Page 1
NMR Spectroscopy for NMR Spectroscopy for
Studying Studying ChiralityChirality
Thomas J. WenzelThomas J. Wenzel
Department of ChemistryDepartment of Chemistry
Bates CollegeBates College
Lewiston, Maine 04240Lewiston, Maine 04240
[email protected] @bates.edu
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ChiralChiral Discrimination Discrimination
NMR SpectroscopyNMR Spectroscopy
•• ChiralChiral derivatizingderivatizing agentsagents
•• ChiralChiral solvating agentssolvating agents
•• Metal complexesMetal complexes
•• Liquid crystalsLiquid crystals
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ChiralChiral DerivatizingDerivatizing AgentsAgents
•• Form a covalent bond between an Form a covalent bond between an
optically pure reagent and the compound optically pure reagent and the compound
of interestof interest
CDA + (CDA + (RR))--Sub = CDASub = CDA--((RR))--Sub Sub
CDA + (CDA + (SS))--Sub = CDASub = CDA--((SS))--SubSub
•• Resulting compounds are Resulting compounds are diastereomersdiastereomers
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ChiralChiral Discriminating AgentsDiscriminating Agents
•• No No racemizationracemization
•• No kinetic resolutionNo kinetic resolution
•• Need 100% optical purity of the reagent if Need 100% optical purity of the reagent if using for the determination of using for the determination of enantiomericenantiomeric excessexcess
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ChiralChiral Solvating AgentsSolvating Agents
•• Form nonForm non--covalent interactions between an covalent interactions between an optically pure reagent and the compound of optically pure reagent and the compound of interestinterest
CSA + (CSA + (RR))--Sub = CSASub = CSA--((RR))--Sub Sub
CSA + (CSA + (SS))--Sub = CSASub = CSA--((SS))--SubSub
•• Resulting compounds are Resulting compounds are diastereomersdiastereomers
•• KKRR and Kand KSS are likely different are likely different –– causes different causes different timetime--averaged averaged solvationsolvation environmentsenvironments
Page 7
ChiralChiral Solvating AgentsSolvating Agents
•• Preferable to have fast exchangePreferable to have fast exchange
•• High concentration of CSA usually leads to High concentration of CSA usually leads to
larger discriminationlarger discrimination
•• Often see enhanced Often see enhanced enantiomericenantiomeric
discrimination at lower temperaturesdiscrimination at lower temperatures
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Assigning Absolute StereochemistryAssigning Absolute Stereochemistry
•• Mechanism of discrimination is understood and Mechanism of discrimination is understood and
characteristic shifts occur in the spectrumcharacteristic shifts occur in the spectrum
–– More common with certain families of More common with certain families of chiralchiral
derivatizingderivatizing agentsagents
–– Possible with some Possible with some chiralchiral solvating agents solvating agents
•• Empirical trendEmpirical trend
–– Best if use known model compounds as close as Best if use known model compounds as close as
possible in structural features to the unknownpossible in structural features to the unknown
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ArylAryl--containing Carboxylic Acidscontaining Carboxylic Acids
--Alcohols and AminesAlcohols and Amines
C COH
CH3O
F3C
O
H3CO
OH
O
OHHC3CO
O
O
C
F
CN
COOHH3C
OH
HN
O
OCH3
O
OH
H3CO
OH
OCH3C
OCH3
COOH
MTPA MPA (O-MMA) O-AMACFTA
N-Boc PG MαNP2-AMA/9-AMA
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ArylAryl--containing Carboxylic Acidscontaining Carboxylic Acids
•• MTPA = MTPA = αα--methoxymethoxy--αα--trifluoromethylphenylacetictrifluoromethylphenylacetic acidacid
•• MPA = MPA = αα--methoxyphenylaceticmethoxyphenylacetic acidacid
•• OO--AMA = AMA = OO--acetyl acetyl mandelicmandelic aciedacied
•• CFTA = CFTA = αα--cyanocyano--αα--fluorofluoro--pp--tolylacetictolylacetic acidacid
•• NN--BocBoc PG = PG = NN--bocboc phenylglycinephenylglycine
•• MMααNPNP = 2= 2--methoxymethoxy--22--(1(1--naphthyl)propionic acidnaphthyl)propionic acid
•• 22--/9/9--AMA = AMA = αα--(2(2--anthryl)anthryl)--αα--methoxyacetic acidmethoxyacetic acid
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L2O
CF3
L1
H O
Ph OMe
(OMe) (Ph) (R)-MTPA
(S)-MTPA
Mosher Method/Modified Mosher Method
-Prepare derivatives with (R)- and (S)-forms of the reagent
-Syn-periplanar arrangement of HC-O-C(O)-Catoms (secondary alcohols)
-Calculate ∆δRS values – negative for L1, positivefor L2
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10
RO
8 9
Me(10) Me(8) Me(9)
MTPA 0.07 -0.017 -0.04
MPA 0.05 -0.021 -0.26
∆δRS H1'
H1
H2
OH
34
56
78
Position MTPA MPA PPA
1 0.07 0.19 0.431' 0.03 0.12 0.202 0.09 0.14 0.183 0.04 0.02 0.034 0.03 0.07 0.144' 0.03 0.06 0.138 0.03 0.04 0.10
PPA = α-phenyl-propionic acid
∆δRS depends on:
-Degree of conformational preference/how it influences the shielding
-Size of the shielding (anthryl > naphthyl > phenyl)
