Chem 215 F12 Notes – Dr. Masato Koreeda - Page 1 of 11.
Date: September 19, 2012
Chapter 14 Aldehydes and Ketones: Addition Reactions at Electrophilic Carbons
Overview of Chapter 14
1. Structures of aldehydes and ketones
electrophilic C
δ
R
C
R'
R, R' = alkyl, aryl:
R = alkyl, aryl; R' = H:
O
δ
Aldehyde C=O carbons are less
sterically hindered and more electrophilic
compared with the corresponding ketone
carbons (i.e., with the same R)
ketones
aldehydes
lone pair: more basic than C=O π
2. Reactions of aldehydes and ketones with an electrophile and a nucleophile
trajectory angle of 107°
Nu:
π-bonding
trajectory of
a nucleophile
approach
lone pairs
σ−framework
R
all of these sigma-bonds
and lone pairs on the
same plane
C
R'
O
with this trajectory
El+
Two lone pairs: Highest occupied
molecular orbitals
(HOMOs) of the C=O group
R
empty
anti-bonding
orbitals
R
C
R'
Lowest unoccupied
molecular orbital
(LUMO)
Nu
Nu
C
O
R'
R
El
R
C
R'
O
R'
all atoms including El
on the same plane
O
sp3
C
O
between sp2 and sp3;
on its way to sp3
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
O
H A
O
H A
H A
becomes even more δ
Lewis
acid
(L.A.)
O
L.A.
; i.e., more electrophilic
O
L.A.
O
or
M
(if M+ is used)
Chem 215 F12 Notes – Dr. Masato Koreeda - Page 2 of 11.
Date: September 19, 2012
Chapter 14: Overview (continued)
4. Four categories of nucleophilic addition reactions
Two classes of nucleophiles: reversible and irreversible
Irreversible Nu:
Reversible Nu:
RO
OR
HO
SN1
OR
Type 3
divalent Nu:
M
O
H
H3O
or
H2O
HO
H
R
M
e.g.,
RLi,
RMgX
(Grignard reagent)
O
R
H3O
or
H2O
HO
R
Type 1
O
H M
e.g.,
ROH, RSH
N
R
HO
E1
H
N R
Type 4
Trivalent
Nu:
e.g., R-NH2
Type 2
==============================================================
I. Nucleophilic Addition Reactions of RR’C=Z (Z: electronegative atom)
Chem 215 F12 Notes – Dr. Masato Koreeda - Page 3 of 11.
Date: September 19, 2012
I-1 (1) Hydride reducing agents (cont’d)
Reduction with LiAlH4:
H
O Al H
H
H
Li
LiAlH4
O
anhyd. aprotic
solvent (e.g., THF)
Li
OH
H 3O
hydrolysis*
H
+ LiOH + Al(OH)3
All of these three Hs could be used in the reduction of a ketone.
AlH4
H
Al
H
H
H
Al H
H
H
O
O
Li
Li
note: O-Al bond stronger than O-Li
*This acid-hydrolysis step may be quite complex, depending upon the stoichiometry between
a ketone and LiAlH4. However, all of those hydrolysis step should involve
H
O
H
Reduction with NaBH4:
X
Al X
X
X: OH or OR
O
usually in a protic
solvent (e.g., ethanol)
H
H
B
OH
NaBH4
H
O
O
Na
H
Na OR
H
H
O
Na
BH4
not very favorable;
Na+ not much Lewis acidic
OR
+ BH3
Na
reacts with the solvent 3 x RO-H to form
B(OR)3 and 3 x H2
Reduction with DIBAL (Al in DIBAL quite Lewis acidic):
O
O Al
DIBAL
anhyd. aprotic
solvent (e.g., THF)
hydrolysis
H
H
Al
OH
H 3O
H2O
HO
O Al
H
+ Al(OH)3 + 2 (H3C)3CH
H
H 2O
H 2O
O Al
H
H3O
O
Al
H
H
C H
H
H
O
H
Chem 215 F12 Notes – Dr. Masato Koreeda - Page 4 of 11.
