-
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 1 of 11.
Date: February 20, 2012
Chapter 14 Aldehydes and Ketones: Addition Reactions at
Electrophilic Carbons
Overview of Chapter 14 1. Structures of aldehydes and
ketones
CR
R'O R, R' = alkyl, aryl: ketonesR = alkyl, aryl; R' = H:
aldehydesδ
δ
electrophilic CAldehyde C=O carbons are lesssterically hindered
and more electrophilic compared with the corresponding ketone
carbons (i.e., with the same R)
lone pair: more basic than C=O π
2. Reactions of aldehydes and ketones with an electrophile and a
nucleophile
CR'
RO
σ−frameworklone pairs
all of these sigma-bonds and lone pairs on thesame plane
El+with this trajectory
π-bonding
Highest occupied molecular orbitals
(HOMOs) of the C=O group
CR'
RO
emptyanti-bondingorbitals
Lowest unoccupied molecular orbital
(LUMO)
Nu:
trajectory ofa nucleophileapproach
trajectory angle of 107°
CR'
RO
Nu
CR'R
O
Nu
sp3between sp2 and sp3;on its way to sp3
CR
R'O
El
all atoms including Elon the same plane
Two lone pairs:
3. Activation of RR’C=Z (Z = O and N) with H-A or a Lewis acid →
activates C=O toward a nucleophilic addition
O OH A
becomes even more δ ; i.e., more electrophilic
OH A
H A
Lewis acid (L.A.)
OL.A. O
L.A.O
M
(if M+ is used)or
-
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 2 of 11.
Date: February 20, 2012 Chapter 14: Overview (continued) 4. Four
categories of nucleophilic addition reactions Two classes of
nucleophiles: reversible and irreversible
O
Reversible Nu: Irreversible Nu:
Type 1H M
O HM H3O
H2O
HO H
Type 2R O RM HO R
RO OR HO OR
HO N
or
e.g.,RLi,RMgX(Grignard reagent)
Type 3divalent Nu:
e.g.,ROH, RSH
SN1
N RH
RE1
Type 4
Trivalent Nu:
e.g., R-NH2
H3O
H2Oor
==============================================================
I. Nucleophilic Addition Reactions of RR’C=Z (Z: electronegative
atom)
-
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 3 of 11.
Date: February 20, 2012 I-1 (1) Hydride reducing agents
(cont’d)
OO
H
AlH
HH
Li
H3O OH
H+ LiOH + Al(OH)3
All of these three Hs could be used in the reduction of a
ketone.
Reduction with LiAlH4:
LiAlH4
OLi
H AlH
HH
OLi
AlHHH
note: O-Al bond stronger than O-Li
hydrolysis*
*This acid-hydrolysis step may be quite complex, depending upon
the stoichiometry betweena ketone and LiAlH4. However, all of those
hydrolysis step should involve
O
H
AlX
XX
H
anhyd. aproticsolvent (e.g., THF)
X: OH or ORReduction with NaBH4:
OOH
H
NaBH4usually in a protic
solvent (e.g., ethanol)O
NaH B
HH
H
ONa
H OR
+ BH3 reacts with the solvent 3 x RO-H to formB(OR)3 and 3 x
H2
Reduction with DIBAL (Al in DIBAL quite Lewis acidic):
OO
H
Al H3O OH
H+ Al(OH)3 + 2 (H3C)3CH
DIBAL
OAl
hydrolysisanhyd. aproticsolvent (e.g., THF)
AlH
H
O
H
AlO
H
AlC
HOH2O H2O
H2O
H3O
HH
HO
HH
Li AlH4
Na BH4Na OR
O
not very favorable;Na+ not much Lewis acidic
-
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 4 of 11.
Date: February 20, 2012 I-1. Irreversible nucleophiles (cont’d)
+
+
++
(b) R nucleophiles: Type 2
O
Could be sp3, sp2, sp carbanions
Grignard reagents (R-MgX)
alkyllithium (R-Li) or sodium (R-Na)
alkenyl lithium (C=CHLi)
alkynyl lithium/sodium or lithium/sodium acetylide (C C-Li; C
C-Na)
R Manhydrous
aprotic solvent
O
R
M H3Ohydrolysis
O
R
H
M(OH)
Grignard reagents: R-MgX (X is usually Br or I, sometimes
X=Cl)
H3C BrMg*
anhydrousTHF or etherδ δ
δ δH3C Mg Br
δH3C Mg Br
2
Formally equivalent to:
polarization reversal
* R X Mg R• •Mg-Xoxidation #: 0 oxiudation #: +2
Prepration of Grignard reagents:(i) Alkyl Grignard reagents from
R-X
(ii) Alkynyl Grignard reagents:
CH3C C HpKa ~26
H3CCH2MgBr CH3C C MgBr
CH3C C MgBr
H3C CH
HH
pKa ~50
+
CH3C C Hnote:
Na, liq NH3or NaNH2, liq NH3
CH3C C Na
Br MgBr
(iii) Alkenyl and aryl grignard reagents from their halide
precursors
Mgusually in anhydrous
THF
Br MgBrMg
anhydrousTHF or ether
note:
Li Li-Br
2 Li
alkenyllithiumCyanide carbanion - often reversible
nucleophile
ONaCNH2O
O
CN
Na H3O OH
CN
electronegativity values: C (2.5); H (2.1); Li (1.0); Na (0.9);
Mg (1.2); Al (1.5); Br (2.8)
R-Mg-X
-
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 5 of 11.
