,
which is consistent with the observed kinetic isotope effects where the DKIE of
LiAB(D) is found to be 2.12. The minor DKIE LiA(D)B value (1.26) is perhaps due
to the barrier of N-H bond breaking step (TS2, +14.0 kcal/mol) is only slightly lower
than the rate-determining step (TS1, +17.2 kcal/mol). The rate-determining barrier,
+17.2 kcal/mol, is much lower than that for AB hydrogenation (+28.0 kcal/mol),[164]
which agrees with the much faster reactions. It is interesting to note that the first step
proposed here somehow resembles to the first step of dehydrogenation of LiAB
calculated in gaseous phase.[168] The solvation effect appears to be strong which
significantly brings down the energy barrier. The difference in the follow-up reactions
lies in that in the dehydrogenation of LiAB, H which is bonding with Li combines
with H(N) to release H2, whereas, in the reduction process, it transfers to C site to
break unsaturated bond.
4.2.4 Reducing aromatic aldehydes with MAB
As reported previously, AB reduces aldehydes and ketones to the corresponding
alcohols through double hydrogen transfer process. Moreover, MAB also reduce
ketones in to alcohol through similar process. Therefore, we assumed that primary
alcohol could be achieved in the reaction of MAB with aldehydes. However, to our
surprise, white precipitate was formed when benzaldehyde reacted with LiAB,
NaAB or CaAB in THF, and no phenylmethanol was detected by GC. On the other
hand, high isolated yield of phenylmethanol can only be achieved after
hydrolyzing the precipitate by aqueous HCl. In order to determine the composition
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of the white precipitate, we collected the sample of LiAB with 3 equiv.
benzaldehyde for Raman and NMR characterizations. From the Raman spectrum
shown in Figure 4.13(a) we can find that B-H stretching vibrations in the range of
2140-2360 cm-1 disappear. However, N-H vibrations are still observable at 3168
and 3210 cm-1. Additionally, only one singlet signal at 1.97 ppm was observed by
11B solid NMR shown in Figure 4.13(b). It is, therefore, very likely that the
precipitate is lithium aminotribenzylborate of formula a (scheme 4.4). The
composition of a was further confirmed by 1H NMR and 13C NMR.
LiNH2BH3 +CHO
3 B OH2C
3LiNH2
THF
a
Scheme 4.4.the process of reducing benzaldehyde by LiAB
2000 2500 3000 35000
2x104
4x104
6x104
8x104
inte
nsity
cm -1
**
W hite precipitate
2000 2500 3000 35000
1x104
2x104
3x104
4x104
NH2
inte
nsity
cm -1
**
NH2
LiAB before reaction
(a)
40 20 0 -20 -40ppm
1.97 ppm
(b)
Figure 4.13. (a) Raman spectra for LiAB (above) and white precipitate (below). The NH2 vibrations
in LiAB at 3306 and 3364 cm-1 shift to 3168 and 3210 cm-1 in white precipitate. (b) 11B solid NMR
spectrum for white precipitate. Singlet at 1.97ppm was observed.
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Similar reactions were observed in reducing other aldehydes with LiAB. The
results are shown in Table 4. The molar ratio of substrate and LiAB is 1 to 1. All
aldehydes reacted rapidly with LiAB to afford 100% conversion rate in 5 min at
room temperature. The high isolated overall yields of corresponding primary
alcohols were only achieved after hydrolysis of borate ester in aqueous HCl
solution.
Clearly, reducing aldehydes by LiAB resembles to the hydroboration of aldehyde by
NaBH4.[52] Both reagents only transfer hydridic H(B) to aldehydes. One possible
explanation for the difference between LiAB and AB in reducing aldehydes is that
N-H bond distance (0.96 Å[140]) in LiAB is shorter than that of AB (1.07 Å[172]). It
makes LiAB difficult to transfer its protic hydrogen to aldehydes. Another possible
explanation for the difference between LiAB reducing aldehydes and reducing
ketones is the relative acidity of primary alcohol and secondary alcohol formed at the
end of reaction. Generally, primary alcohol is more acidic than secondary alcohol
with similar structure. Therefore, this difference in acidity may affect the transfer of
protic hydrogen from LiAB in reducing aldehydes or ketones.
Table 4.4.Reactions of LiAB and aldehydes in THF [a]
R H
O 1.LiAB, THF
R H
OH
2. H3O+
Entry Substrate t/min Yield %[b] w/t hydrolysis Yield %[c] after hydrolysis
1 CHO 5 N.A. 85
2 CHO
5 N.A. 91
3 CHO
O
5 N.A. 93
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82
4 CHO
Cl
5 N.A. 91
5 CHO
O2N
5 N.A. 88
6 CHO
O
O
5 N.A. 91
[a] The ratio of substrate and LiAB was 1 to 1 and the concentration of LiAB (or substrate) was
0.167M. [b] Detected by GC [c] Isolated overall yields.
4.3 Conclusion
Reductions of aldehydes, ketones and imines are fundamental reactions in organic
chemistry. Borohydrides, such as NaBH4,[52, 173] NaBH3CN,[174-175]
NaBH(OAC)3[176-178], BH3·Me2S
[179-180] and BH3·THF[60, 181-182] are common reducing
agents in laboratory scale. However, those agents have certain limitations in terms of
side reaction, poor solubility in aprotic solvent or environmental pollution. For
examples, the solubility of NaBH4 or NaBH(OAC)3 is low in THF;[183] NaBH3CN is
toxic and may generate HCN upon reaction with substrates;[184] BH3·Me2S forms
stable complex with imine.[185] Comparatively, LiAB, NaAB and CaAB are soluble
in THF, low-toxic, and highly reactive with less side reaction, and thus, possess
certain merits for organic reduction.
Moreover, metal amidoboranes are efficient reducing agents. They differ from
borohydride compounds in that the N-H bond participates in the reduction. Secondary
alcohols or amines are directly formed in reducing ketones or imines. It avoids
hydrolysis step. Metal amidoboranes are also hydrogen transfer reagent of high
reactivity. No catalyst is needed and the reaction conditions are milder. The
substitution of H in AB by metal leads to significantly altered nature of B-H and B-N
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bonds, such an alteration manifests in the different pathways of AB and MAB in the
self-dehydrogenation[186], [168] and reduction of unsaturated bonds.
4.4 Experimental Section
4.4.1 General remarks
Solvent and most of reagents were purchased commercially and used without further
purification: THF (J&K, HPLC, dried over NaH), acetophenone (Sigma-Aldrich, 99%,
entry 1, Table 4.1), 4-methylacetophenone (Alfa Aesar, 96%, entry 2, Table 4.1),
4-methoxyacetophenone (Alfar Aesar, 99%, entry 3, Table 4.1), 4-chloroacetophenone
(TCI, 95%, entry 4, Table 4.1), 4-nitroacetophenone (J&K, 99%, entry 5, Table 4.1),
benzylacetone (TCI, 95%, entry 6, Table 4.1), benzophenone (Sigma Aldrich, 99%,
entry 7, Table 4.1), N-benzylideneaniline (Alfa Aesar, 98%, entry 1, Table 4.2),
benzaldehyde (Sigma-Aldrich, 99%, entry 1, Table 4.4), 4-methylbenzaldehyde (Alfa
Aesar, 98%, entry 2, Table 4.4), 4-methoxybenzaldehyde (J&K, 99%, entry 3, Table
4.4), 4-chlorobenzaldehyde (Acros, 99%, entry 4, Table 4.4), 4-nitrobenzaldehyde
(J&K, 99%, entry 5, Table 4.4), 4-formylphenyl acetate (Alfa Aesar, 98%, entry 6,
Table 4.4)
4.4.2 Synthesis of imines (entry 2 to entry 8, Table 4.2)
The other imines investigated in this work were synthesized by reacting
corresponding aldehydes and amines in the presence of molecular sieve catalyst. The
aldehyde (10 mmol) and the amine (10 mmol) were mixed together in a glass bottle
and stirred without solvent for 10 min. Then 20 mL of CH2Cl2 and 2.5 g 5 Å
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84
molecular sieve were added. The mixture was stirred at room temperatue for 3hr.
When the reaction finished, the mixture was filtered and the solvent evaporated under
reduced pressure. The crude products were recrystallized from hexane. All the imine
products were characterized by 1H NMR and 13C NMR.
4.4.3 General experimental procedure for reducing ketones with LiAB, NaAB or
CaAB
5 ml 0.1M LiAB (or 0.1 M NaAB, or 0.05 M CaAB) solution (THF as solvent) was
added to 1ml 1M ketone solution at room temperature in a closed glass bottle. FT-IR
spectrometer was used to monitor the consumption of C=O and formation of OH
group. After the reaction, THF was evaporated. Then 10 ml diethyl ether was added to
the glass bottle to extract alcohol for three times. The diethyl ether solution further
underwent centrifugation to remove suspended substance. Next, diethyl ether was
evaporated to leave transparent liquid residue which was further purified by column
chromatography (silica gel, 200-300 mesh, hexane/ EtOAc (v/v, 10/1) as an eluent).
Alcohol products were characterized by 1H NMR, 13C NMR, FT-IR and GC-MS.
4.4.4 General experimental procedure for reducing imines with LiAB, NaAB or
CaAB
5 ml 0.1M LiAB (or 0.1 M NaAB, or 0.067 M CaAB) solution (THF as solvent) was
added to 1ml 0.5M imine solution (THF as solvent) at room temperature in a closed
glass bottle. FT-IR spectrometer was used to monitor the consumption of C=N group
and formation of N-H group. After the reaction, THF was evaporated. Then 10 ml
diethyl ether was added to the glass bottle to extract the amine product for three times.
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The diethyl ether solution further underwent centrifugation to remove suspended
substance. Next, diethyl ether was evaporated to leave transparent liquid residue
which was further purified by column chromatography (silica gel, 200-300 mesh,
hexane/ EtOAc (v/v, 10/1) as an eluent). Amine products were characterized by 1H
NMR, 13C NMR, FT-IR and GC-MS.were characterized by 1H NMR, 13C NMR,
FT-IR and GC-MS.
4.4.5 Products characterization
HO D (86%)
α-Deutero-α-phenylbenzenemethanol 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 2.28 (s, 1H; O-H), 5.80 (s, 0.14H; CH), 7.25-7.35 ppm (m,
10H; ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 75.83 (t, JCD= 22.02 Hz),
126.54, 127.55, 128.47, 143.77 ppm; FT-IR (film) : νmax = 3259, 3086, 3059, 3027,
2155, 1596, 1492, 1446, 1273, 1197, 1175, 1017, 761, 739, 701 cm-1; MS (EI): m/z
(%) 185 [M]+ (31), 105 (100), 78 (54).
CH N
H
(81%) D
α-Deuterio-N-phenylbenzylamine 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 4.08 (s, 1H; N-H), 4.30 (s, 1.18H; CHD), 6.63-6.71 (m, 3H;
Ar-H), 7.16-7.35 ppm (m, 7H; ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3): δ =
48.07 (t, JCD= 20.71 Hz), 112.93, 117.64, 127.23, 127.54, 128.62, 129.26, 139.36,
148.10 ppm; FT-IR (film): νmax = 3419,3052, 3026, 2920, 2841, 2116, 1602, 1505,
1452, 1324, 750, 693 cm-1; MS (EI): m/z (%) 184 [M]+ (41), 92 (100), 107 (15), 77
(22).
α-methylbenzenemethanol (entry 1, Table 4.1): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 1.40 (d, 3JHH = 6.45Hz, 3H; CH3), 1.96 (s, 1H; O-H), 4.77-4.82 (m, 1H;
CH), 7.17-7.20 (m, 1H; ArH), 7.25-7.30 ppm (m, 4H; ArH); 13C NMR (126 MHz,
CDCl3, 25oC; CDCl3) : δ = 25.16, 70.42, 125.40, 127.47, 128.51, 145.84 ppm;
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86
FT-IR(film): νmax = 3359, 3085, 3062, 3028, 2972, 2873, 1492, 1451, 1368, 1203,
1077, 898 cm-1; MS (EI): m/z (%): 122 [M]+ (36), 107 (100), 79 (90), 43 (23), 51
(20).