Date: September 19, 2012
I-1. Irreversible nucleophiles (cont’d)
(b) R nucleophiles:
Type 2
O M
R M
O
anhydrous
aprotic solvent
O H
H3O
hydrolysis
R
R
+ M(OH)
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)
Grignard reagents: R-MgX (X is usually Br or I, sometimes X=Cl)
electronegativity values: C (2.5);
H (2.1); Li (1.0); Na (0.9);
Mg (1.2); Al (1.5); Br (2.8)
Prepration of Grignard reagents:
(i) Alkyl Grignard reagents from R-X
δ δ
δ
H3C Mg Br
Mg*
Br
δ
H3C
δ
Formally equivalent to:
anhydrous
THF or ether
+ Mg
H3C
2
+ Br
polarization reversal
*
R
X
R•
Mg
•Mg-X
R-Mg-X
oxiudation #: +2
oxidation #: 0
(ii) Alkynyl Grignard reagents:
H3CCH2MgBr
H3C C C H
MgBr + H3C
H3C C C
pKa ~26
H
C H pKa ~50
H
H3C C C MgBr
note:
Na, liq NH3
or NaNH2, liq NH3
H3C C C H
H3C C C
Na
(iii) Alkenyl and aryl grignard reagents from their halide precursors
Br
note:
Mg
Br
usually in
anhydrous
THF
2 Li
Li
+
MgBr
Mg
anhydrous
THF or ether
MgBr
Li-Br
alkenyllithium
Cyanide carbanion - often reversible nucleophile
O
NaCN
H2O
O
C
Na
H3O
OH
C
N
N
Chem 215 F12 Notes – Dr. Masato Koreeda - Page 5 of 11.
Date: September 19, 2012
Chapter 14 I-1. Irreversible nucleophiles
(b) R M (Type 2; organometallic reagents) (cont'd)
Note: Reactions with epoxides
H
O
SN2!
H
PhMgBr
work-up
with
aq NH4Cl*
MgBr
O
H
Ph
Ph
Ph
OH
*NH4Cl: weakly acdic; pKa ~9.7;
Not with aq NH4Cl!
commonly used for the work-up of
organometallic reactions; the only
exception is the work-up of a
O
δ
carboxylate product (you need to Ph MgBr
C
acdity the solution to pH~1-2).
δ
O
pKa 4.2
Ph C
O
O
MgBr
H3O
pH 1-2
O H
Ph C
+ Mg(OH)2
O
+ Br
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
(a) ROH (alcohols)
oxygen atom
ROH, H
O
OH
or L.A.
ROH, H
OR
or L.A.
+
OR
ketone
OR
hemiketal
H2O
ketal
oxygen atom
ROH, H
O
OH
or L.A.
ROH, H
H OR
H
aldehyde
OR
or L.A.
+
H
hemiacetal
H2O
OR
acetal
meaning
"mercury capturers"
Tend to be unsatble intermediates!
(b) RSH (thiols or mercaptans)
oxygen atom
O
RSH, H
OH
or L.A.
RSH, H
SR
or L.A.
+
SR
ketone
SR
hemithioketal
H2O
thioketal
oxygen atom
O
H
aldehyde
RSH, H
OH
or L.A.
H
SR
hemithioacetal
RSH, H
SR
or L.A.
+
H
SR
thioacetal
H2O
Chem 215 F12 Notes – Dr. Masato Koreeda - Page 6 of 11.
Date: September 19, 2012
Chapter 14: I-2. Reversible nucleophiles (cont’d)
(c) Mechanism (similar for both ROH and RSH nucleophile additions)
O
H3CO
CH3OH, p-TsOH*(catalytic)
OCH3
+
Ts
H2O
O
SH
SH
BF3•O(CH2CH3)2**
(catalytic)
Not a base!
H3C
pKa ~-1
S O H
O
S
S
+
*p-TsOH (or TsOH)
para-toluenesufonic acid; strong, organic
solvent-soluble acid.
**boron trifluoride diethey etherate;
F
gives better yields of thioketals &
thioacetals than p-TsOH
F B
H2O
F
O
------------------------------------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:
H B
O
O
H
O
B
H
O
H
B
CH3
O
O
H
H
O
CH3
CH3
SN1!
B
O
H
H2O
CH3
O
H
O
CH3
O
B
H
B
O
CH3
H2O
resonancestabilized
oxoniom
ion
B H
H
lone pair-assisted
ionization!!
CH3
O
CH3
H3CO
OCH3
+
dimethyl ketal
H B
O
H
O
CH3
B
Chem 215 F12 Notes – Dr. Masato Koreeda - Page 7 of 11.