Date: February 20, 2012
Chapter 14 I-1. Irreversible nucleophiles
δ
δ+ Mg(OH)2
(b) R M (Type 2; organometallic reagents) (cont'd)Note:
Reactions with epoxides
OH PhMgBr OH
Ph
OHH
Ph
MgBr
PhSN2!
work-upwith
aq NH4Cl*
*NH4Cl: weakly acdic; pKa ~9.7; commonly used for the work-up of
organometallic reactions; the only exception is the work-up of a
carboxylate product (you need to acdity the solution to
pH~1-2).
Ph MgBr OMgBr
CO
PhO
CO
Ph CO
O HH3OpH 1-2
+ Br
pKa 4.2
Not with aq NH4Cl!
I-2. Reversible nucleophiles
Type 3: Divalent nucleophiles (ROH & RSH); requires an acid
catalyst Type 4:
Trivalent nucleophiles (R-NH2 & RR'NH); w/o activation by an
acid
+O
ketone
oxygen atom
ROH, H or L.A. OH
OR
OR
OR
ROH, H or L.A.H2O
+H
O
aldehyde
oxygen atom
ROH, H or L.A.
H
OH
OR H
OR
OR
ROH, H or L.A.H2O
hemiketal
hemiacetal
ketal
acetal
Tend to be unsatble intermediates!
+O
ketone
oxygen atom
RSH, H or L.A. OH
SR
SR
SR
RSH, H or L.A.H2O
+H
O
aldehyde
oxygen atom
RSH, H or L.A.
H
OH
SR H
SR
SR
RSH, H or L.A.H2O
hemithioketal
hemithioacetal
thioketal
thioacetal
(a) ROH (alcohols)
(b) RSH (thiols or mercaptans)
meaning"mercury capturers"
-
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 6 of 11.
Date: February 20, 2012
Chapter 14: I-2. Reversible nucleophiles (cont’d)
+
(c) Mechanism (similar for both ROH and RSH nucleophile
additions)
O H3CO OCH3H2O
CH3OH, p-TsOH (catalytic)
SHSH
BF3•O(CH2CH3)2(catalytic) + H2O
SS*p-TsOH (or TsOH) para-toluenesufonic acid; strong,
organicsolvent-soluble acid.
H3C S OO
OH
pKa ~-1
**
*
OBFF
F
**boron trifluoride diethey etherate;gives better yields of
thioketals & thioacetals than p-TsOH
Ts Not a base!
-------------------------------------
Since ROH and RSH are not nucleophilic enough to add to a C=O,
the C=O has to be activated by the use of H+ or a Lewis acid.
Incidentally, their conjugate bases, RO-/RS- can add (quite easily
as being highly nucleophilic) to the C=O, but the adducts are less
stable than the original C=O, thus reverse back to the C=O and RO-
/RS-.
Mechanism using H-B for the acid catalyst, p-TsOH:
+
O
H3CO OCH3
H BO
B
HO
B
H
HO
CH3O
H
OH
CH3
B
OH
OCH3
HBO
H
OCH3
H
lone pair-assistedionization!!
H2O
H2O
O CH3
O CH3
SN1!
resonance-stabilizedoxoniom
ionHO
CH3
OCH3
OCH3
HB
H B
BB
dimethyl ketal
-
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 7 of 11.
Date: February 20, 2012
Chapter 14: I-2. Reversible nucleophiles: Mechanism (cont’d)
Comments:1. The ketalization and acetalization reactions from
ketone and aldehyde, respectively, under acid- catalyzed conditions
are reversible. High yields of ketals and acetals can be achieved
by the use of excess alcohols and/or continuous removal of the
resulting water (using, e.g., a Dean-Stark apparatus).2.
Conversely, if a ketone or aldehyde is desired from its
corresponding ketal or acetal, a large excess of water needs to be
added to the solution of ketal of acetal in the presence of an acid
catalyst.3. Throughout the mechanism for the acid-catalized
ketalization and acetalization, DO NOT involve negatively-charged
intermediates. The only negatively charged species allowed is the
conjugate base (:B-) of a strong acid catalyst.Lastly,
OH
OCH3
HH3CO OCH3
Does not involve an SN2 step!