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Secondary AlcoholsSecondary Alcohols
•• MPA > MTPA (conformational preference MPA > MTPA (conformational preference that produces greater difference in that produces greater difference in shielding)shielding)
•• MPA MPA –– early synthetic procedures early synthetic procedures –– high high degree of degree of racemizationracemization
•• Better procedures for MPA Better procedures for MPA derivatizationderivatizationnow existnow exist
•• Mix and shake methodMix and shake method
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I
OH
MPA derivative
2.7 Hz differential shielding for the methyl group 9-bonds removed From the chiral center
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Effect of temperatureEffect of temperature
•• For MPA derivatives of secondary alcohols, For MPA derivatives of secondary alcohols,
lowering the probe temperature by about 100 K lowering the probe temperature by about 100 K
(to 175(to 175--200K) approximately doubles the 200K) approximately doubles the ∆δ∆δRSRS
valuesvalues
•• Alters conformational preference further toward Alters conformational preference further toward
the the spsp formform
•• Can measure Can measure ∆δ∆δTT11TT22values as a confirmation of values as a confirmation of
stereochemicalstereochemical assignmentassignment
•• Effect not as pronounced with MTPA or AMAEffect not as pronounced with MTPA or AMA
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Barium Method Barium Method
MPA/secondary alcoholsMPA/secondary alcohols
O
O
MeO
H
Ph
L1
L2
Ba+2
α α'
O
O
MeO
H
Ph
L1
L2
α α '
Ba+2
sp
sp-Ba+2 complex
O
OMeO
H
Ph
L1
L2
Ba+2
O
OO
H
Ph
L1
L2
ap
ap-Ba+2 complex
Ba+2
Me
Barium binds in a chelatemanner with the ester and alters the conformation preference toward the spconformer.
Leads to enhancement in the shielding and get larger ∆δRS values.
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La(hfa)La(hfa)33 method with MTPA method with MTPA
Secondary alcoholsSecondary alcohols
X
CF3
MeO
H O
R1
R2
sp
X
OMe
H O
R1
R2CF3
sp'
M
X
OMe
F3C
H O
R1
R2
sp'
X
CF3
H O
R1
R2OMe
sp
M
(S)-MPTA derivative (R)-MPTA derivative
X = O or NH
(b)
OMTPA
H
R1 R2
MTPA plane
∆δ0S,R< 0
∆δMS,R > 0
∆δ0S,R> 0
∆δMS,R < 0
M M
Chelate bonding of the La reverses the orientation of the phenyl ring and the shifts of the hydrogen resonances
This reversal in shifts can be used to confirm the stereochemicalassignment
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22--AMA/9AMA/9--AMA AMA –– Linear Linear vsvs cyclic cyclic
secondary secondary carbinolscarbinols
O
Me
Me
H
OO
H
MeO
HMeO
HR1 R2
HMeO
HR1 R2
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MMααNPNP (secondary alcohols)(secondary alcohols)
CH3C
OCH3
COOH
-∆δRS about 4-times greater than with MTPA
-Less prone to racemization with methyl group on chiral carbon
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CFTA (secondary alcohols)CFTA (secondary alcohols)
•• The The ∆δ∆δRSRS values are typically 2values are typically 2--times greater times greater than MTPAthan MTPA
•• Much faster reaction than MTPA with Much faster reaction than MTPA with hindered compoundshindered compounds
•• 11H and H and 1919F NMR can be usedF NMR can be used
C
F
CN
COOHH3C
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H
ORSRR
O
F
C
MeN
CFTA ester plane
CFTA - Conformational Preferencesyn-periplanar arrangement
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Secondary Secondary DiolsDiols and and PolyolsPolyols
•• If groups are far enough apart, can If groups are far enough apart, can
determine the configuration of each group determine the configuration of each group
independentlyindependently
•• If groups are close together, bound If groups are close together, bound
reagent may influence the shielding or reagent may influence the shielding or
deshieldingdeshielding at more than one siteat more than one site
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MPA for MPA for DiolsDiols
•• Analysis of (Analysis of (synsyn and and antianti):):
–– 1,21,2--
–– 1,31,3--
–– 1,41,4--
–– 1,51,5--diols with known configurationsdiols with known configurations
•• Observe reproducible trends that can be applied Observe reproducible trends that can be applied
to compounds with unknown configurationsto compounds with unknown configurations
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Primary AlcoholsPrimary Alcohols
•• MTPA MTPA –– CC22 chiralchiral
•• CFTACFTA
•• 99--AMAAMA
∗ OH
O
O
OMeEtOOC ∗ OH
OMOM
2.116
HO
N
N
N
N
ClMeO
O
H
L1Ar L2H
O
α1'
2'
MPA - Unreliable
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Tertiary AlcoholsTertiary Alcohols
OHCH2
HC HB HA
CH2
HX HY HZ
Me
O
O
OMe
HNap (R)-2NMA
(H) (Nap) (S)-2NMA
2NMA plane
(a)
(b)
HY
HX
HZ
∆δ < 0H2C C
Me
H2C HB
HA
HC
∆δ > 0
O-2NMA
MTPA
2-NMA
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Secondary AminesSecondary Amines
•• MTPAMTPA
•• HH22 had a had a ∆δ∆δRSRS of 2.44 of 2.44 ppmppm!!