Date: September 19, 2012
Chapter 14: I-2. Reversible nucleophiles: Mechanism (cont’d)
Comments:
1. The ketalization and acetalization reactions from ketone and aldehyde, respectively, under acidcatalyzed 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,
H
H
O
H3CO
O
CH3
H
OCH3
O
H
O
CH3
x
Does not involve an SN2 step!
H
O
CH3
Representative reactions:
(1) cyclic acetal formation
OH
(excess)
H
O
OH
p-TsOH
(catalytic)
Δ
O
H
O
S
H
S
+
H2O
(2) cyclic thioacetal formation
SH
(excess)
H
O
SH
BF3•O(CH2CH3)2
(catalytic)
Δ
+
H2O
(3) cyclic ketal formation from diols: acetonide formation
OH
OH
H3C acetone
O
H3C (excess)
p-TsOH
(catalytic)
H3C
O CH3
O CH3 (excess)
H3C
milder
reaction
conditions
p-TsOH
(catalytic)
H3C
H2C
Mechanism?
Δ
O CH3
(excess)
p-TsOH
(catalytic)
O
CH3
O
CH3
+
H2O
called (5-membered) acetonide (i.e., acetone adduct)
O
CH3
O
CH3
O
CH3
O
CH3
+
2 H O CH3
+
H O CH3
Chem 215 F12 Notes – Dr. Masato Koreeda - Page 8 of 11.
Date: September 19, 2012
Chapter 14: I-2 reversible nucleophiles-ROH/RSH Representative reactions (cont’d)
(4) Transketalization reaction: Spiroketal formation
H3CO OCH3
H3CO OCH3
p-TsOH
(catalytic)
DIBAL ( 2 mol equiv)
O
H H
O
mild workup
with aq NH4Cl
Δ
spiro system
+
O O
HO
OH
2 HOCH3
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
extremely acid
unstable
H
H
p-TsOH
(catalytic)
OH
H2O
(excess)
OH
This reaction does not need to be heated!
Mechanism for the hydrolysis shown on the next page.
+
O
Chem 215 F12 Notes – Dr. Masato Koreeda - Page 9 of 11.
Date: September 19, 2012
Chapter 14: I-2 reversible nucleophiles-ROH/RSH Representative reactions (cont’d)
(5) Hydrolysis of ketals and acetals:
Mechanism:
H
O
H
H
B
H
O
H
H
O
H
O H
H
O
B
H O H
O
O
H
O
O
lone pair-assisted
ionization!
OH
H
O
OH
H
+
H
O H
O
O
B
H
H
H
H
O
B
H
O
lone pair-assisted
ionization!
H
O
============================================
The “take-home message:”
Lone pair-assisted ionization!
O
R
H
H B
O
R'
O
R
SN1!
H
O
+
O
R'
R
R'
HOR"
Not an SN2!!
O
R
O
O
R''
O H
Chem 215 F12 Notes – Dr. Masato Koreeda - Page 10 of 11.
Date: September 19, 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
H
+
aldehyde
N CH
3
Δ
H2N CH3
H
or H+
1°-amine
+
H2O
imine
Mechanism:
H B
O
H
H2N CH3
O
OH
H N CH3
H
H
H N CH3
H
H
B
H B
O H
H
These two steps may be reversed in order.
aminol
N CH
3
H
imine
N
H
H
B
CH3
H
H
O H
CH3
H
N
N
CH3
H
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 F12 Notes – Dr. Masato Koreeda - Page 11 of 11.
Date: September 19, 2012
Chapter 14 I-2. Reversible nucleophiles: Type 4 nucleophiles (trivalent nucleophiles)
(cont’d)
(2) Oxime formation
+
O
Δ
H2N OH
N
OH
or Δ, H+
hydroxylamine
+
H2O
+
H2O
oxime
(3) Hydrazone formation
+
O
Δ
H2N NH2
hydrazine
N
or Δ, H+
NH2
hydrazone
Application: Wolff-Kishner reduction
Reduction of RR’C=O to RR’CH2
O
H
H H
H
H2N NH2
KOH, Δ
ketone
methylene
H
N
N
H
H
H
N
OH
N
H
N
OH
OH
N2 (gas)
N
H
hydrazone
An alternative method for the formation of a methylene group from a C=O:
Reduction of thioacetal/thioketal derivatives with Raney Ni.
Type 3 reversible nucleophile!
HS
O
HS
BF3•O(CH2CH3)2
S
S
thioketal
Raney Ni
ethanol, Δ
H
H
OH