4-methyl-α-methylbenzenemethanol (entry 2, Table 4.1): 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 1.48 (d, 3JHH = 6.46 Hz, 3H; CH3), 1.96 (s, 1H; O-H), 2.36
(s, 3H; CH3), 4.86 (q, 3JHH = 6.14Hz, 1H; CH), 7.17 (d, 3JHH = 7.84 Hz, 2H; ArH),
7.27 ppm (d, 3JHH = 8.06 Hz, 2H; ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) :
δ = 21.04, 25.03, 70.18, 125.31, 129.11, 137.07, 142.86 ppm; FT-IR(film): νmax =
3368, 3021, 2972, 2924, 2868, 1513, 1088, 1009, 898, 817 cm-1; MS (EI): m/z (%)
136 [M]+ (36), 121 (100), 93 (68), 77 (32), 43 (25).
4-methoxyl-α-methylbenzenemethanol (entry 3, Table 4.1): 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 1.47 (d, 3JHH = 6.44 Hz, 3H; CH3), 1.89 (s, 1H; O-H), 3.80
(s, 3H; CH3), 4.85 (q, 3JHH = 6.38 Hz, 1H; CH), 6.87-6.89 (m, 2H; ArH), 7.28-7.30
ppm (m, 2H, ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 24.98, 55.27,
69.94, 113.86, 126.63, 138.03, 159.00 ppm; FT-IR (film) : νmax =3377, 2063, 2970,
2931, 2836, 1611, 1583, 1511, 1301, 1245, 1176, 1087, 897, 832 cm-1; MS (EI): m/z
(%) 152 [M]+ (28), 137 (100), 135 (82), 91 (43), 109 (38), 119 (40).
4-chloro-α-methylbenzenemethanol (entry 4, Table 4.1): 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 1.45 (d, 3JHH= 6.45 Hz, 3H; CH3), 2.25 (s, 1H; O-H), 4.84
(q, 3JHH = 6.39Hz, 1H; CH), 7.27-7.31 ppm (m, 4H; ArH); 13C NMR (126 MHz,
CDCl3, 25oC; CDCl3) : δ = 25.23, 69.67, 126.80, 128.57, 133.03, 144.30 ppm; FT-IR
(film) : νmax = 3349, 2974, 2928, 2888, 1597, 1492, 1406, 1370, 1089, 1013, 897, 828
cm-1 ; MS (EI): m/z (%) 156 [M]+ (23), 141 (100), 77 (81), 113 (31).
4-nitro-α-methylbenzenemethanol (entry 5, Table 4.1): 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 1.49 (d, 3JHH=1.53 Hz, 2H; CH2), 2.50 (s, 1H; O-H), 4.98 (q,
3JHH=6.14 Hz, 1H; CH), 7.50-7.53 (m, 2H; ArH), 8.15-8.17 ppm (m, 2H; ArH); 13C
NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 25.44, 69.41, 123.71, 126.12, 147.15,
153.22 ppm; FT-IR (film) : νmax = 3521, 3112, 2924, 2884, 1602, 1511, 1458, 1344,
1196, 1057, 736 cm-1; MS (EI): m/z (%) 166 [M-H]+ (1), 152 (100), 107 (45), 77 (42),
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87
43 (24).
methylbenzenepropanol (entry 6, Table 4.1): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 1.24 (d, 3JHH = 6.20 Hz, 3H; CH3), 1.62 (s, 1H; O-H), 1.73-1.84 (m, 2H;
CH2), 2.65-2.8 (m, 2H; CH2), 3.82-3.86 (m, 1H; CH), 7.19-7.23 (m, 3H; ArH ),
7.28-7.31 ppm (m. 2H; ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 23.58,
32.15, 40.82, 67.37, 67.38, 125.83, 128.42, 142.09 ppm; FT-IR (film) : νmax = 3351,
3082, 3062, 3026, 2965, 2927, 2860, 1603, 1495, 1454, 1129, 745, 698 cm-1; MS (EI):
m/z (%) 150 [M]+ (1), 117 (100), 91 (83), 132 (48), 78 (20).
α-phenylbenzenemethanol (entry 7, Table 4.1): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 2.22 (d, 3JHH = 3.58 Hz, 1H; O-H), 5.73 (d, 3JHH = 3.42 Hz, 1H; CH),
7.15-7.30 ppm (m, 10H; ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 76.29,
126.55, 127.58, 128.50, 143.82 ppm; FT-IR (film) : νmax = 3259, 3086, 3059, 3027,
2906, 1596, 1492, 1446, 1273, 1197, 1175, 1017, 761, 739, 701 cm-1; MS (EI): m/z
(%) 184 [M]+ (48), 105 (100), 77 (43).
N-benzylaniline (entry 1,Table 4.2): 1H NMR (500 MHz, CDCl3, 25 oC; TMS): δ =
4.05 (s, 1H; N-H), 4.36 (s, 2H; CH2), 6.67-6.78 (m, 3H; Ar-H), 7.20-7.42 ppm (m, 7H;
ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3): δ = 48.31, 112.84, 117.55, 127.19,
127.48, 128.60, 129.23, 139.45, 148.15 ppm; FT-IR (film): νmax = 3419,3052, 3026,
2920, 2841, 1602, 1505, 1452, 1324, 750, 693 cm-1; MS (EI): m/z (%) 182 [M-H]+
(100), 91 (70), 106 (12), 77 (10), 65 (9).
N-(4-methylbenzyl)aniline (entry 2, Table 4.2): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 2.37 (s, 3H; CH3), 3.99 (s, 1H; N-H), 4.30 (s, 2H; CH2), 6.65-6.75 (m, 3H;
Ar-H), 7.17-7.29 ppm (m, 6H; Ar-H); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3): δ =
21.05, 48.09, 112.84, 117.48, 127.50, 129.22, 129.28, 136.38, 136.84, 148.24 ppm;
FT-IR (film): νmax = 3419, 3049, 3020, 2920, 2860, 1603, 1505, 1325, 1266, 806, 748
cm-1; MS (EI): m/z (%) 196 [M-H]+ (85), 105 (100), 77 (18).
N-(4-methoxybenzyl)aniline (entry 3, Table 4.2): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 3.80 (s, 3H; CH3), 3.93 (s, 1H; N-H), 4.25 (s, 2H; CH2), 6.63-6.89 (m, 5H;
Ar-H), 7.16-7.30 ppm (m, 4H; Ar-H); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3): δ =
Page 104
88
47.86, 55.31, 112.88, 114.08, 117.53, 128.80, 129.24, 131.50, 148.26, 158.94 ppm;
FT-IR (film): νmax = 3398, 3047, 2962, 2836, 1604, 1514, 1425, 1302, 1253, 1175,
1034, 818, 748, 694cm-1; MS (EI): m/z (%) 212 [M-H]+ (50), 121 (100), 77 (13).
N-(4-chlorobenzyl)aniline (entry 4, Table 4.2): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 4.05 (s, 1H; N-H), 4.32 (s, 2H; CH2), 6.61-6.76 (m, 3H; Ar-H), 7.17-7.32
ppm (m, 6H; Ar-H); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3): δ = 47.58, 112.86,
117.78, 128.66, 128.72, 129.26, 132.84, 137.98, 147.80 ppm; FT-IR(film): νmax =
3419, 3052, 3022, 2923, 2852, 1701, 1603, 1088, 1014, 817, 750, 692cm-1; MS (EI):
m/z (%): 216 [M-H]+ (98), 125 (100), 90 (17), 77 (13), 106 (10), 181 (13).
N-(4-nitrobenzyl)aniline (entry 5, Table 4.2): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 4.25 (s, 1H; N-H), 4.48 (s, 2H; CH2), 6.58-6.77 (m, 3H; Ar-H), 7.15-7.55
(m, 4H; Ar-H), 8.18-8.20 ppm (m, 2H; Ar-H); 13C NMR (126 MHz, CDCl3, 25oC;
CDCl3) : δ = 47.66, 112.95, 118.26, 123.87, 127.70, 129.38, 147.25, 147.33, 147.46
ppm; FT-IR (film): νmax = 3373, 2929, 1605, 1519, 740 cm-1; MS (EI): m/z (%) 227
[M-H]+ (100), 106 (40), 89 (24), 181 (21), 77 (19).
N-benzyl-4-methylaniline (entry 6, Table 4.2): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 2.29 (s, 3H; CH3), 3.93 (s, 1H; N-H), 4.35 (s, 2H; CH2), 6.59-7.04 (m, 4H;
Ar-H), 7.26-7.42 ppm (m, 5H; Ar-H); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3): δ =
20.34, 48.62, 112.98, 126.70, 127.10, 127.46, 128.55, 129.71, 139.66, 145.92 ppm;
FT-IR (film): νmax =3416, 3027, 2918, 2863, 1617, 1521, 807, 742, 697cm-1; MS (EI):
m/z (%) 196 [M-H]+ (100), 91 (78), 120 (18), 65 (11).
N-benzyl-4-methoxylaniline (entry 7, Table 4.2): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 3.74 (s, 3H; CH3), 3.83 (s, 1H; N-H), 4.28 (s, 2H; CH2), 6.60-6.62 (m, 2H;
Ar-H), 6.93-6.96 (m, 2H; Ar-H), 7.23-7.38 ppm (m, 5H; Ar-H); 13C NMR (126 MHz,
CDCl3, 25oC; CDCl3): δ = 49.27, 55.83, 114.14, 114.95, 127.55, 128.59, 128.74,
142.50, 144.95, 152.23 ppm; FT-IR (film): νmax = 3392, 3060, 3028, 2998, 2906, 2833,
1624, 1512, 1245, 1034, 820, 742, 694 cm-1; MS (EI): m/z (%) 212 [M-H]+ (100), 122
(53), 91 (47), 195 (43), 167 (18).
N-benzyl-4-chloroaniline (entry 8, Table 4.2): 1H NMR (500 MHz, CDCl3, 25 oC;
Page 105
89
TMS): δ = 4.06 (s, 1H; N-H), 4.31 (s, 2H; CH2), 6.54-6.57 (m, 2H; Ar-H), 7.10-7.14
(m, 2H; Ar-H), 7.28-7.36 ppm (m, 5H; Ar-H); 13C NMR (126 MHz, CDCl3, 25oC;
CDCl3): δ = 48.40, 113.96, 122.17, 127.40, 127.45, 128.73, 129.10, 138.98, 146.70
ppm; FT-IR (film): νmax = 3427, 3062, 3028, 2922, 2852, 1600, 1500, 1321, 1177, 815,
733, 698 cm-1; MS (EI): m/z (%) 216 [M-H]+ (82), 91 (100), 65 (9), 139 (9).
phenylmethanol (entry 1, Table 4.4): 1H NMR (500 MHz, CDCl3, 25 oC; CHCl3): δ
= 2.80 (s, 1H; O-H), 4.64 (s, 2H; CH2), 7.30-7.40 ppm (m, 5H; ArH); 13C NMR (126
MHz, CDCl3, 25oC; CDCl3): δ = 65.00, 126.94, 127.49, 128.44, 140.86 ppm; FT-IR
(film): νmax = 3335 (O-H), 3087, 3064, 3030, 2931, 2873, 1496, 1453, 1208, 1201,
734, 697 cm-1; MS (EI): m/z (%) 108 [M]+ (94), 79 (100), 51 (19), 91 (16).
4-methylphenylmethanol (entry 2, Table 4.4): 1H NMR (500 MHz, CDCl3, 25 oC;
CHCl3): δ = 1.95 (s, 1H; O-H), 2.38 (s, 3H; CH3), 4.65 (s, 2H; CH2), 7.19 (d, 3JHH =
7.89Hz, 2H; ArH), 7.27 ppm (d, 3JHH = 8.08Hz, 2H; ArH); 13C NMR (126 MHz,
CDCl3, 25oC; CDCl3): δ = 21.17, 65.22, 127.14, 129.25, 137.37, 137.40 ppm ; FT-IR
(film) : νmax = 3334, 3048, 3021, 2950, 2919, 1518, 1445, 1032, and 802 cm-1; MS
(EI): m/z (%) 122 [M]+ (92), 107 (100), 91 (69), 79 (65).