OH
OCH3
H
H O CH3
x
Representative reactions:
+
+
H
O
OH
OH(excess)
p-TsOH(catalytic)
ΔH
O OH2O
(1) cyclic acetal formation
(2) cyclic thioacetal formation
+H
O
SH
SH(excess)
BF3•O(CH2CH3)2(catalytic)
Δ
HS S
H2O
(3) cyclic ketal formation from diols: acetonide formation
OH
OH H3C
H3CO
acetone
(excess)
O
O CH3
CH3H2O
p-TsOH(catalytic)
Δ
+H3C
H3C
(excess)
O
O CH3
CH3p-TsOH(catalytic)
+H2C
H3CO
(excess)
O
O CH3
CH3p-TsOH(catalytic)
OO
CH3CH3
O CH3H2
CH3
O CH3H
milderreaction
conditions
called (5-membered) acetonide (i.e., acetone adduct)
Mechanism?
-
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 8 of 11.
Date: February 20, 2012 Chapter 14: I-2 reversible
nucleophiles-ROH/RSH Representative reactions (cont’d)
(4) Transketalization reaction: Spiroketal formation
+
OCH3H3CO
OH H
O
DIBAL ( 2 mol equiv)
mild workupwith aq NH4Cl
OCH3H3CO
OHHO
p-TsOH(catalytic)
Δ
O O2 HOCH3
spiro system
By boiling off methanol, this spiroketal can be obtained in high
yield.
Mechanism for the spiroketalization step:
(5) Hydrolysis of ketals and acetals - Acid-catalyzed
ketal-acetal formation reactions from, respectively, ketones and
aldehydes are reversible. Therefore, treatment of ketals or acetals
with an acid and excess water should produce their corresponding
carbonyl compounds. This process is called “hydrolysis.” Mechanism
of the reaction is exactly the same as the formation of ketals and
acetals except going to the opposite direction.
O
O
H
extremely acidunstable
p-TsOH(catalytic)
H2O(excess)
This reaction does not need to be heated!
OH
OH
H
O+
Mechanism for the hydrolysis shown on the next page.
-
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 9 of 11.
Date: February 20, 2012 Chapter 14: I-2 reversible
nucleophiles-ROH/RSH Representative reactions (cont’d)
(5) Hydrolysis of ketals and acetals:
Mechanism:
O
O
HH B
O
O
HH
O
OH
HHO H O
OH
H
O
H
H
B
O
OH
H
O H
HB
O
OH
H
O H
H
OH
OH
H
O
+
H
B
H
O
lone pair-assistedionization!
lone pair-assistedionization!
============================================ The “take-home
message:”
Lone pair-assisted ionization!
O OR'R
O OR'R
HO O
R'R
HH B +
SN1!
O OR''R
HOR"
Not an SN2!!
-
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 10 of 11.
Date: February 20, 2012
Chapter 14 I-2. Reversible nucleophiles (cont’d)
Type 4 nucleophiles: Trivalent nucleophiles
Amines are sufficiently nucleophilic enough to add to ketone and
aldehyde C=O carbons without activation of the C=O oxygen atom by
an acid. However, the last dehydration step from the aminol
intermediates requires an activation of the hydroxyl oxygen atom
(by H+ or L.A.). (1) Imine formation [from a ketone/aldehyde and a
1°-amine]
+O
HH2N CH3
N
H
CH3+ H2O
imine1°-aminealdehyde
Δ
or H+
Mechanism:
O
HH2N CH3
O
H N CH3H H
H BOH
H N CH3H
H BO
H N CH3
H
H
H B
O
HN CH3
H
HH
aminol
H
NCH3
H
B
N
HCH3
imine
These two steps may be reversed in order.
Those RR’C=N-Z formation reactions from RR’C=Os have the optimum
rate at around pH = 4.7. If the conditions are too acidic, the
formation of such derivatives becomes slow, presumably due to the
exclusive protonation of an amine, thus depriving the
nucleophilicity of an amine. Although the protonation is required
for the dehydration from the aminol intermediate, the formation of
these RR’C=N-Z compounds can be achieved even without adding an
acid catalyst, especially when the reaction involves an aldehyde
(often heating is required to complete the reaction, though).
Amazingly, the formation of hydrazones (RR’C=NNH2) can be achieved
under basic conditions with strong heating.
-
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 11 of 11.
Date: February 20, 2012
Chapter 14 I-2. Reversible nucleophiles: Type 4 nucleophiles
(trivalent nucleophiles) (cont’d)
(2) Oxime formation
O H2N NOH
+ +Δ
or Δ, H+
oxime
H2O
(3) Hydrazone formation
O NNH2
+ +Δ
H2Oor Δ, H+
OHhydroxylamine
H2N NH2hydrazine
hydrazone Application: Wolff-Kishner reduction Reduction of
RR’C=O to RR’CH2
O
H2N NH2KOH, Δ
H H
NN
HH
hydrazone
OHN
NH
H OH NN
H
H
OH
H H OH
N2 (gas)
ketone methylene
An alternative method for the formation of a methylene group
from a C=O:
Reduction of thioacetal/thioketal derivatives with Raney Ni.
OS
S
H
H
HS
HSBF3•O(CH2CH3)2
Raney Niethanol, Δ
thioketal
Type 3 reversible nucleophile!