•• Values so large only need one MTPA Values so large only need one MTPA
derivative (use (derivative (use (RR))--acid chloride since more acid chloride since more
reactive than (reactive than (SS))--acid chloride)acid chloride)
N
MTPA
N
MTPA
N
O
CF3
PhOMe
2
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Primary Amines Primary Amines –– αα--substitutedsubstituted
•• MTPA gives larger MTPA gives larger ∆δ∆δRSRS values than MPA or values than MPA or
99--AMA AMA -- MTPA amides have greater MTPA amides have greater
preference for the preference for the spsp conformer than conformer than
observed with esters.observed with esters.
•• BPG BPG –– preference for preference for apap conformer conformer –– typical typical
∆δ∆δRSRS values are 2values are 2-- to 3to 3--times larger than with times larger than with
MTPA MTPA
OH
HN
O
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Aryl Aryl MethoxyMethoxy Reagents Reagents -- SummarySummary
•• Want larger Want larger ∆δ∆δRSRS values values –– either through either through
high conformational preference or larger high conformational preference or larger
aromatic ring (shielding)aromatic ring (shielding)
•• Values should all be positive for one Values should all be positive for one
substituentsubstituent (L(L11) and negative for the other ) and negative for the other
(L(L22) )
•• Need resonances in both Need resonances in both substituentssubstituents
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CamphanicCamphanic AcidAcid
•• propro--((RR) and ) and propro--((SS) positions of ) positions of αα--deuterateddeuterated
primary and secondary alcoholsprimary and secondary alcohols
•• Primary amines as wellPrimary amines as well
O
O
OHO
DH
Ph
HD
HO N
O
O
OH
D H
H Ph
D
D
R
H
OH
H
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22--(2,3(2,3--Anthracenedicarboximido)Anthracenedicarboximido)--
cyclohexane carboxylic acidcyclohexane carboxylic acidN
O
O
HOOC
N
O
O
(Me)(Me)
Me
MeO
∗
O
N
O
O
O
O
Analysis of primary and secondary alcohols –especially effective for compounds with remotely disposed chiral centers
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2,2,22,2,2--TrifluoroTrifluoro--11--(9(9--anthryl)ethanol anthryl)ethanol
(TFAE) ((TFAE) (PirklePirkle’’ss Alcohol)Alcohol)
HCF3C OH
Versatile chiral solvating agent-Can determine optical purity-Can assign absolute configurations for certain classes of compounds
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Absolute Configurations Absolute Configurations -- TFAETFAE
O
H
C
O
Si-propyl
CH3
C6H5
CF3 H
O
H
C
O
SCH3
i-propyl
C6H5
CF3 H
(R, R) (R, S)
N
CH3
CH2
CH3
O
H
C
CF3H
O
C
H
O
CF3
H
C
H
C
O
OCH3
N
H3CH H
C
H
O
CF3
H
C
CH3
C
O
OCH3
N
HH H
Sulfoxides
N-oxides
Amino Acids
Page 33
Absolute Configurations Absolute Configurations -- TFAETFAE
O
C
Ph
CF3
H
H
N
O
CA, B
R
O
C
Ph
CF3
H
H
N
O
CA, B
R
C N
CCH3H
Ph
Me2
Me1
H
O
C
R1
H CF3
C N
CPh
H
CH3
Me2
Me1
H
O
C
R1
H CF3
(R, R) (R, S)
H O
O
C
H
Ar
F3C
O
C R1
R2
H O
O
C
H
Ar
F3C
O
C R2
R1
Oxaziridines Imines
Lactones
NO
Lactams
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TFAE TFAE –– EnantiomericEnantiomeric PurityPurity
C C
O
R2
R3
R1
HO
-O
O
O-
NH2
NH2
N
R2R1
H CH3
OCH3
O
1 2 3Cl CH3 CH3
H H CH3
R1=R2=
O
N N
RR R R
O O
a (R = i-Pr)
b (R = Et)
N
N
X
X = ClX = NO2X = CH3
Epoxides2,3-diamino succinate – methinesignals for meso versus dl-isomers
Axial Chiral Compounds Slow Rotation
Page 35
TFAE TFAE –– EnantiomericEnantiomeric PurityPurity
Cl
Nb
S
S
OCl
Nb
S
S
O
N N
Pd
Cl
Ar Ar
1
O N
Ph P(OCH2CH3)2
O
O N
Ph P(OCH2CH3)2
O
OOPr
Pr
PrOPrO
Cr(CO)3
Metal Complexes
Phosphine OxidesCalixarenes
Page 36
Alcohols as Alcohols as CDAsCDAs for Carboxylic Acidsfor Carboxylic Acids
•• Methyl Methyl mandelatemandelate
•• MentholMenthol
•• 22--(2,3(2,3--anthracenedicarboximido)anthracenedicarboximido)--11--cyclohexanolcyclohexanol
HC COCH3
OH
O
HO N
O
O
HO
Page 37
GlycosidationGlycosidation ShiftsShifts