4-methoxylphenylmethanol (entry 3, Table 4.4): 1H NMR (500 MHz, CDCl3, 25 oC;
CHCl3): δ = 2.21 (s, 1H; O-H), 3.81 (s, 3H; CH3), 4.59 (s, 2H; CH2), 6.89-6.90 (m,
2H; ArH), 7.27-7.29 ppm (m, 2H; ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) :
δ = 55.33, 64.91, 113.98, 128.65, 133.24, 159.19 ppm; FT-IR(film): νmax = 3354,
3032, 3001, 2935, 2836, 1612, 1514, 1247, 1033, 816cm-1; MS (EI): m/z (%) 138[M]+
(100), 109 (73), 121 (52), 77 (50), 94 (33).
4-chlorophenylmethanol (entry 4, Table 4.4): 1H NMR (500 MHz, CDCl3, 25 oC;
CHCl3): δ = 2.14 (s, 1H; O-H), 4.65 (s, 2H; CH2), 7.23-7.34 ppm (m, 4H; ArH); 13C
NMR (126 MHz, CDCl3, 25oC; CHCl3): δ = 64.50, 128.29, 128.68, 133.36, 139.34
ppm; FT-IR (film): νmax = 3342, 2953, 2920, 2855, 2731, 1597, 1491, 1450, 1405,
1086, 1012, 708 cm-1 ; MS (EI): m/z (%) 142 [M]+ (60), 77 (100), 107 (68), 113 (18).
4-nitrophenylmethanol (entry 5, Table 4.4): 1H NMR (500 MHz, CDCl3, 25 oC;
CHCl3): δ = 2.24 (s, 1H; O-H), 4.84 (s, 2H; CH2), 7.54 (d, 3JHH = 8.86Hz, 2H; ArH ),
Page 106
90
8.22 ppm (d, 3JHH = 8.76Hz, 2H; ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) :
δ = 64.00, 123.75, 127.04, 147.34, 148.30 ppm; FT-IR(film): νmax = 3521, 3112, 2924,
2884, 1602, 1511, 1344, 1196, 1057, 736 cm-1; MS (EI): m/z (%) 153 [M]+ (34), 77
(100), 107 (50), 89 (41), 51 (28), 136 (22).
methyl 4-(hydroxymethyl)benzoate (entry 6, Table 4.4): 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 2.08 (s, 1H; O-H), 3.91 (s, 3H; CH3), 4.76 (s, 2H; CH2),
7.41-7.43 (m, , 2H; ArH ), 8.00-8.02 ppm (m, 2H; ArH); 13C NMR (126 MHz, CDCl3,
25oC; CDCl3) : δ = 52.04, 64.67, 126.44, 129.35, 129.82, 145.96, 166.94 ppm;
FT-IR(film): νmax = 3384, 3032, 3001, 2935, 2836, 1710, 1612, 816 cm-1; MS (EI):
m/z (%) 166 [M]+ (40), 77 (100), 107 (60), 136 (30).
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91
Chapter 5. Chemoselectively reducing -unsaturated aldehydes
and ketones into allylic alcohols by metal amidoboranes
5.1 Introduction
-unsaturated aldehydes and ketones have interesting properties which result
from conjugation of C=C with C=O. The systems of the C=C and C=O overlap
to form an extended p system which increases electron delocalization. In resonance
terms, electron delocalization is -unsaturated carbonyl compounds is
represented by contributions from three resonance structures as shown in Scheme
5.1.[51, 187]
O O
O
Scheme 5.1. Three resonance structures of -unsaturated carbonyl compound
The carbonyl group withdraws electron density from the double bond and both
the carbonyl carbon and the carbon are postively charged. A hydride can attack
an -unsaturated carbonyl compound either at the carbonyl group or at the
position (Scheme 5.2). When attack occurs at the carbonyl group, protonation of
the oxygen leads to a product with the hydride and the proton having added to
adjacent atom. It is called 1,2-reduction. On the other hand, when attack occurs at
the position rather than at the carbonyl group, the reactions proceed via enol
intermediates and are described as 1,4-reduction. The net result is the addtion of
the hydride and a hydrogen atom across a double bond that is conjugated with a
carbonyl group.
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92
R1
R2
O
R3
R1
R2
O
R3
HH+ R1
R2
O
R3
H
HH
R1
R2
O
R3
R1
R2
O
R3
H+
H
R1
R2
OH
R3H
1,2-reduction
1,4-reduction
H
H
Scheme 5.2. 1,2- and 1,4- reduction process of -unsaturated carbonyl compound
Hydride addition to -unsaturated carbonyl is governed either by kinetic control
or thermodynamic control (Scheme 5.3).[51, 153-154] Under conditions in which the
1,2- and 1,4-reduction products do not equilibrate, 1,2-reduction predominates
because it is under kinetic control and therefore, it is faster than 1,4-reduction. On
the other hand, thermodyamic control is observed when 1,4-reduction
predominates. The product of 1,4-reduction which retains the C=O, is more stable
then the product of 1,2-reduction, which retains the C=C. C=O is stronger than
C=C because the greater electronegativities of oxygen permits the p electrons to be
bound more strongly.
R1
R2
O
R3
+f ast
1,2-addition
R1
R2
OH
R3H
less stable, under kinetic controlslow
1,4-addition
R1
R2
OH
R3
H
f ast
keto-enolisomerism
R1
R2
O
R3
H
H
more stable, under thermodyamic control
H
+
Scheme 5.3. Two different control types that govern 1,2- and 1,4-addition
The chemoselective reduction of -unsaturated carbonyl compounds is one of
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93
the important processes in synthetic organic chemistry. Electron transfer
reduction[188-194], catalytic hydrogenation,[7, 195-196] transfer hydrogenation[197-199]
and hydridic reduction are traditonal methods to be applied in this transformation.
Hydridic reducing agents, such as NaBH4 are usually employed as primary choice
in 1,2-reduction due to convenient operation.[200-201] The result of reducing
-unsaturated ketone by NaBH4 generally depends on steric hindrance of double
bonds, solvent and other reaction conditions: increasing steric hindrance on the
C=C increases 1,2-attack[200]; alcoholic and etheric solvents can achieve mixture of
1,2- and 1,4-reduction[202]. Meanwhile, substantial amount of fully reduced
alcohols are also produced in some cases.[203] Improved 1,2-selective reduction of
-unsaturated carbonyl groups can be achieved by introducing additives, such as
stoichiometric lanthanide chlorides such as CeCl3 developed by Luche and his
co-workers,[204-205] to NaBH4 reaction system (scheme 5.4). One of the
disadvantages of such a process is the formation of toxic cerium byproducts.
Besides lanthanide chlorides, other additives such as calcium chloride (CaCl2),[206]
guanidine chloride[183] and pentafluorophenol,[207] aluminum oxide[208] are also
employed to achieve high selectivity to 1,2-reduction. Another type of reliable
reagent for 1,2-reduction of conjugated carbonyl compounds is lithium
aminoborohydrides (LiNRR’BH3), such as lithium pyrrolidinoborohydride,[113-114,
209] which can be applied in most of -unsaturated carbonyl compounds with
essentially quantitative yield of allylic alcohols upon hydrolysis of intermediate
borates. On the other hand, high 1,4-reduction can be achieved in
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94
NaBH4-pyridine,[202] and NaBH4-CoCl2.[203]
ONaBH4/ MeOH
CeCl3
OH
97%
Scheme 5.4. One example for reducing -unsaturated carbonyl compound by Luche reagent
MAB resembles similar structure to lithium aminoborohydride. Since lithium
aminoborohydride shows high chemoselectivity in 1,2 reduction of
-unsaturated carbonyl compound, we deduced that MAB may also be a good
reagent in reducing conjugated unsaturated carbonyl compound to allylic alcohol.
5.2 Results and Discussion
5.2.1 Reactivity study
In the attempt of reducing chalcone by LiAB in THF, we observed that LiAB
exhibited superior selectivity in reducing it to the corresponding allylic alcohol and
the alcohol was directly obtained after reaction. Therefore, in order to clarify the
effects of the reaction medium on the chemoselectivity, chalcone 1a was selected as a
model to react with MAB in different solvents (scheme 5.5). The results are listed in
the Table 5.1. In all cases, 1,3-diphenylpropan-1-one 4a, the 1,4 reduction product,
was not observed. However, both 1,3-diphenylprop-2-en-1-ol 2a (the 1,2-reduction
product) and 1,3-diphenylpropan-1-ol 3a (fully saturated product) were obtained in
most cases (Table 5.1, entry 1-5). When THF was utilized as solvent, the reduction
was fastest, and 2a resulted in high yield without observation of 3a. When 1a was
treated with LiAB and CaAB, it was completely turned into 2a. However, a small
amount of 3a formed when NaAB reacted with 1a.
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95
OLiAB
OH
+
OH
1a 2a 3a
+
O
4a
Scheme 5.5 Three possible products obtained in the reaction between chaclone (1a) and LiAB
Table 5.1. Reducing 1a in different solvents[a]
Entry Solvent MAB Time/hr 1a Conversion % 2a / 3a
1 CH2Cl2 LiAB 3 78 52 / 26
2 CHCl3 LiAB 3 45 26 / 19
3 CCl4 LiAB 3 25 2 / 23
4 Et2O LiAB 3 93 36 / 57
5 glyme LiAB 3 93 85 / 8
6 THF LiAB
NaAB
CaAB
0.5
1
1
>99
>99
>99
> 99 / 1
97 / 3
> 99 / 1
[a] Reaction conditions: 1mmol 1a reacted with 0.5 mmol LiAB, 0.5 mmol NaAB or 0.25 mmol
CaAB in 5 ml solvent at ambient temperature. Conversion rate of 1a and 2a / 3a were determined
by GC analysis.
In light of these results, a series of-unsaturated ketones were chosen to react with
LiAB and CaAB in THF at ambient temperature. The results are listed in the Table 5.2.
The molar ratio of ketone and MAB was 2:1 for LiAB and 4:1 for CaAB, respectively.
-unsaturated ketones were chemoselectively reduced in-between 30 to 60 minutes.
In all the cases, conversion rates of ketones were all above 99 % measured by GC. We
also tested the applicability of large dose of LiAB in chemoselectively reducing 1a:
87% isolated yield of 2a was obtained after 15mmol LiAB reacting with 30mmol 1a
Page 112
96
in THF (scheme 5.6).
O15mmol LiAB
OH
30mmol/ 6.25g
65ml THF
87% isola ted yield 5.49groom temp.30min1a 2a
Scheme 5.6 The results of the reaction of LiAB and chalcone in large scale
Table 5.2. Reducing -unsaturated ketones by LiAB or CaAB[a]
R2R1
O
R2R1
OHMAB
THF
Entry Substrate MAB t/min Yield % [b]
1 O
LiAB CaAB
30 60
85[c] 93
2 O
LiAB CaAB
30 60
86 89
3 O
LiAB CaAB
30 60
87 96
4 O
LiAB CaAB
30 60
88 82
5 O
O
LiAB CaAB
30 60
92 98
6 O
Cl
LiAB CaAB
30 60
90 89
7 O
O2N
LiAB CaAB
30 60
80 71
8 O
LiAB CaAB
30 60
82 95
9 O
O
LiAB CaAB
30 60
88 94
Page 113
97
[a] The ratio of substrate and LiAB was 2 to 1 and the concentration of LiAB was 0.083 M; the ratio of
substrate and CaAB was 4 to 1 and the concentration of CaAB was 0.05 M. [b] Isolated overall yields.
[c] The yield of allylic alcohol was 87% when the molar ratio of LiAB and chalcone was 1:1.
5.2.2 Mechanism study
In order to prove that double transfer process discussed in Chapter 4 is also involved
in the reaction of MAB and -unsaturated ketones. LiND2BH3 (LiA(D)B) was
employed to react with chalcone in THF. A singlet at δ = 0.65 ppm attributed to O-D
is observed in 2H NMR spectrum evidencing the transfer of deuterium on N to the O
of carbonyl group upon reduction (Figure 5.1.). In a related experiment of reacting
LiNH2BD3 (LiAB(D)) and chalcone in THF, a deuterated product at the carbon end of
the C=O bond, which was of 88% isolated yield, was obtained. It shows the transfer
of the deuterium on B of LiAB to the C of carbonyl group in the reduction. These
experimental results confirm that both protic H(N) and hydridic H(B) in LiAB
participate in the reduction and add directly to the O and C site of ketone, respectively
10 O
Cl
LiAB CaAB
30 60
91 96
11 O
NO2
LiAB CaAB
30 60
90 70
12 O
CN
LiAB CaAB
30 60
90 84
13 O
LiAB CaAB
30 60
93 98
14 n-C5H11 n-C4H9
O
LiAB CaAB
30 60
88 92
15 O
LiAB CaAB
30 60
86 83
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98
(Scheme 5.7).
5 4 3 2 1 0 -1 -2ppm
0.65 ppm
Figure 5.1. 2H NMR result for LiND2BH3 (LiA(D)B)reacting chalcone in THF. O-D peak at δ = 0.65
ppm is observed.
N
B D
H
Li
C
O
R R'
O
C
R R'
D
H
N
B H
D
Li
C
O
R R'
O
C
R R'
H
D
R= PhR'= CH=CH-Ph
Overall reaction model f or LiAB with conjugated ketone
N
B Hb
Ha
Li
C
O
R'' R'''
O
C
R'' R'''
Hb
Ha
D
H
H
H
D
D
H
H
H
Scheme 5.7. The deuterium labelling study and the reaction model for LiAB with-unsaturated
ketones
5.2.3 Reducing -unsaturated aldehydes with MAB
Comparing with LiAB, CaAB shows similar reactivity in reducing -unsaturated
ketones. However, in the case of reducing -unsaturated aldehydes, although both
the two reagents show high chemoselectivity in 1, 2-reduction, CaAB is slightly
different from LiAB in double hydrogen transfer process. The results are shown in
Table 5.3. The molar ratio of conjugated aldehydes and CaAB was 4:1 and high
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99
isolated yields of allylic alcohols were achieved after reduction without hydrolysis,
which implies that CaAB transferred all the four protic hydrogens to C sites of
carbonyl groups to form four equivalent alcohols. However, when LiAB reacted with
two equivalent conjugated aldehydes, only ca. 50% of allylic alcohols were obtained.
High isolated yields up to 98% can be achieved only after hydrolysis of reduction
product with aqueous HCl solution (entry 1-3, Table 5.3). Therefore, LiAB could
transfer only half of its protic hydrogens to conjugated aldehyde. One possible reason
that may account for this difference is that the Lewis acidity of the intermediate
product R=C-CH2-O-BH=NH-Li may be weaker than the corresponding allylic
alcohol. Therefore, the protic hydrogen transfer was thermodynamically unfavored.
In Chapter 4, the reactions of MAB and aromatic aldehydes were discussed. It was
found that MAB cannot transfer protic hydrogens to aromatic aldehydes. However, in
this chapter, CaAB is feasible to transfer all protic hydrogen and LiAB tends to
transfer one of its protic hydrogen to -unsaturated aldehydes. The reasons for this
difference are still uncertain.
Table 5.3. Reducing-unsaturated aldehydes by CaAB and LiAB[a]
RCHO
LiAB or CaAB
THF RCHO
Entry Substrate MAB Time/ min Yield %[b] 1 CHO
CaAB LiAB LiAB
15 15 15
88 52[c] 97[d]
2 CHO
CaAB LiAB LiAB
15 15 15
80 53[c] 98[d]
3 CHO
O
CaAB LiAB LiAB
15 15 15
84 52[c] 90[d]
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100
4 CHO
Cl
CaAB 15 85
5 CHO
Br
CaAB 15 87
6
OCHO
CaAB 15 88
7 CHO
CaAB 15 93
8 CHO
CaAB 15 82
[a] The ratio of substrate to CaAB was 4 to 1 and the concentration of CaAB was 0.05 M. The ratio of
substrate and LiAB was 2 to 1 and the concentration of LiAB was 0.083 M. [b] Isolated overall yield.
[c]. yield without hydrolysis. [d] yield after hydrolysis with aqueous HCl solution.
5.2.4 Explanation on 1,2-reduction property of MAB
Chemoselectivity of borohydride reduction of -unsaturated aldehydes and ketones
has been attempted using HSAB (hard and soft acids and bases) concept as
explaination.[204, 210]Relatively soft hydrides preferentially add to the conjugated
system through 1,4-reduction, while hard hydride go through 1,2-reduction.
Borohydrides such as NaBH4 are considered softer than the corresponding aluminum
hydrides which are good 1,2-reduction reagent.[211-212]Replacement of a hydride group
on boron by alkoxide group turns it into a harder reagent because the B-H bonds
become longer. It is similar to MAB case after substituting one N-H from AB: B-H
bonds become longer.[140] Therefore, MAB owns harder hydrides. Additionally,
lithium salts are harder than sodium species. Therefore, LiAB gives more 1,2-attack
than NaAB.
5.3 Conclusion
In summary, highly chemoselective reduction of -unsaturated ketones and
aldehydes to allylic alcohols was successfully achieved by using LiAB or CaAB as
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101
reducing reagent. Isotopic labeling studies show that double hydrogen transfer process
is also involved in this reduction. High reducibility, double hydrogen transfer and
chemoselectivity make this approach practical for the synthesis of allylic alcohols.
5.4 Experimental section
5.4.1 General remarks:
Most solvents and some of reagents were purchased commercially and used
without further purification: THF (Honywell, HPLC, dried over NaH),
cinnamaldehyde (entry 1, Table 5.3, Aladin, 97%), -methylcinnamaldehyde
(entry 2, Table 5.3, Aladin, 95%), 4-methoxycinnamaldehyde (entry 3, Table 5.3,
Alfa Aesar, 98%), -chlorocinnamaldehyde (entry 4, Table 5.3, Aladin, 97%),
-bromocinnamaldehyde (entry 5, Table 5.3, Alfa Aesar, 98%),
2-methyl-3-(2-furyl)propenal (entry 6, Table 5.3, Alfa Aesar, 97%),
2-Methyl-2-pentenal (entry 7, Table 5.3, Alfa Aesar, 97%), trans-2-decenal(entry 8,
Table 1, Alfa Aesar, 95%), chalcone (entry 1, Table 5.2, Alfa Aesar, 97%),
4’-methoxychalcone (entry 9, Table 5.2, Alfa Aesar, 97%),
3-methyl-2-cyclohexen-1-one (entry 14, Table 5.2, Alfa Aesar, 98%). Other
conjugated ketones were synthesized by corresponding aldehydes and ketones.
5.4.2 Synthesis of -unsaturated ketones
5.4.2.1 -unsaturated ketones (entry 3-8, entry 10-12, Table 5.2)
In a 50 mL flask, corresponding aldehyde (10 mmol), corresponding ketone (10 mmol)
and ethanol (20 ml) were placed, and the solution was stirred at room temperature. To
the solution, NaOH aqueous solution (1.5M, 10ml) was slowly added. After 5 hrs, the
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102
reaction mixture was neutralized with 2M aqueous HCl solution. Crude
-unsaturated ketone was obtained after filtration. Then, the crude product was
recrystallized from ethanol.
5.4.2.2 -unsaturated ketones (entry 2, entry 13, Table 5.2)
In a 50 mL flask, corresponding aldehyde (10 mmol), corresponding ketone (10 mmol)
and ethanol (20 ml) were placed, and the solution was stirred at room temperature. To
the solution, NaOH aqueous solution (1.5M, 10ml) was added slowly. After 5 hrs, the
reaction mixture was neutralized with 2M aqueous HCl solution. The solution was
extracted with DCM (3 X 10 mL). The organic layer was washed with aqueous NaCl
(2 X 10 mL) and dried over Na2SO4. The solvent was evaporated and the residue was
purified by column chromatography with hexane/EtOAc (v/v,10/1) as an eluent to
obtain -unsaturated ketone.
5.4.3 General experimental procedure for reducing -unsaturated ketones
or aldehydes with CaAB
5 ml 0.05M CaAB solution (or 5ml 0.1 M LiAB solution) was added to 1ml 1M
substrate solution (THF as solvent) at room temperature in a closed glass bottle
under argon gas protection. FT-IR spectrometer was used to monitor the
consumption of C=O group and formation of OH group. After the reaction, THF
was evaporated. Then 10 ml diethyl ether was added to the glass bottle to extract
alcohol for three times. The diethyl ether solution further underwent centrifugation
to remove suspended substance. Next, diethyl ether was evaporated to leave
transparent liquid residue which was further purified by column chromatography
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(silica gel, 200-300 mesh, hexane/ EtOAc (v/v, 10/1) as an eluent). Alcohol
products were characterized by 1H NMR, 13C NMR, FT-IR and GC-MS.
5.4.4 Products characterization
OHD (87%)
1H NMR (500 MHz, CDCl3, 25 oC; TMS): δ = 2.05 (s, 1H; OH),
5.39 (s, 0.13H; CH), 6.37-6.40 (m, 1H; CH), 6.69 (d, 3JHH = 15.80 Hz, 1H; CH),
7.24-7.43 ppm (m, 10H; ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ =
74.70 (t, JCD= 22.08 Hz; CD), 126.32, 126.60, 127.76, 127.79, 128.54, 128.61, 130.59,
131.48, 131.54, 136.53, 142.78 ppm ; FT-IR (film): νmax = 3348, 3077, 3059, 3026,
2128 (CD), 1600, 1493, 1448 cm-1; MS (EI): m/z (%) 211 [M]+ (10), 105 (100), 77
(40).
1,3-diphenylprop-2-en-1-ol (entry 1, Table 5.2): 1H NMR (500 MHz, CDCl3, 25
oC; TMS): δ = 2.07 (s, 1H; OH), 5.38 (s, 1H; CH), 6.36-6.40 (m, 1H; CH), 6.68 (d,
3JHH = 15.80 Hz, 1H; CH), 7.24-7.42 ppm (m, 10H; ArH); 13C NMR (126 MHz,
CDCl3, 25oC; CDCl3) : δ = 75.11, 126.32, 126.59, 127.75, 127.77, 128.54, 128.60,
130.56, 131.51, 136.53, 142.78 ppm ; FT-IR (film): νmax = 3342, 3077, 3059,
3027, 1599, 1449, 1493, 1092, 1067, 1009, 966, 744, 695 cm-1; MS (EI): m/z (%)
209 [M-H]+ (47), 105 (100), 191 (67), 178 (27), 77 (33), 115 (30).
1-phenyl-3-o-tolylprop-2-en-1-ol (entry 2, Table 5.2): 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 2.07 (s, 1H; OH), 2.37 (s, 3H; CH3), 5.41 (s, 1H; CH),
6.30-6.40 (m, 1H; CH), 6.92 (d, 3JHH = 15.60 Hz, 1H; CH), 7.15-7.44 ppm (m, 9H;
ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 19.78, 75.33, 125.79,
126.06, 126.34, 127.65, 127.77, 128.41, 128.61, 130.28, 132.87, 135.62, 142.86
ppm ; FT-IR (film): νmax = 3349, 3061, 3062, 2969, 2863, 1601, 1487, 1463cm-1;
MS (EI): m/z (%) 224 [M]+ (3), 105 (100), 206 (16), 77 (26).
1-phenyl-3-m-tolylprop-2-en-1-ol (entry 3, Table 5.2): 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 2.16 (s, 1H; OH), 2.34 (s, 3H; CH3), 5.38 (s, 1H; CH),
6.37-6.40 (m, 1H; CH), 6.66 (d, 3JHH = 15.55 Hz, 1H; CH), 7.07-7.44 ppm (m, 9H;
Page 120
104
ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 21.35, 75.16, 123.81,
126.34, 127.30, 127.76, 128.46, 128.60, 130.68, 131.36, 136.48, 138.11, 142.85
ppm ; FT-IR (film): νmax = 3350, 3056, 3028, 2955, 2919, 2862, 1602, 1491, 1453
cm-1; MS (EI): m/z (%) 224 [M]+ (15), 105 (100), 119 (36), 77 (33).