•• React secondary alcohol with DReact secondary alcohol with D--glucose or glucose or
DD--mannosemannose
•• Pronounced differences in the Pronounced differences in the 1313C NMR C NMR
spectrum that correlate with absolute spectrum that correlate with absolute
configuration configuration –– see trends in both sugar see trends in both sugar
and alcohol resonancesand alcohol resonances
•• Also see differences in the Also see differences in the 11H NMR H NMR
spectrum of secondary alcohols with tetraspectrum of secondary alcohols with tetra--
OO--acetylglucoseacetylglucose
Page 38
ββ--DD-- and and ββ--LL--FucofuranosideFucofuranoside and and
ArabinofuranosideArabinofuranoside
•• Use Use tetraacetatetetraacetate derivative of sugar derivative of sugar
((arabinoarabino easier to prepare)easier to prepare)
•• React with secondary or tertiary React with secondary or tertiary
alcoholalcohol
•• Also works with 1,2Also works with 1,2--glycolsglycols
•• Alkaline hydrolysis of acetate groupsAlkaline hydrolysis of acetate groups
•• See differences in the See differences in the 11H and H and 1313C C
spectra of product that correlate with spectra of product that correlate with
absolute configurationabsolute configuration
O
HO
HO
OH
CHOH
CH3
Page 39
2,22,2’’--DihydroxyDihydroxy--1,11,1’’binaphthalenebinaphthalene
(BINOL)(BINOL)
•• Potential Potential chiralchiral solvating solvating
agent for several classes of agent for several classes of
substrates including alcohols, substrates including alcohols,
sulfoxidessulfoxides, , selenoxidesselenoxides, ,
amines, amines, ketonesketones, amides, , amides,
and amino alcoholsand amino alcohols
OH
OH
OH
OH
O
SCH3 Ph
OH
OH
O
SCH3 Ph
(S) (R)
Page 40
ButaneButane--2,32,3--diol/Butanediol/Butane--2,32,3--thiolthiol
•• ChiralChiral derivatizingderivatizing agent for the analysis of agent for the analysis of
chiralchiral ketonesketones –– produce produce diastereomericdiastereomeric ketalsketals
•• For For cyclohexanonescyclohexanones in the chair conformation, in the chair conformation,
the the 1313C shifts correlate with absolute C shifts correlate with absolute
stereochemistrystereochemistry
O
RSRS
O
O
Me
Me
X
O
O
X = CH2OS
Page 41
PEA, NEA and AEAPEA, NEA and AEACH3CH NH2 CH3CH NH2 CH3CH NH2
Useful with carboxylic acids-chiral solvating agent – formation of diastereomeric salts-chiral derivatizing agent – formation of amides – can assignabsolute stereochemistry with certain compounds
Et N
H
H
Ph
Me
H
Me
HO
H
Me N
Et
H
Ph
H
H
Me
HO
H
H N
Me
H
Ph
Et
H
Me
HO
H
Et N
Me
H
Ph
H
H
Me
HO
H
Me N
H
H
Ph
Et
H
Me
HO
H
H N
Et
H
Ph
Me
H
Me
HO
H
i (major) ii (major') iii (minor)
Page 42
PEA, NEA and AEAPEA, NEA and AEA
•• Phosphorus Phosphorus thioacidsthioacids
•• PhosphonicPhosphonic acidsacids
•• SulfonylSulfonyl chlorideschlorides
•• IsocyanatesIsocyanates
P
OH
SMe
R
P OH
OH
HC
O
R
OH
CH2SO2ClO
OCN
OR'
O
R
Page 43
PEA, NEA and AEA PEA, NEA and AEA -- KetonesKetones
•• Method 1Method 1
–– Convert to acid Convert to acid oximeoxime using NHusing NH22OCHOCH22COOHCOOH
–– Add NEA to form salt Add NEA to form salt –– see discriminationsee discrimination
•• Method 2Method 2
–– Reductively Reductively aminateaminate the the enoneenone with PEA with PEA
perchlorateperchlorate –– see discrimination in productssee discrimination in products
Page 44
PhenylglycinePhenylglycine methyl ester and methyl ester and dimethyldimethyl
amide (PGME)amide (PGME)
Absolute configuration of Absolute configuration of
carboxylic acids carboxylic acids –– ∆δ∆δRSRS valuesvalues
H3CO CHC
O
NH2
HA HB HC
HZ HY HX
H
Z
O Ph H
H O
(H) (Ph) (R)
(S)
PGME (PGDA) plane
α-Substituted
β,β-substituted acidsN
OMe
H O
H O
R2
R1
H
PGME plane
Page 45
PGME PGME -- examplesexamples
OO
H
OH
O
Me H
HOOC
O
COOMe
O
O
H
COOH
HO
COOH
OH
O
O
O
O
O
MeMe
OH
Me
H
H
Me
H
OH
H
H
H
MeH
O
H
H
O
O
OHO
HO
O
Me
Me
H
H
H
Me
H
H
H
H
HO
O Me
H
Page 46
1,21,2--DiphenylDiphenyl--1,21,2--diaminoethanediaminoethane