1-phenyl-3-p-tolylprop-2-en-1-ol (entry 4, Table 5.2): 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 1.99 (s, 1H; OH), 2.33 (s, 3H; CH3), 5.38 (s, 1H; CH),
6.31-6.36 (m, 1H; CH), 6.66 (d, 3JHH = 15.80 Hz, 1H; CH), 7.11-7.44 ppm (m, 9H;
ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 21.71, 75.23, 126.31,
126.51, 127.73, 128.58, 129.25, 130.50, 130.59, 133.78, 137.66, 142.88 ppm;
FT-IR (film): νmax = 3342, 2081, 3026, 2919, 2859, 1513, 1493, 1451 cm-1; MS
(EI): m/z (%) 223 [M-H]+ (47), 105 (100), 207 (50), 119 (60), 77 (40).
3-(4-methoxyphenyl)-1-phenylprop-2-en-1-ol (entry 5, Table 5.2): 1H NMR
(500 MHz, CDCl3, 25 oC; TMS): δ = 2.04 (s, 1H; OH), 3.80 (s, 3H; CH3), 5.37 (s,
1H; CH), 6.23-6.27 (m, 1H; CH), 6.63 (d, 3JHH = 15.80 Hz, 1H; CH), 6.84 (d, 3JHH
= 8.35 Hz, 2H; ArH), 7.29-7.44 ppm (m, 7H; ArH); 13C NMR (126 MHz, CDCl3,
25oC; CDCl3) : δ = 55.27, 75.30, 113.98, 126.28, 127.69, 127.81, 128.57, 129.26,
129.40, 130.26, 142.99, 159.38 ppm ; FT-IR (film): νmax = 3374, 3060, 3030, 3005,
2956, 2935, 2836, 1606, 1511, 1250 cm-1; MS (EI): m/z (%) 239 [M-H]+ (43),
121 (100), 222 (36), 178 (36), 77 (38), 105 (37).
3-(4-chlorophenyl)-1-phenylprop-2-en-1-ol (entry 6, Table 5.2): 1H NMR (500
MHz, CDCl3, 25 oC; TMS): δ = 2.07 (s, 1H; OH), 5.37 (d, 3JHH = 6 Hz, 1H; CH),
6.33-6.37 (m, 1H; CH), 6.64 (d, 3JHH = 15.80 Hz, 1H; CH), 7.25-7.42 ppm (m, 9H;
ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 74.99, 126.32, 127.79,
127.93, 128.69, 128.71, 129.19, 132.16, 133.40, 135.05, 142.58 ppm; FT-IR (film):
νmax = 3338, 3060, 3029, 2958, 2924, 2856, 1593, 1491, 1452, 1404 cm-1; MS (EI):
m/z (%) 244 [M]+ (37), 105 (100), 139 (32), 190 (27), 77 (33).
3-(4-nitrophenyl)-1-phenylprop-2-en-1-ol (entry 7, Table 5.2): 1H NMR (500
MHz, CDCl3, 25 oC; TMS): δ = 2.15 (s, 1H; OH), 5.44 (s, 1H; CH), 6.55-6.58 (m,
1H; CH), 6.78 (d, 3JHH = 15.80 Hz, 1H; CH), 7.33-8.17 ppm (m, 9H; ArH); 13C
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105
NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 74.68, 123.97, 126.40, 127.10, 127.85,
128.24, 128.85, 136.23, 142.03, 143.12, 147.02 ppm; FT-IR (film): νmax = 3392,
3105, 3062, 3030, 2931, 2850, 1596, 1514, 1342 cm-1; MS (EI): m/z (%) 254
[M-H]+ (30), 105 (100), 178 (12), 77 (35)
3-phenyl-1-p-tolylprop-2-en-1-ol (entry 8, Table 5.2): 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 1.98 (d, 3JHH = 3.45 Hz, 1H; OH), 2.35 (s, 3H; CH3),
5.36 (t, 3JHH = 4.52 Hz, 1H; CH), 6.36-6.41 (m, 1H; CH), 6.68 (d, 3JHH = 15.85 Hz,
1H; CH), 7.18-7.39 ppm (m, 9H; ArH); 13C NMR (126 MHz, CDCl3, 25oC;
CDCl3) : δ = 21.11, 74.96, 136.31, 126.58, 127.70, 128.53, 129.30, 130.31, 131.66,
136.60, 137.56, 139.86 ppm; FT-IR (film): νmax = 3338, 3083, 3026, 2971, 2919,
1599, 1578, 1509 cm-1; MS (EI): m/z (%) 223 [M-H]+ (47), 119 (100), 206 (98),
105 (60), 191 (70), 77 (40).
1-(4-methoxyphenyl)-3-phenylprop-2-en-1-ol (entry 9, Table 5.2): 1H NMR
(500 MHz, CDCl3, 25 oC; TMS): δ = 1.96 (s, 1H; OH), 3.81 (s, 3H; CH3), 5.35 (s,
1H; CH), 6.36-6.41 (m, 1H; CH), 6.67 (d, 3JHH = 15.85 Hz, 1H; CH), 6.91 (d, 3JHH
= 7.90 Hz, 2H; ArH), 7.23-7.39 ppm (m, 7H; ArH); 13C NMR (126 MHz, CDCl3,
25oC; CDCl3) : δ = 55.31, 74.66, 114.01, 126.57, 127.69, 128.54, 130.20, 131.69,
135.01, 136.61, 159.28 ppm; FT-IR (film): νmax = 3379, 3059, 3026, 2956, 2908,
2835, 1610, 1511, 1449 cm-1; MS (EI): m/z (%) 239 [M-H]+ (43), 223 (100), 135
(85), 178 (50), 77 (35).
1-(4-chlorophenyl)-3-phenylprop-2-en-1-ol (entry 10, Table 5.2): 1H NMR (500
MHz, CDCl3, 25 oC; TMS): δ = 2.04 (s, 1H; OH), 5.37 (s, 1H; CH), 6.31-6.35 (m,
1H; CH), 6.67 (d, 3JHH = 15.80 Hz, 1H; CH), 7.25-7.27 ppm (m, 9H; ArH); 13C
NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 74.48, 126.62, 127.69, 127.97, 128.61,
128.71, 131.03, 131.08, 133.49, 136.25, 141.16 ppm; FT-IR (film): νmax = 3334,
3078, 3059, 3027, 2957, 2925, 2870, 1597, 1490, 1449, 1404 cm-1; MS (EI): m/z
(%) 244 [M]+ (36), 139 (100), 105 (60), 192 (60), 77 (33).
1-(4-nitrophenyl)-3-phenylprop-2-en-1-ol (entry 11, Table 5.2): 1H NMR (500
MHz, CDCl3, 25 oC; TMS): δ = 2.19 (s, 1H; OH), 5.49 (s, 1H; CH), 6.27-6.32 (m,
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1H; CH), 6.73 (d, 3JHH = 15.80 Hz, 1H; CH), 7.25-7.37 ppm (m, 5H; ArH), 7.61 (d,
3JHH = 7.90 Hz, 2H; ArH), 8.22 (d, 3JHH = 7.85 Hz, 2H; ArH); 13C NMR (126 MHz,
CDCl3, 25oC; CDCl3) : δ = 74041, 123.76, 126.69, 126.96, 128.34, 128.69, 130.07,
132.30, 135.82, 147.39, 149.71 ppm; FT-IR (film): νmax = 3427, 3107, 3081, 3027,
1855, 1600, 1519, 1345 cm-1; MS (EI): m/z (%) 237 [M-H2O]+ (98), 105 (100),
150 (65), 77 (40).
4-(1-hydroxy-3-phenylallyl)benzonitrile (entry 12, Table 5.2): 1H NMR (500
MHz, CDCl3, 25 oC; TMS): δ = 2.31 (s, 1H; OH), 5.43 (d, 3JHH = 6.85 Hz, 1H;
CH), 6.26-6.31 (m, 1H; CH), 6.70 (d, 3JHH = 15.80 Hz, 1H; CH), 7.26-7.65 ppm (m,
9H; ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 74.51, 111.37, 118.78,
126.68, 126.89, 128.26, 128.68, 130.25, 132.05, 132.37, 135.92, 147.87 ppm;
FT-IR (film): νmax = 3426, 3059, 3027, 2924, 2229, 1607, 1494, 967 cm-1; MS (EI):
m/z (%) 235 [M]+ (100), 105 (98), 217 (50), 130 (60), 91 (50).
1,5-diphenylpenta-2,4-dien-1-ol (entry 13, Table 5.2): 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 2.01 (s, 1H; OH), 5.32 (d, 3JHH = 6.35 Hz, 1H; CH),
5.98-6.02 (m, 1H; CH), 6.45-6.50 (m, 1H; CH), 6.58 (d, 3JHH = 15.65 Hz, 1H; CH),
6.75-6.81 (m, 1H; CH), 7.21-7.42 ppm (m, 10H; ArH); 13C NMR (126 MHz,
CDCl3, 25oC; CDCl3) : δ = 74.86, 126.30, 126.39, 127.65, 127.78, 128.07, 128.60,
130.98, 133.23, 135.49, 137.08, 142.79 ppm; FT-IR (film): νmax = 3290, 3080,
3059, 3026, 1599, 1492, 1449 cm-1; MS (EI): m/z (%) 235 [M-H]+ (25), 105 (100),
217 (90), 128 (50), 202 (50), 77 (33).
dodec-6-en-5-ol (entry 14, Table 5.2): 1H NMR (500 MHz, CDCl3, 25 oC; TMS):
δ = 0.8 (s, 6H), 1.29-1.33 (m, 12H), 2.01-2.07 (m, 4H), 4.02 (s, 2H; OH), 5.39 ppm
(s, 1H; CH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 13.94, 13.98, 22.53,
22.84, 27.38, 27.76, 29.42, 30.83, 31.56, 67.30, 127.09, 139.09 ppm; FT-IR (film):
νmax = 3344, 2928, 2397, 1378, 1331, 1086 cm-1; MS (EI): m/z (%) 184 [M]+ (9),
57 (100), 81 (39), 71 (76), 94 (35).
3-methylcyclohex-2-enol (entry 15, Table 5.2): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 1.38 (s, 1H; CH), 1.55-1.61 (m, 2H, CH2), 1.68 (s, 3H; CH3), 1.72-1.92
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107
(m, 4H), 4.17 (s, 1H; OH), 5.49 (s, 1H, CH); 13C NMR (126 MHz, CDCl3, 25oC;
CDCl3) : δ = 18.89, 23.60, 30.06, 31.67, 65.86, 124.23, 138.72 ppm; FT-IR (film):
νmax = 3342, 2935, 2862, 1447, 1376, 1033 cm-1; MS (EI): m/z (%) 112 [M]+ (30), 97
(100), 79 (80), 69 (25).
3-phenylprop-2-en-1-ol (entry 1, Table 5.3): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 1.52. (s, 1H; OH), 4.33 (s, 2H; CH2), 6.34-6.38 (m, 1H; CH), 6.61 (d,
JHH= 15.63 Hz,1H; CH), 7.24-7.38 ppm (m, 5H; ArH); 13C NMR (126 MHz,
CDCl3, 25oC; CDCl3) : δ = 63.73, 126.45, 127.69, 128.48, 128.58, 131.21, 136.71
ppm ; FT-IR (film): νmax = 3322, 3081, 3058, 3027, 2920, 2861, 1494, 1448, 966
cm-1; MS (EI): m/z (%) 134 [M]+ (50), 91 (100), 78 (60), 105 (40).
2-methyl-3-phenylprop-2-en-1-ol (entry 2, Table 5.3): 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 1.64. (s, 1H; OH), 1.90 (s, 3H; CH3), 4.18 (s, 2H; CH2),
6.52 (s, 1H; CH), 7.22-7.33 (m, 5H; ArH); 13C NMR (126 MHz, CDCl3, 25oC;
CDCl3) : δ = 15.26, 68.99, 125.04, 126.43, 128.13, 128.86, 137.54, 137.65 ppm;
FT-IR (film): νmax = 3325, 3054, 3023, 2914, 2858, 1491, 1444, 1009 cm-1; MS
(EI): m/z (%) 148 [M]+ (55), 91 (100), 115 (70), 105 (40)
3-(4-methoxyphenyl)prop-2-en-1-ol (entry 3, Table 5.3): 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 1.38 (s, 1H; OH), 3.80 (s, 3H; CH3), 4.29 (s, 2H; CH2),
6.21-6.24 (m, 1H; CH), 6.55 (d, JHH= 15.87 Hz,1H; CH), 7.85-7.31 (m, 5H; ArH);
13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ =55.27, 63.91, 114.01, 126.26,
127.64, 129.42, 130.97, 159.34 ppm; FT-IR (film): νmax = 3368, 3033, 2969, 2917,
2841, 1605, 1511, 1460 cm-1; MS (EI): m/z (%) 164 [M]+ (30), 121 (100), 108 (30),
77 (20), 91 (20).