CH HC
NH2H2N
O
Rn*
H2N NH2
PhPhNHHN
PhPh
n* R
NHHN
PhPh
n* R
3-substituted cyclohexanones and cyclopentanones-forms the corresponding aminal-can determine enantiomeric purity
Page 47
NN,,NN’’--Substituted 1,2Substituted 1,2--diphenyldiphenyl--1,21,2--
diaminoethanediaminoethane
RCHO
Ph Ph
NH HN
N
N
R
Ph
Ph
* **
*
Reacts with Aldehydes-forms the corresponding imidazolidine-can be used to determine enantiomeric purity
Page 48
N-(3,5-Dinitrobenzoyl)-1-phenylethylamine (DNB-PEA)
N-(3,5-Dinitrobenzoyl)-L-leucine(DNB-Leu)
N-(3,5-Dinitrobenzoyl)-4-amino-3-methyl-1,2,3,4-tetrahydrophen-Anthrene (Whelk-O-1)
O2N
O2N
C
O
NH CH
CH3
O2N
O2N
C
O
NHHC COH
O
CH2
CH
H3C CH3
CH3
N O
O2N NO2
H
Amides as Chiral Solvating AgentsSoluble Pirkle LC Phases
Page 49
PhosphorusPhosphorus--based Reagentsbased Reagents
•• P(V) reagents (P=O or P=S) groupP(V) reagents (P=O or P=S) group
•• P(III) reagentsP(III) reagents
•• P(V) reagents are more stable than P(III) P(V) reagents are more stable than P(III) reagents but usually have smaller reagents but usually have smaller enantiomericenantiomericdiscriminationdiscrimination
•• 3131P signal usually monitored P signal usually monitored –– splits into two splits into two singletssinglets for the two for the two diastereomersdiastereomers for for derivatizingderivatizing agentsagents
Page 50
P(V) Reagents P(V) Reagents -- ExamplesExamples
O
P
NCH3
Ph
S
Cl
O
P
NCH3
Ph
O
Cl
CH3
CH3
P
O
OO
ClP
Ph
Cl
O
O
O
P
O
Cl
Ph
N
P N
H
PhO
Cl
-Alcohols and amines react at the chlorine atom
-Primarily used for determining enantiomeric purity
Page 51
Me
NH
PhO
H
Me
PCl
O
+ P
S
OEtO
Me
NH
PhO
H
Me
PO
P
O
S
OEt
Me
NH
PhO
H
Me
PO
P
OEtS
O
+
+
Me
NH
PhO
H
Me
PO
O
P
S
OEt
Me
NH
PhO
H
Me
PO
O
P
S
OEt
=18OO =16O
Configurational analysis of thiophosphatemonoester that is chiral by virtue of different oxygen isotopes
P
S
OEtO
=18OO =16O
18O and 16O in the bridging position have different effects on the shift of the phosphorus resonance
Page 52
PhosphinothioicPhosphinothioic AcidsAcids
P
SPh
Me OH
P
SPh
ButOH
R
P
O
Ph S
H S
P
OH R
Ph R
P
O
Ph S
H S
P
OH Ph
R
Effective chiral solvating agents for:
-Phosphine oxides -Alcohols/Diols-Phosphonates -Amines-Sulfoxides -Thiols-Amine oxides -Amino alcohols
Page 53
P(III) ReagentsP(III) ReagentsNH
NH
Me
Me
Phos13
NH
NH
Me
Me
Phos14
NH
NH
Me
Me
Phos15
CF3
CF3
N
CH3
N
CH3
Phos16
N
CH3
N
CH3
Phos17
N
CH3
N
CH3
Phos18
NH
NH
CH3
CH3
Phos19
N
NH
Phos20
N
N
P Cl
R1
R1
R2
R2 N
N
P N
R1
R1
R2
R2
CH3
CH3
-Primary, secondary andtertiary alcohols
-Thiols-Carboxylic acids-α-hydroxyphosphonates
Page 54
P(III) ReagentsP(III) Reagents
O
P
OR
R
Cl
HO CO2R
CO2RHO
R = Et oriPr
Phos21 Phos22
OH
OH
O
O
OH
HO
Phos23
H3C OH
OHH3C
Phos24
OH
OH
Phos25
O
O
OH
OH
Phos26
OH
OH
Phos27
(CH3)2NC
O
(CH3)2NC
O
-Primary, secondary andtertiary alcohols
-Primary amines-Carboxylic acids
Page 55
[5] HELOL [5] HELOL PhosphitePhosphite
Cl P
O
O
OMe
OMe
MeO
MeO
MeOOMe
OMe MeO
Ph
OH
CH3
-Primary and secondary alcohols
-Phenols-Amines-Carboxylic acidsafter coupling to2-aminophenol
Page 56
TRISPHAT, BINPHAT, BINTROPTRISPHAT, BINPHAT, BINTROP
O P
O
O
O
O O
ClCl
Cl
Cl
Cl
Cl Cl
Cl
Cl
Cl
ClCl
O
P
O
O
O
O
O
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
O
O
P
O
O
O
O
Useful for ionic compounds
Page 57
TRISPHAT TRISPHAT –– Metal ComplexesMetal Complexes
NN
N N
Fe
3
2+
7.62
Cp*M
O
R
+
Mn(CO)3
R2
R1
R''
Cr(CO)3
Ru S
Me
I(depe)2
N
(OC)3Cr Pd
Cl
py
NRu
Ru
O
O
O
O
OO
(R)
(S)
Page 58
TRISPHAT, BINPHAT TRISPHAT, BINPHAT –– Other Other CationsCations
N N
S4D2
P CH3
CD3
O
Me
N
N
N N
X
N N
X
X = Br, H
N NPrPr
OMeMeOBF4
S
Me
Page 59
BINTROP BINTROP
–– Limited studies on anionsLimited studies on anions
R
R
O
O
B
t-Bu
t -Bu
O
O O
O
O O
O
O
O
OO
O
N
N
N
N
Page 60
Configuration of PhosphatesConfiguration of Phosphates
•• React (React (cyclizecyclize) with ) with
propanepropane--1,21,2--dioldiol
•• React (React (cyclizecyclize) with ) with
(S)(S)--22--iodoiodo--11--
phenylethanolphenylethanol
O
PO
∅CH3O
OCH3
PO
∅O
O
PO
∅CH3O
OCH3
PO
∅O
∅
PO
OCH3O
∅CH3
PO
OO
∅ = 17O = 18O
S P
OH
H
Ph
O
Ø
S
P
OH
PhO
MeS
P
OH
Ph Ø
OMeS
P
OH
Ph
ØMe
S
P
OH
PhOMe
S
P
OH
PhØMe
OS
P
OH
Ph
Ø
Me
Page 61
SeleniumSelenium--containing Reagent containing Reagent 7777Se NMRSe NMR
N OH
Se
Ph
R-OH or R-Br N O
Se
Ph
R
N OH
Se
Ph
-Carboxylic acids – react at NH group-Alcohols and alkyl halides react at selenium
atom-Amines with triphosgene react at the NH
group
S
S
OH
O
H
Effective for compounds with remotely disposed chiralcenters – because of shift range of 77Se NMR
Page 62
αα--, , ββ-- and and γγ--CyclodextrinsCyclodextrins
O
HO OH
O
OH
123
4
5
6
Native – underivatized-Water-soluble-Effective for water-soluble substrates-Determination of enantiomeric purity -Substrates usually contain an aromatic ring (phenyl or bicyclic)
Page 63
CyclodextrinsCyclodextrinsPermethylated cyclodextrins-β-Derivative is more water-soluble than native β-CD-Organic-soluble as well-Broadly applicable for determining enantiomeric purity-Especially useful for the analysis of allenes
C CC
R3
H
R1
R2
Carboxymethylated (-CH2CO2-) cyclodextrins - Anionic
-Especially useful for organic cations-Can add paramagnetic lanthanides – these associate at the carboxy group and cause shifts inthe spectra that enhance the enantiomericdiscrimination
Page 64
Crown EthersCrown Ethers(18-Crown-6)-2,3,11,12-tetracarboxylic acid
O
O
O
OO
O
COOH
COOH
HOOC
HOOC
O
O
O
OO
O
H H
N
R
H
Useful for primary amines-As hydrochloride salts-As neutral amines (neutralization reaction with crown ether)
-In methanol, acetonitrile, or water(usually best in methanol)
Page 65
Crown EthersCrown Ethers(18-Crown-6)-2,3,11,12-tetracarboxylic acid
O
O
O
OO
O
H H
N
HOOC
HOOC COOH
O
O
R R'
Useful for secondary amines-As neutral amines (neutralization reaction with crown ether)
-In methanol-Effective for pyrrolidines, piperidines, piperazines,alkyl aryl amines
Page 66
Calix[4]resorcarenesCalix[4]resorcarenes
RR R
RR
(a) (b)
(c) (d)
CH2
N
OH
O
HO OH
HC
CH2
CH2
SO3 4
Sulfonated analog with L-prolinegroups-Water-soluble-Effective for mono or bicyclicaromatic compounds – singly orortho-substituted
Page 67
Lanthanide Lanthanide tristris((ββ--diketonatesdiketonates))
O
CF3
O
O O
O
CF2CF2CF3
O
tfc
hfc
dcm
Organic-soluble
Page 68
•• Suitable for a wide range of hard Lewis bases Suitable for a wide range of hard Lewis bases ––
oxygenoxygen-- and nitrogenand nitrogen--containing compounds containing compounds ––
metal complexes with binding groups in metal complexes with binding groups in ligandsligands
•• ParamagnetismParamagnetism of lanthanide ions does cause of lanthanide ions does cause
broadening broadening –– worse at higher field strengthsworse at higher field strengths
–– Use a lower field instrument (300 MHz or lower)Use a lower field instrument (300 MHz or lower)
–– Run Run 1313C spectraC spectra
–– Use Use Sm(IIISm(III) ) chelateschelates
–– Use a polar solventUse a polar solvent
–– Warm the sample (50Warm the sample (50--7575ooC)C)
Page 69
““ChiralizationChiralization”” of Xenonof Xenon
MeO O
O MeO
(CH2)2
O OMe
(CH2)2
O OMe
OMe MeO O O
(CH2)2
-Racemic cryptophane binds xenon in the cavity-Addition of Eu(hfc)3 causes the appearance of two 129Xe signals
Page 70
Lanthanides Lanthanides -- Absolute ConfigurationAbsolute Configuration
Empirical TrendsEmpirical Trends
•• Alkyl aryl Alkyl aryl carbinolscarbinols
•• BenzhydrolsBenzhydrols
•• 22--Aryloxypropionyl derivativesAryloxypropionyl derivatives
•• Amino acid methyl estersAmino acid methyl esters
•• MenthylMenthyl butanoatesbutanoates
•• NN--phthaloylphthaloyl--αα--methylcyanoglycinatesmethylcyanoglycinates
•• LactonesLactones
•• EpoxidesEpoxides and and arenearene oxidesoxides
Page 71
Secondary and Tertiary Secondary and Tertiary CarbinolsCarbinols
•• Use Pr(hfc)Use Pr(hfc)33
•• Measure Measure 1313C NMR spectrumC NMR spectrum