2-chloro-3-phenylprop-2-en-1-ol (entry 4, Table 5.3): 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 2.18. (s, 1H; OH), 4.34 (s, 2H; CH2), 6.79 (s, 1H; CH),
7.25-7.64 (m, 5H; ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 67.75,
124.81, 128.10, 128.27, 129.16, 132.47, 134.12 ppm; FT-IR (film): νmax = 3344,
3056, 3026, 2921, 2863, 1652, 1492, 1446 cm-1; MS (EI): m/z (%) 168 [M]+ (65),
115 (100), 133 (90), 102 (50).
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2-bromo-3-phenylprop-2-en-1-ol (entry 5, Table 5.3): 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 2.26 (s, 1H; OH), 4.41 (s, 2H; CH2), 7.08 (s, 1H; CH),
7.31-7.62 (m, 5H; ArH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 69.39,
125.32, 127.83, 128.20, 128.99, 134.96 ppm; FT-IR (film): νmax = 3338, 3056,
3025, 2918, 2858, 1646, 1491, 1445 cm-1; MS (EI): m/z (%) 212 [M-H]+ (50), 115
(100), 133 (90), 102 (50), 77 (55).
3-(furan-2-yl)-2-methylprop-2-en-1-ol (entry 6, Table 5.3): 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 1.69 (s, 1H; OH), 1.99 (s, 3H; CH3), 4.14 (s, 2H; CH2),
6.25-6.38 (m, 3H), 7.35 (s, 1H); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ =
15.75, 68.59, 108.67, 111.09, 113.76, 136.32, 141.24, 153.06 ppm; FT-IR (film):
νmax = 3337, 2916, 2857, 1491, 1066, 1015 cm-1; MS (EI): m/z (%) 138 [M]+ (90),
81 (100), 68 (60), 77 (50), 95 (50).
2-methylpent-2-en-1-ol (entry 7, Table 5.3): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 0.94 (m, 3H; CH3), 1.63 (s, 3H; CH3), 1.82 (s, 1H; CH), 3.71 (s, 1H;
OH), 3.96 (s, 2H; CH2); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 13.99,
20.85, 68.99, 128.16, 134.06 ppm; FT-IR (film): νmax = 3337, 2916, 2857, 1066,
1015 cm-1; MS (EI): m/z (%) 100 [M]+ (45), 71 (100), 43 (90), 57 (40), 69 (40).
dec-2-en-1-ol (entry 8, Table 5.3): 1H NMR (500 MHz, CDCl3, 25 oC; TMS): δ =
0.86 (m, 3H; CH3), 1.25 (s, 10H), 1.32 (s, 1H; OH), 2.06 (m, 2H; CH2), 4.06 (s, 2H;
CH2), 5.58-5.69 (m, 2H; CH); 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ =
14.03, 22.62. 29.13, 31.80, 32.18, 63.81, 128.83, 133.53 ppm; FT-IR (film): νmax
= 3347, 2956, 2925, 2855, 1465, 969 cm-1; MS (EI): m/z (%) 156[M]+ (1), 57
(100), 43 (50), 67 (40), 29 (30).
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109
Chapter 6. Reductive amination of aldehydes and ketones with
primary amines by using lithium amidoborane
6.1 Introduction
Reductive amination where an aldehyde or ketone and an amine are treated together
with a reductant is one of the most useful and fundamental methods for the
preparation of primary, secondary and tertiary amines in organic chemistry.[213]
Primary amines can be obtained by condensation of ammonia, ammonium salt, or
hydroxylamine with a ketone or an aldehyde followed by reduction of the imine or
oxime. Hydroxylamine is more frequently used among others because most oximes
are stable. Secondary amines are achieved by condensation of a ketone or an aldehyde
with a primary amine in the presence of reducing reagent. Tertiary amines are derived
from condensation of secondary amine with a ketone or an aldehyde.
As shown in scheme 6.1, the reductive amination involves the initial nuleophilic
addition of carbonyl compound by amine and followed by proton transfer to form a as
an aminol intermediate or carbinol amine through step 1. Subsequently, a dehydrates
to form b after protonation of the carbinolamine on oxygen as iminium ion or imine
through step 2. Finally, b is reduced by reducing reagent to achieve the respective
alkylated amine c through step 3. (scheme 6.1) Generally, imine formation (step 2) is
usually the rate-determining step in reductive amination and it is under equilibrium
control. Therefore, it is necessary to remove H2O either by separating it physically or
by adding a drying agent during the imine formation in order to break the equilibrium.
Reductive amination prefers acid solution. However, if the solution is too acidic,
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110
protonation of the amine block step 1. Therefore, the optimum pH is about 5 at which
the reaction rate is a maximum. Too basic a solution reduces the rate of step 2.[51]
R1 C R2
O H
R1 C R2
O
H
NR4R3
H
R1 C R2
O
N R4H
R3
H
R1 C R2
O
N R4
R3
H
H +
R1 C R2
O
N R4
R3
HH
R1 C R2
N R4
R3
+ H2OR1 C R2
N R4
R3
R1 C R2
N R4
H
R3
a
[H]
bc
step 1
step 2step 3
Scheme 6.1. Mechanism of reductive amination
Several reducing reagents have been reported as effective in reductive amination:
catalytic hydrogenation,[9, 42, 214-216] NaBH3CN,[184, 217] NaBH(OAc)3,[218-219]
decaborane,[220] NaBH4-ZnCl2,[221] NaBH4-Ti(OiPr)4,
[222] zinc borohydride in the
presence of Lewis acids,[223-224] pyridine-BH3,[225] 2-picoline-BH3
[226],
dimethylamine-BH3,[227] benzylamine-BH3
[228], etc. However, most of these reagents
may have drawbacks. For example, catalytic hydrogenation is incompatible with other
functional groups such as cyano, nitro, and carbon-carbon double bonds.[229]
Cyanoborohydride generates toxic by-products such as HCN and NaCN upon
workup.[230] NaBH(OAc)3 is flammable and insoluble in most of the common organic
solvents.[223]
In 2010, Ramachandran et al[231] reported reductive amination using AB. In this
literature, a variety of primary, secondary and tertiary amines were prepared in high
yields using AB as reducing reagent. Since LiAB is a better dehydrogenation material
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111
than AB, we postulate that LiAB could also be better reductive amination reagent than
AB.
6.2 Results and Discussion
6.2.1 Choice of Lewis acid
As mentioned previously, reductive amination favors acid solution and the removal of
water is a key factor in the rate determining step.[213, 219] Generally, Lewis acids are
suitable co-reactants to promote abstraction of H2O in the imine formation step and
provide acid environment. Therefore, we first performed reductive amination of
benzaldehyde and aniline by LiAB with a number of common Lewis acids to figure
out additive effect. It should be noted that imine formation does not occur without
Lewis acids in our experiment. In a typical reaction procedure, 0.5 mmol
benzaldehyde was firstly added to the solution of 0.6 mmol aniline in 2 mL THF.
Then, 0.75mmol Lewis acid was introduced into the mixture and the reaction system
was stirred for 1 h at room temperature. Subsequently, 5ml of 0.15M LiAB solution
was added and stirring was continued at the room temperature until the completion of
the reaction (detected by GC). Based on the results listed in the Table 6.1, AlCl3
exhibits the best performance. It is interesting to note that Ti(OiPr)4, the most effective
Lewis acid previously observed in the reductive amination using AB10, did not
perform well upon using LiAB as the reducing reagent. In addition, most of the
reducible transition metal salts are inferior to AlCl3 and ZnCl2. Such a phenomenon
may be due to the fact that LiAB or AB can readily reduce transition metal salts
giving rise to metallic species or alloys which can further catalyze the
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112
self-decomposition of LiAB or AB.
Table 6.1. Reductive amination using LiAB in the presence of different Lewis acids
CHO+
NH2
1. Lewis acid (1.5 eq)THF, 1hr
2. LiAB (1.5 eq)RT
NH
Entry Lewis acid Time/ hr Yield %a 1 ZnCl2 2 85 2 NiCl2 5 18 3 AlCl3 1 98 4 FeCl3 4 41 5 TiCl3-THF 3 46 6 CoCl2 4 50 7 Ti(OiPr)4 4 28 a. GC yield.
6.2.2 Reactivity study
According to the experimental results above, the reduction aminations of various
aldehydes and ketones with primary amine were carried out under room temperature.
The ratio of carbonyl: amine: AlCl3: LiAB was 1:1.2:1.5:1.5. The results are shown in
Table 6.2. All the reactions involving aldehydes were completed within 1 hr. On the
other side, reactions involving ketones were slower. Additionally, LiAB presents
higher reactivity than AB in reductive amination. For example, AB needs 6 hr to
aminate benzaldehyde and aniline reported by Ramachandran and his coworkers[231]
However, only 1 hr is needed in the case of LiAB. Meanwhile, we tried to process
reductive amination of aldehydes and ketones with secondary amines such as
morpholine. However, the results were unsatisfactory because alcohols derivate from
carbonyl compounds were obtained in large amount. The reason may due to the
iminium salts formed after condensation of a ketone or an aldehyde with a secondary
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amine. Iminium salts are frequently unstable. The reducing agent used in the reaction
must be capable of reducing the iminium salt, but it must not reduce the carbonyl
group of the ketone or aldehyde. For example, NaBH3CN works well for this
reduction because it is less reactive than NaBH4 and it does not reduce the carbonyl
group. Therefore, it is assumed that LiAB, which exhibits strong reactivity in
reducing ketones and aldehydes as discussed in Chapter 4, cannot be reducing reagent
in reductive amination of carbonyl compounds with secondary amines.
Table 6.2. Reductive amination of carbonyl compounds and primary amines by using AB in the presence of AlCl3
Entry Carbonyl
compound
amine Time/ hr Product Yield %[a]
1 CHO
N H2
1
NH
93
2 CHO
NH2
1
NH
98
3 CHO
NH2
O
1
NH
O
78
4 CHO
NH2
Cl
1 NH
Cl
81
5 CHO
NH2
O2N
1
NH
NO2
85
6 CHO
NH2
1 NH
81
7 CHO
NH2 1 NH
82
8 CHO
N H2
1
NH
91
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114
9 CHO
N H2
1 NH
87
10 CHO
N H2
1
NH
87
11 CHO
O
N H2
1
NH
O
82
12 CHO
Cl
N H2
1
NH
Cl
85
13 CHO
NH2
1
NH
83
14 CHO
NH2
1
NH
81
15 CHO
NH21 NH
80
16 CHO
NH2 1 NH
85
17
O
CHO
NH2
1
NHO
94
18 O
NH2
2 HN
81
19 O
NH2 2 HN
82
20 O
NH2
2
NH
86
21 O
NH2
2
N H
84
[a] isolated yield based on carbonyl.
6.3 Conclusion
In conclusion, LiAB is a powerful reductive amination reagent. The formation of
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secondary amines was achieved in good yield from aldehydes or ketones with primary
amines by LiAB in the presence of AlCl3. Therefore, this reductive amination method
may provide a novel way for synthesizing amines in organic chemistry due to simple
preparation of LiAB.