•• Examine shifts of neighboring carbonsExamine shifts of neighboring carbons
•• Works for Works for diolsdiols as well if separated by two or as well if separated by two or
more carbonsmore carbons
Me OH
Me MeMe Me Me MeOH OH OH OH
4
R OH
Y X
α-orientation∆∆δ = negative
HO R
Y X
β-orientation∆∆δ = positive
∆∆δ = ∆δ(R)-Pr(tfc)3 - ∆δ(S)-Pr(tfc)3
Page 72
Binuclear LanthanideBinuclear Lanthanide--Silver Silver
ReagentsReagents
•• Effective for soft Lewis basesEffective for soft Lewis bases
–– OlefinsOlefins
–– AromaticsAromatics
–– AlkynesAlkynes
–– PhosphinesPhosphines
–– Halides (iodide and bromide)Halides (iodide and bromide)
Ln(β-dik)3 + Ag(β-dik) = [Ln(β-dik)4]Ag
Page 73
Binuclear LanthanideBinuclear Lanthanide--Silver Silver
Reagents Reagents –– Organic SaltsOrganic Salts
•• Ammonium saltsAmmonium salts
•• IsothiouroniumIsothiouronium saltssalts
•• SulfoniumSulfonium saltssalts
[Ln(β-dik)4]Ag + R+X- = [Ln(β-dik)4]R + AgX(s)
Page 74
Lanthanide Complexes Lanthanide Complexes
WaterWater--solublesoluble•• ChelatesChelates of of pdtapdta (anionic (anionic ligandligand))
•• ChelatesChelates of of tppntppn (neutral (neutral ligandligand))
•• Effective for carboxylic acids Effective for carboxylic acids –– absolute absolute configurations of amino acidsconfigurations of amino acids
N
N
CO2H
CO2H
HO2C
HO2C
N N
NN
N N
H3C
Page 75
PalladiumPalladium--Amine Amine DimersDimers
Pd
Cl
NMe2Me
Pd
Cl
Me2N Me
Pd
Cl
NMe2Me
Pd
Cl
Me2N Me
cis
trans
Pd
ClPd
Cl
cis
NMe2 Me2N
Me Me
Pd
Cl
trans
NMe2
Me
ClPd
Me2N
Me
Pd
N
P
P
Me2H
Me
* Cl-
-Mono- and diphosphines bind to the palladium-Can use for enantiomeric purity and absolute configuration (often with NOE data)
Page 76
Palladium/Platinum ComplexesPalladium/Platinum Complexes
P
PO
O
M
Ph2
Ph2
P
P
Pt
Ph2
Ph2
-Alkenes and alkynes can displace the ethylene ligand
-Enantiomeric purity
Page 77
PlatinumPlatinum--Amine ComplexesAmine Complexes
Covalent and IonicCovalent and Ionic
Pt
Cl
Cl
H2N
HC
Ph
CH3 Pt
Cl
Cl
Cl
[AmH]+
-Olefins and allenes displace the ethylene group-Measure 195Pt signal - used for enantiomeric purity-Substrates have two prochiral faces-If only one face binds – two 195Pt signals-If both faces bind – four 195Pt signals
Page 78
PlatinumPlatinum--Amine Amine
ComplexesComplexes
CDA Am enantiodiscriminatedsubstrates
Pt
Cl
Am Cl
cisNH2
H
Me
Ph
unsaturated ethers
Pt
Cl
Cl Am
transNH2
H
Me
Ph
selected cases of allenes
Pt
Cl
Cl Cl
ionic
AmH+
NH
Me N 1 - Np
Me
H
H
1 - Np
H allenes, olefins, vinyl and allylethers
β-olefins
Pt
Cl
Cl Am
trans
NHα-olefins
Page 79
Rhodium Rhodium DimerDimer with MTPAwith MTPA
O
Rh
O
O O
R
R
OO
R
OO
R
Rh
O
Rh
O
O O
R
R
OO
R
OO
R
Rh
O
Rh
O
O O
R
R
OO
R
OO
R
RhL
+ L
- L
+ L
- L
L L
OO
Rh
O
Rh
O O
OO
R
R
R
O
R
RO2 = MTPA
Page 80
Rhodium Rhodium DimerDimer with MTPAwith MTPA
•• OlefinsOlefins
•• PhosphinesPhosphines
•• Aryl alkyl Aryl alkyl selenidesselenides
•• PhosphinePhosphine selenidesselenides (P=Se)(P=Se)
•• Phosphorus Phosphorus thionatesthionates (P=S)(P=S)
•• PhospholenePhospholene and and phospholanephospholane chalcogenideschalcogenides
•• SpirochalcogenuranesSpirochalcogenuranes
•• Alkyl iodides, Alkyl iodides, diiodobiphenylsdiiodobiphenyls
•• NitrilesNitriles
•• OxiranesOxiranes
•• OxatriazolesOxatriazoles, , thiatriazolesthiatriazoles, , tetraazolestetraazoles
PR
PhX
X = O, S, Se
O
Ch
O
CH3H3C
H3C CH3
Ch = S, Se, Te
H3C
X
R
H3C
X'
R
I
I
O R
H2
H3'
H3
N
NO
N
N
Ph
HC
CH3
Page 81
Zinc Zinc PorphyrinsPorphyrins ((TweezerTweezer))
ZnNN
N N
ZnNN
N NO
O
O
O
Especially effective for bifunctional substrates (diamines)
Page 82
Database TechniquesDatabase Techniques
•• 1313C or C or 11H shiftsH shifts
•• NN,,αα--DimethylbenzylamineDimethylbenzylamine (DMBA)(DMBA)
•• BisBis--1,31,3--methylbenzylaminemethylbenzylamine--22--
methylpropane (BMBAmethylpropane (BMBA--pMepMe))
H3CHC N
CH3
CH3
HN
HN
Me
Me
Me
Page 83
Structural MotifsStructural MotifsOH OH
Me Me
OH OH OH
AcO
OAc
OAc OAc
OH
Me
OH OAc
Me
OAc
HO Me