6.4 Experimental Section
6.4.1 General remarks:
Solvent and reagents were purchased commercially and used without further
purification. THF (Honywell, HPLC, dried over NaH), AlCl3 (Alfa Aesar, 97%),
cinnamaldehyde (Aladin, 97%), 2-methyl-3-(2-furyl)propenal (Alfa Aesar, 97%),
benzaldehyde (Sigma-Aldrich, 99%), 4-methylbenzaldehyde (Alfa Aesar, 98%),
4-methoxybenzaldehyde (J&K, 99%), 4-chlorobenzaldehyde (Acros, 99%),
cyclohexanone (Sigma-Aldrich, 98%), hexan-2-one (Alfa Aesar, 98%), aniline (Alfa
Aesar, 99%), 4-methylanline (Alfa Aesar, 98%), 4-methoxylaniline (Alfa Aesar, 98%),
4-chloroaniline (Alfa Aesar, 99%), 4-nitroaniline (Alfa Aesar, 98%), propylamine
(Alfa Aesar, 95%), benzylamine (Alfa Aesar, 98%).
6.4.2 General experimental procedure for reducing amination with LiAB:
0.5 mmol ketone or aldehyde was firstly added to the solution of 0.6 mmol primary
amine in 2 mL THF. Then, 0.6 mmol AlCl3 was introduced into the mixture and the
reaction system was stirred for 1 h at room temperature. Subsequently, 5ml of 0.15M
LiAB solution was added and stirring was continued at room temperature until the
completion of the reaction (The extent of reaction was determined by GC analyses
and TLC). Then, THF was removed under vacuum. After this, the resulting mixture
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was treated with HCl (4ml, 2M) and stirred for an additional hour. Then, NaOH (2M)
solution was added to adjust the pH value to 8. Next, the solution was extracted with
10 ml diethyl ether for 3 times. The combined diethyl ether extracts were washed with
brine, dried with NaSO4 overnight and concentrated in vacuum. In the final step, the
residue was purified by silica gel flash chromatography to obtain the desired product.
The product was characterized by FTIR, 1H NMR, 13C NMR and GC-MS.
6.4.3 Products characterization
N-benzylaniline (entry 1,Table 6.2): 1H NMR (500 MHz, CDCl3, 25 oC; TMS): δ =
4.00 (s, 1H; N-H), 4.32 (s, 2H; CH2), 6.64-6.72 (m, 3H; Ar-H), 7.16-7.36 ppm (m, 7H;
ArH).13C NMR (126 MHz, CDCl3, 25oC; CDCl3): δ = 48.36, 112.87, 117.59, 127.23,
127.52, 128.64, 129.27, 140.51 ppm. FT-IR (KBr): νmax = 3419,3052, 3026, 2920,
2841, 1602, 1505, 1452, 1324, 750, 693 cm-1.MS (EI): m/z (%) 182 [M-H]+ (100), 91
(70), 106 (12), 77 (10), 65 (9).
N-benzyl-4-methylaniline (entry 2, Table 6.2): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 2.25 (s, 3H; CH3), 3.89 (s, 1H; N-H), 4.31 (s, 2H; CH2), 6.57-7.00 (m, 4H;
Ar-H), 7.28-7.36 ppm (m, 5H; Ar-H).13C NMR (126 MHz, CDCl3, 25oC; CDCl3): δ =
20.39, 48.67, 113.02, 126.75, 127.15, 127.50, 128.60, 129.75, 139.70, 145.96 ppm.
FT-IR (KBr): νmax =3416, 3027, 2918, 2863, 1617, 1521, 807, 742, 697cm-1. MS (EI):
m/z (%) 196 [M-H]+ (100), 91 (78), 120 (18), 65 (11).
N-benzyl-4-methoxyaniline (entry 3, Table 6.2): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 3.74 (s, 3H; CH3), 3.77 (s, 1H; N-H), 4.28 (s, 2H; CH2), 6.60-6.62 (m, 2H;
Ar-H), 6.78-6.79 (m, 2H; Ar-H), 7.28-7.37 ppm (m, 5H; Ar-H). 13C NMR (126 MHz,
CDCl3, 25oC; CDCl3): δ = 49.27, 55.83, 114.14, 114.97, 127.17, 127.55, 128.60,
139.75, 142.52, 152.26 ppm. FT-IR (KBr): νmax = 3392, 3060, 3028, 2998, 2906, 2833,
1624, 1512, 1245, 1034, 820, 742, 694 cm-1.MS (EI): m/z (%) 212 [M-H]+ (100), 122
(53), 91 (47), 195 (43), 167 (18).
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N-benzyl-4-chloroaniline (entry 4, Table 6.2): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 4.04 (s, 1H; N-H), 4.30 (s, 2H; CH2), 6.54-6.57 (m, 2H; Ar-H), 7.09-7.10
(m, 2H; Ar-H), 7.27-7.34 ppm (m, 5H; Ar-H). 13C NMR (126 MHz, CDCl3, 25oC;
CDCl3): δ = 48.36, 113.93, 122.13, 127.37, 127.41, 128.70, 129.07, 138.96, 146.67
ppm. FT-IR (KBr): νmax = 3427, 3062, 3028, 2922, 2852, 1600, 1500, 1321, 1177, 815,
733, 698 cm-1. MS (EI): m/z (%) 216 [M-H]+ (82), 91 (100), 65 (9), 139 (9).
N-benzyl-4-nitroaniline (entry 5, Table 6.2): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 4.41 (s, 2H; CH2), 4.86 (s, 1H; N-H), 6.54-6.56 (m, 2H; Ar-H), 7.31-7.35
(m, 5H; Ar-H), 8.05-8.07 ppm (m, 2H; Ar-H). 13C NMR (126 MHz, CDCl3, 25oC;
CDCl3): δ = 47.70, 111.34, 113.238, 126.37, 127.35, 127.87, 128.96, 137.38, 153.04
ppm. FT-IR (KBr): νmax = 3373, 2929, 1605, 1519, 740 cm-1. MS (EI): m/z (%) 227
[M-H]+ (100), 106 (40), 89 (24), 181 (21), 77 (19).
Dibenzylamine (entry 6, Table 6.2): 1H NMR (500 MHz, CDCl3, 25 oC; TMS): δ =
1.62 (s, 1H; NH), 3.80 (m, 4H; CH2), 7.25-7.33 ppm (m, 10H; Ar-H). 13C NMR (126
MHz, CDCl3, 25oC; CDCl3): δ = 53.18, 58.72, 126.94, 128.15, 128.39, 128.80, 128.97,
129.58, 134.42, 140.35 ppm. FT-IR (KBr): νmax = 3308, 3195, 3062, 3027, 2920, 2837,
1495, 1454cm-1. MS (EI): m/z (%) 197 [M]+ (100), 91 (78), 120 (18), 65 (11).
N-benzylpropan-1-amine (entry 7, Table 6.2): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 0.90 (t, 3JHH = 7.41 Hz, 3H; CH3), 1.23 (s, 1H; NH), 1.49-1.53 (m, 2H;
CH2), 2.58 (t, 3JHH = 7.24 Hz, 2H; CH2), 3.76 (s, 2H; CH2), 7.29-7.31 ppm (m, 5H;
ArH). 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 11.74, 23.14, 51.32, 54.00,
126.85, 128.10, 128.35, 129.11ppm. FT-IR (KBr): νmax = 3306, 3063, 3028, 2959,
2928, 2873, 2817, 1494, 1454 cm-1. MS (EI): m/z (%) 149 [M]+ (10), 91(100), 106 (5),
120 (60), 65 (15), 77 (5).
N-(2-methylbenzyl)aniline (entry 8, Table 6.2): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 2.41 (s, 3H; CH3), 3.83 (s, 1H; N-H), 4.30 (s, 2H; CH2), 6.67-6.77 (m, 5H;
Ar-H), 7.23-7.37 ppm (m, 4H; Ar-H). 13C NMR (126 MHz, CDCl3, 25oC; CDCl3): δ =
18.96, 46.44, 112.76, 117.51, 126.21, 127.46, 128.30, 129.32, 130.37, 136.37, 137.08,
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148.37 ppm. FT-IR (KBr): νmax = 3416, 3050, 3019, 2969, 2919, 2859, 1602, 1505,
1332, 747cm-1. MS (EI): m/z (%) 197 [M]+ (50), 105 (100), 77 (40), 93 (20)
N-(3-methylbenzyl)aniline (entry 9, Table 6.2): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 2.38 (s, 3H; CH3), 3.99 (s, 1H; N-H), 4.31 (s, 2H; CH2), 6.67-6.75 (m, 3H;
Ar-H), 7.12-7.26 ppm (m, 6H; Ar-H). 13C NMR (126 MHz, CDCl3, 25oC; CDCl3): δ =
21.46, 48.40, 112.89, 117.56, 124.63, 128.03, 128.33, 128.57, 129.29, 138.45, 139.45,
148.31ppm. FT-IR (KBr): νmax = 3418, 3050, 3021, 2919, 2860, 1602, 1505, 1323,
749cm-1. MS (EI): m/z (%) 197 [M]+ (50), 105 (100), 77 (40), 93 (30).
N-(4-methylbenzyl)aniline (entry 10, Table 6.2): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 2.36 (s, 3H; CH3), 3.96 (s, 1H; N-H), 4.30 (s, 2H; CH2), 6.64-6.73 (m, 3H;
Ar-H), 7.17-7.27 ppm (m, 6H; Ar-H). 13C NMR (126 MHz, CDCl3, 25oC; CDCl3): δ =
21.10, 48.11, 112.87, 117.51, 127.53, 129.26, 129.32, 136.41, 136.87, 148.27 ppm.
FT-IR (KBr): νmax = 3419, 3049, 3020, 2920, 2860, 1603, 1505, 1325, 1266, 806, 748
cm-1. MS (EI): m/z (%) 196 [M-H]+ (85), 105 (100), 77 (18).
N-(4-methoxybenzyl)aniline (entry 11, Table 6.2): 1H NMR (500 MHz, CDCl3, 25
oC; TMS): δ = 3.81 (s, 3H; CH3), 3.93 (s, 1H; N-H), 4.26 (s, 2H; CH2), 6.65-6.90 (m,
5H; Ar-H), 7.19-7.30 ppm (m, 4H; Ar-H). 13C NMR (126 MHz, CDCl3, 25oC; CDCl3):
δ = 47.83, 55.31, 112.89, 114.89, 117.53, 128.82, 129.27, 131.49, 148.27, 158.92 ppm.
FT-IR (KBr): νmax = 3398, 3047, 2962, 2836, 1604, 1514, 1425, 1302, 1253, 1175,
1034, 818, 748, 694cm-1. MS (EI): m/z (%) 212 [M-H]+ (50), 121 (100), 77 (13).
N-(4-chlorobenzyl)aniline (entry 12, Table 6.2): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 4.02 (s, 1H; N-H), 4.30 (s, 2H; CH2), 6.60-6.73 (m, 3H; Ar-H), 7.17-7.30
ppm (m, 6H; Ar-H). 13C NMR (126 MHz, CDCl3, 25oC; CDCl3): δ = 47.63, 112.91,
117.82, 128.69, 128.75, 129.29, 132.89, 138.00, 147.85 ppm. FT-IR(KBr): νmax =
3419, 3052, 3022, 2923, 2852, 1701, 1603, 1088, 1014, 817, 750, 692cm-1. MS (EI):
m/z (%): 216 [M-H]+ (98), 125 (100), 90 (17), 77 (13), 106 (10), 181 (13).
N-cinnamylaniline (entry 13, Table 6.2): 1H NMR (500 MHz, CDCl3, 25 oC; TMS):
δ = 3.83(s, 1H; NH), 3.95 (s, 2H; CH2), 6.33-6.36 (m, 1H; CH), 6.70 (d, 3JHH = 15.80
Hz, 1H; CH), 6,74-7.76 ppm (m, 3H; ArH) 7.21-7.39 ppm (m, 7H; ArH). 13C NMR
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(126 MHz, CDCl3, 25oC; CDCl3): δ = 46.24, 113.10, 117.60, 126.37, 127.12, 127.56,
128.60, 129.31, 131.56, 136.93, 148.10 ppm. FT-IR (KBr): νmax = 3414, 3052, 3023,
2917, 2834, 1602, 1504, 1322, 966, 748, 692cm-1. MS (EI): m/z (%) 208 [M-H]+ (60),
117 (100), 91 (20), 77 (19).
N-cinnamyl-4-methylaniline (entry 14, Table 6.2): 1H NMR (500 MHz, CDCl3, 25
oC; TMS): δ = 2.23 (s, 3H; CH3), 3.68 (s, 1H; NH), 3.90 (s, 2H; CH2), 6.32-6.34 (m,
1H; CH), 6.57-6.59 ppm (m, 3H; ArH) 7.00-7.36 ppm (m, 7H; ArH). 13C NMR (126
MHz, CDCl3, 25oC; CDCl3): δ = 20.36, 46.61, 113.28, 126.32, 126.88, 127.34, 127.46,
128.54, 129.75, 131.42, 136.96, 145.81 ppm. FT-IR (KBr): νmax = 3414, 3052, 3023,
2917, 2834, 1602, 1504, 1322, 966, 748, 692cm-1. MS (EI): m/z (%) 223 [M]+ (80),
117 (100), 91 (40), 77 (19).
N-benzyl-3-phenylprop-2-en-1-amine (entry 15, Table 6.2): 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 1.55 (s, 1H; NH), 3.44 (s, 2H; CH2), 3.84 (s, 2H; CH2)
6.29-6.34 (m, 1H; CH), 6.53 (d, 3JHH = 15.80 Hz, 1H; CH), 7.21-7.36 ppm (m, 10H;
ArH). 13C NMR (126 MHz, CDCl3, 25oC; CDCl3): δ = 51.22, 53.36, 126.28. 126.98,
127.34, 128.20, 128.44, 128.48, 128.54, 131.41, 137.18, 140.29 ppm. FT-IR (KBr):
νmax = 3311, 3059, 3025, 2918, 2816, 1494, 1452, 966, 734 cm-1. MS (EI): m/z (%)
223 [M]+ (40), 117 (100), 91 (20), 77 (19).
3-phenyl-N-propylprop-2-en-1-amine (entry 16, Table 6.2): 1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ = 0.92 (t, 3JHH = 7.40 Hz, 3H; CH3), 1.48-1.56 (m, 2H; CH2),
1.75 (s, 1H; NH), 2.60 (t, 3JHH = 7.24 Hz, 2H; CH2) 3.38-3.40 (m, 2H; CH2),
6.26-6.31 (m, 1H; CH), 6.51 (d, 3JHH = 15.87 Hz, 1H; CH), 7.18-7.35 ppm (m, 5H;
ArH). 13C NMR (126 MHz, CDCl3, 25oC; CDCl3): δ = 11.76, 23.20, 51.35, 51.87,
126.24, 127.29, 128.50, 128.59, 131.18, 137.17 ppm. FT-IR (KBr): νmax = 3307, 3059,
3025, 2958, 2929, 2872, 2813, 1494, 1448, 966, 742 cm-1. MS (EI): m/z (%) 175[M]+
(20), 117 (100), 84 (25), 146 (20), 77 (5).
N-(3-(furan-2-yl)-2-methylallyl)aniline (entry 17, Table 6.2):1H NMR (500 MHz,
CDCl3, 25 oC; TMS): δ =2.03 (s, 3H; CH3), 3.80 (s, 2H; CH2), 3.98 (s, 1H; NH), 2.60
(t, 3JHH = 7.24 Hz, 2H; CH2), 6.22 (s, 1H; CH), 6.32-6.69 (m, 5H; ArH), 7.14-7.35
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ppm (m, 3H; Furan-H). 13C NMR (126 MHz, CDCl3, 25oC; CDCl3) : δ = 16.78, 52.08,
108.42, 111.06, 112.86, 114.21, 117.50, 129.23, 134.67, 141.04, 148.13, 153.24 ppm.
FT-IR (KBr): νmax = 3420, 3051, 3030, 2911, 2851, 1602, 1507, 1310, 1266 cm-1. MS
(EI): m/z (%) 213 [M]+ (90), 121 (100), 93 (85), 198 (20), 77 (90).
N-cyclohexylaniline (entry 18, Table 6.2): 1H NMR (500 MHz, CDCl3, 25 oC; TMS):
δ = 1.10-2.05 (m, 10H; CH), 3.24 (s, 1H; CH), 3.48 (s, H; NH) 6.58-6.64 (m, 3H;
ArH), 7.13 (m, 2H; ArH). 13C NMR (126 MHz, CDCl3, 25oC; CDCl3): δ = 25.00,
25.94, 33.50, 51.69, 113.144, 116.82, 129. 23, 147.42 ppm. FT-IR (KBr): νmax = 3404,
3052, 3019, 2958, 2929, 2859, 1601 cm-1. MS (EI): m/z (%) 175 [M]+ (20), 132 (100),
106 (10), 93 (15), 77 (10).
N-benzylcyclohexanamine (entry 19, Table 6.2): 1H NMR (500 MHz, CDCl3, 25
oC; TMS): δ = 1.10-1.89 (m, 13H; CH), 2.46 (s, 1H; NH), 3.79 (s, 2H; CH2),
7.32-7.29 (m, 5H; ArH). 13C NMR (126 MHz, CDCl3, 25oC; CDCl3): δ = 25.00, 26.19,
33.56, 51.04, 56.17, 126.75, 128.06, 128.36, 141.01ppm. FT-IR (KBr): νmax = 3404,
3052, 3019, 2958, 2929, 2859, 1601 cm-1. MS (EI): m/z (%) 189 [M]+ (30), 91 (100),
146 (90), 160 (10), 77 (1).
N-(hexan-2-yl)aniline (entry 20, Table 6.2): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 0.90-1.34 (m, 11H; CH), 3.44 (s, 1H; NH), 6.57-6.6 (m, 3H; ArH), 7.15 (m,
2H; ArH). 13C NMR (126 MHz, CDCl3, 25oC; CDCl3): δ =14.06, 20.80, 22.76, 28.36,
36.96, 48.46, 113.08, 116.75, 129.25, 147.76 ppm. FT-IR (KBr): νmax = 3404, 3052,
3019, 2958, 2929, 2859, 1601, 1505, 1318 cm-1. MS (EI): m/z (%) 177 [M]+ (20), 120
(100), 162 (10), 106 (5), 77 (10).
N-benzylhexan-2-amine (entry 21, Table 6.2): 1H NMR (500 MHz, CDCl3, 25 oC;
TMS): δ = 0.88-1.28 (m, 13H; CH), 2.62 (s, 1H; NH), 3.70-3.82 (m, 2H; CH2),
7.22-7.29 (m, 5H; ArH). 13C NMR (126 MHz, CDCl3, 25oC; CDCl3): δ =14.04, 20.29,
22.88, 28.19, 36.79, 51.39, 52.54, 126.77, 128.10, 128.35, 140.89 ppm. FT-IR (KBr):
νmax = 3312, 3063, 3027, 2958, 2957, 3858, 1454, 1376 cm-1. MS (EI): m/z (%) 191
[M]+ (5), 117 (100), 84 (80), 91 (70), 175 (60).
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Chapter 7. Conclusion and future work
7.1 Conclusion
The motivation of this research is to study the properties of AB and MABs in organic
reductions. Therefore, the objectives are to utilize AB and MABs in reducing typical
organic functional groups, to examine reactivities of these materials toward reduction,
and to investigate the reduction mechanism.
In the first part of this study, AB was found to possess high reactivities in reducing
aldehydes at ambient temperature and in reducing ketones at 65 oC. Based on the
in-situ FT-IR and NMR measurements, we found that not only the hydridic hydrogens
of AB transferred to carbonyl groups, but also the protic hydrogens of AB participated
in reaction. This finding provides a new perspective in defining the role of AB in
organic reduction. In 1980, AB was first reported as a reducing reagent but only
contributed its hydridic hydrogen in the reduction.[103] The reduction was via a
two-step process including hydroboration and the follow-up hydrolysis or solvolysis.
However, our experimental results challenge such a commonly accepted explanation
in that AB is not only a hydride transfer agent but also a double hydrogen transfer
agent. In order to understand the mechanism on how AB transfers two different
hydrogens to unsaturated functional groups, kinetic study and DFT calculations have
been carried out. Those results show that 1) the reaction between AB and carbonyl
obeys a second-order rate law, being first order of each reactant; 2) the dissociations
of both N-H and B-H bonds are involved in the rate determining step; 3) concerted
double-H-transfer pathway is more kinetic favorable than step-wised pathway and
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agrees with the kinetic results. Therefore, it should be the dominant path in the
reduction. The simulation results are similar to the pathway proposed by Berke et al
on AB reducing imines.[164] However, there are several limitations in this part of study.
Firstly, only aldehydes and ketones were utilized as substrates to react with AB. Other
unsaturated functional groups such as ester and amides were not considered in this
thesis. It should be noted that this is not a critical issue since the results of reducing
other unsaturated functional groups can be deduced from the present results. The
reactions between AB and aldehydes or ketones are simpler than reactions of reducing
esters or amides. Therefore, the simulation results of those reactions may be more
accurate. A second limitation is that the difference of energy barrier between
concerted and step-wised pathway is only 3.1 kcal/mol. Therefore, the dominated
pathway cannot be clearly distinguished. However, the limitation is also not a critical
one because both pathways show that double hydrogen transfer procedure is
applicable. The overall process may be the combination of both pathways.
In the second part of this study MABs, including LiAB, NaAB and CaAB, were
utilized to react with compounds of unsaturated functional groups. It was found that
MABs had higher reactivity toward unsaturated functional groups than AB: carbonyl
compounds and imines can be reduced by MABs within 1hr at ambient temperature.
Such a high reactivity can be attributed to the weaker B-H bond in MABs than that in
AB. Moreover, the protic hydrogens of MABs participated in the reduction and
transferred to unsaturated functional groups as evidenced by in situ FT-IR and NMR
characterizations. This finding is significant because MABs are regarded as novel
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hydrogen storage materials recently due to their high hydrogen contents. Few
literatures on their reducing reactivity were reported. Therefore, this work provides a
new perspective in the application of MABs in organic reduction. In order to
understand the mechanism of how MABs transfer two different hydrogens to
unsaturated functional groups, kinetics study and DFT calculations were also carried
out. In addition, LiAB was used as representative of MABs. These results show that 1)
the reaction between LiAB and carbonyl or imines obeys a first-order rate law, being
first order of LiAB;2) the rate-determining step of reduction is the elimination of LiH
from LiAB followed by the transfer of H(Li) to C site of unsaturated bond.[168] In
addition, MABs were also found to be highly chemoselective reagents for the
reduction of -unsaturated ketones to allylic alcohols and to be reducing reagents
for reductive amination. These two applications evidence that MABs are attractive
reagents for organic reductions. However, it should be pointed out that there are still
some limitations in this part of work. Firstly, the MABs studied in this thesis are
restricted to LiAB, NaAB and CaAB. Other MAB such as KAB and YAB are
excluded. It should be noted that this is not a critical issue since LiAB, NaAB and
CaAB are three representatives for MABs in hydrogen storage research and these
three compounds are stable. The second limitation is that solid residues of MABs after
reaction are unknown. The reason is that those residues are amorphous, insoluble in
most aprotic solvents and sensitive to air and moisture. Therefore, the products are
difficult to be characterized by XRD and/or NMR.
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7.2 Future work
There are several interesting directions for future work and applications in areas of
research presented in this thesis:
One possible avenue for future work is to extend the application of MABs in other
organic reductions. Since MABs are demonstrated to be strong reducing reagents in
this study, they may be used to reduce other organic unsaturated functional groups
such as olefin, nitrile, amide and ester. The research on using borohydrides in those
reductions has been carried out over one century. Therefore, the future work on
application of MABs in those reductions should be feasible and straightforward based
on the previous experiences. In addition, the instability of MABs should be taken into
consideration in the experiments.
Another interesting area for future research is to utilize AB and MABs as hydrogen
donor in transfer hydrogen reaction. Generally speaking, there are three commonly
used hydrogen donors: 2-propanol, formic acid and its salts, and Hantzsch ester.
Although they are stable and inexpensive, they transfer double hydrogen under
vigorous condition or with the aid of catalysts. However, AB and MABs can release
hydrogen without any catalyst at temperature below 100 oC. Therefore, these two
materials may be good alternatives for tradition hydrogen donors in transfer hydrogen
reaction.
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