OH
Me
OH
Me
Prepare and examine all possible stereoisomers
Page 84
13C or 1H Database -subtract chemical shiftof particular nucleus in one stereoisomer from average of value in all eight
Page 85
DMBA database-Difference in 13C shifts between (R)-and (S)-DMBA
Page 86
saturated secondaryalcohols
(acyclic and cyclic)
∆δ =negative
∆δ =positiveC C
OHA
biaryl alcohols &benzyl alcohols ∆δ =
positive∆δ =
negativeC C
OHB
saturated tertiaryalcohols ∆δ =
positive∆δ =
negativeC C
OHC
Me
H
O
H
N
H
N
Ph
Ph
Me
Me
BMBA-pMe – For assigning the stereochemistry of secondary and tertiary alcohols
Binding of BMBA-pMeto a secondary alcohol
Observed trends
Page 87
Liquid CrystalsLiquid Crystals
poly(poly(γγ--benzylbenzyl--LL--glutamate) (PBLG)glutamate) (PBLG)
•• Forms ordered material in a magnetic fieldForms ordered material in a magnetic field
•• Pair of Pair of enantiomersenantiomers have different have different
molecular orientations in PBLGmolecular orientations in PBLG
•• Three discrimination mechanismsThree discrimination mechanisms
–– Chemical shift anisotropy (least useful)Chemical shift anisotropy (least useful)
–– Different dipolar coupling constants (Different dipolar coupling constants (11HH--1313C)C)
–– Differences in Differences in quadrupolarquadrupolar splitting (splitting (22H) (most H) (most
useful)useful)
Page 88
QuadrupolarQuadrupolar SplittingSplitting•• Not observed in solution because of rapid Not observed in solution because of rapid
tumblingtumbling
•• Observed in ordered media and extent of Observed in ordered media and extent of
splitting depends on orientation relative to the splitting depends on orientation relative to the
applied magnetic fieldapplied magnetic field
Proton-decoupleddeuterium NMR spectrum
Page 89
PBLG PBLG -- Incredible VersatilityIncredible Versatility
•• Only need different packing ordersOnly need different packing orders
•• Do not need specific interactions between Do not need specific interactions between the substrate and the liquid crystalthe substrate and the liquid crystal
•• Effective for virtually any class of Effective for virtually any class of compoundcompound
–– Includes aliphatic hydrocarbonsIncludes aliphatic hydrocarbons
•• Especially effective for resonances of Especially effective for resonances of nuclei remote to the nuclei remote to the chiralchiral centercenter
Page 90
Deuterium LabelingDeuterium Labeling
•• Only need deuterium as a signal Only need deuterium as a signal –– better better
to use to use achiralachiral reagents so no concern reagents so no concern
about kinetic resolution or about kinetic resolution or racemizationracemization
–– Convert COConvert CO22H to COH to CO22CDCD33
–– Add Add perdeuteroperdeutero benzoylbenzoyl group (have ogroup (have o--, m, m--
and pand p--protons as potential probesprotons as potential probes
•• Provides a single, strong signal (or a few Provides a single, strong signal (or a few
easily assigned signals) for the analysiseasily assigned signals) for the analysis
Page 91
ExamplesExamples
O
SS
O D D D
D
D
D
D
4
DHO
DOH
D
D D
OH
HOOH
-Remote chiral center-2H signal for the para-positionshowed different quadrupolarsplitting
(R,R)-, (S,S)- and (R,S)-(meso)-isomer distinguished
Can distinguish (R,R,R)-, (R,R,S)-, (S,S,R)- and (S,S,S)-isomers
Page 92
PerdeuteratedPerdeuterated/Natural Abundance /Natural Abundance 22HH
•• Complicated spectraComplicated spectra
–– each each 22H signal is a doubletH signal is a doublet
–– each each 22H signal may be two doublets if the H signal may be two doublets if the enantiomersenantiomers have different have different quadrupolarquadrupolarsplittingsplitting
–– cancan’’t predict a priori the magnitude of the t predict a priori the magnitude of the quadrupolarquadrupolar splittingsplitting
•• Procedures have been devised to aid in Procedures have been devised to aid in the assignment of the assignment of 22H spectraH spectra