CHEM 73/8311 CS7 Reactions of carbonyls.doc
2012March 9
1
Reactions of Carbonyl Compounds
I. General Considerations
A. many reactions involve formation of tetrahedral intermediate followed by elimination:
AN + DN
1. carbonyl - provides sink for electrons, accessible
tBu
tBu
O
carbon, simultaneous bond forming/breaking
O
L
H
L
H
2. lone pairs must be antiperiplanar for group to
leave tetrahedral intermediate, similar to acetal decomposition
3. acid/base and nucleophilic catalysis (Benzoin reaction)
B. Carbonyl is activated by electron withdrawing groups, deactivated by bulky groups
O
O
O
O
O
OH
Ph
H
1. alkyl groups stabilize electronically
2. steric effect: alkyl groups are closer together after hybridization change: sp 2 to sp3
C. Good nucleophiles readily add to carbonyl groups, may be reversible (second step)
D. Carbonyl must be activated by acid to react with weak nucleophiles like water
O
O
+
OH
H2O
BuLi
Bu
O
Bu
O
NaOH
O
+ RSH
R
O
H
O
R
S
OH
OH
H
-H
RSH
II. Hydration
R
S
R
SH
R
OH
H2O
S
S
CHEM 73/8311 CS7 Reactions of carbonyls.doc
2012March 9
Keq
O
H
40
HO
OH
H
H
H
2x10-2 HO
O
H218O
18
O
OH
H
H
-5
O
O
2x10
HO
OH
Unfavorable for most carbonyl compounds
Reaction is fast when acid or base catalyzed, even if not favorable
III. addition of alcohol
A. acid or base forms hemiacetal, only acid the acetal
B. acetal is base stable
C. reversible with excess water
D. ketals normally only form with 1,2-diols
E. thioacetals also form, not readily reversible
H
RO
OR
+H+
H
-H+
RO
H
OR
H
RO
HO
H
H
+H+
-H+
HO
OR
H
OR
H
OH2
+H+
-H+
HO
OR
H
H
O
H
OR
HO
OR
H
H
IV. Addition/elimination of acid derivatives (sometimes acid or base catalyzed)
2
CHEM 73/8311 CS7 Reactions of carbonyls.doc
O
O
2012March 9
O
X
X
R
R
X
Y
Y
R
Y
3
acyl transfer
O
O
>
R
Cl R
O
O
O
R
>
O
>
R
OR' R
NH2
V. hydrolysis of esters, page 380 in March, 7 of 8 mechanisms observed
A. base hydrolysis of esters follows this mechanism: BAC2 (AN + DN)
O
O
R
18
OR'
R
OH
18
O 18OR'
O HOR'
18
OH
OR'
OH
R
O
R
no attack on R’
OH-, OR-, RNH2 attack carbonyl without catalysis
B. acid catalyzed hydrolysis: AAC2 (Ah + AN + Dh + Ah + DN + Dh)
O
R
H+
OR' R
H2O
18
O
H
18
O
OR' R
H2O
H
2 steps
18
OR' R
HO
O
H
OR' R
18
O
H
-H+
18
OH
H
OR' R
O
OH
H
O-acyl not O-ether cleavage
C. stable carbocations (tert-butyl or benzyl) favor AAL1 (Ah + DN + AN +Dh) carboyxlate
leaves
OH
OH
R
18
OCH2Ph
R
18
O
CH2Ph
OH2
H2OCH2Ph
CHEM 73/8311 CS7 Reactions of carbonyls.doc
2012March 9
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D. bulky acyl group promotes AAC1 (Ah + DN + AN +Dh) as does concentrated acid with OR bonds not easily cleaved
O
O
O
18
18
OEt
OH2
OEt
H
H
VI. Meerwein-Ponndorf-Verley reaction
O
i
Pr O
OPri
Me
Me
Al
OPri
R
R
O
OPri
O
Al
H
O
R
Me
Me
R
OPri
O
O
OPri
R
A. metal alkoxide transfer  H
B. 6-member cyclic transition state
C. Al is important in bringing together alkoxide and carbonyl
D. equilibrium determined by reactivity of carbonyl
E. driven by removal of propanone by distillation
VII. Cannizzaro Reaction
A. disproportionation
B. Rate = k[PhCHO]2[HO-]
C. does not work with ketones: alkyl does not migrate
D. metal coordinates oxygens like MPV reaction
+
R
H
HO
H
Al
H
R
OPri R
R
R
CHEM 73/8311 CS7 Reactions of carbonyls.doc
2012March 9
Na
O
Na
O
O
Ph
O
O
Ph
H
Ph
Ph
Ph
H
HO
OH
Ph
OH
OH
O
H
H
5
H
Na
H
O
Ph
H
VIII. amine addition
O
-
+
O
+ RNH2
N H2R
HO
B
+
NHR
BH
+
H2 O
+
NHR
N HR
H2O +
two steps
NR
B
NHR
+
A. at low pH water elimination is fast, amine group is protonated and amine addition is
rate limiting
B. at high pH, water elimination is slow and rate limiting and amine addition is faster.
C. imine is more stable than enamine but tends to polymerize
D. secondary amines can only form enamines
E. R = OH, H, alkyl, NH2, NHCONH2, NHPh
IX. Grignard addition
A. chelation important
Br
R'
Mg
R
R
R'
R'
O
Mg Br
Br
Br
Mg
Mg
R
O
R
R'
R'
Mg Br
R'
O
R
Mg Br
R
RMgBr +
Ph
Br
Br
O
Mg
Ph
R
et
Mg
O
Mg
O
R
Ph
Ph
evidence for radical reaction?
Ph
Br
Br
Ph
Mg
O
R
R
Ph
Ph
Ph
OH
+
O
H
H2O
Ph
R
Ph
Ph
CHEM 73/8311 CS7 Reactions of carbonyls.doc
2012March 9
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side reactions
B. Grignard with -H add hydride (analogous to MPV)
MgBr
CH2
O
+
H C
H H
MgBr
CH2
O
1. THF
H C
H H
MgBr
CH2
C
H H
OH
+
2. H
O
H2O
H
H
C. carbonyl with -H
MgBr
O
CH2 +
Br
1.
THF
Mg
Br
CH2 H
CH3
CH3
Mg
O
O
2.
CH3
CH2
+
O
H
H2O
CH3 H2C
X. Alkyl lithium reagents
A. forms dimers and tetramers which affect steric demands
B. Grignard and lithium reagents both follow Cram’s rule
XI. aldol condensations
A. base catalyzed – enolate formation
1. equilibrium favorable for aldehydes, note stereochemistry of transition state
2. not favorable for ketones, why doesn’t NaOH work for crossed aldol?
O
H
H
LDA/-78 C O
CH2CH3
H
(LiN(iPr)2)
Li
CHCH3
PhCHO
H
H3C
1. favorable for aldehydes and ketones
2. tertiary alcohols dehydrate
Li
O
O
H
B. acid catalyzed – enol formation
H
Ph
H
H3C
Li
O
O
H
Ph
CHEM 73/8311 CS7 Reactions of carbonyls.doc
2012March 9
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C. crossed aldol – mixed aldehydes gives four possible products if both aldehydes have
-H
O
H
OH
HCl
H
CH3
OH
CH2 H
OH
CH3
H
CH2
OH
H
H
C
H2O
OH
CH3
O
OH
H
CH2
H
CH3
H
OH2
H
H
XII. Claisen Condensation (why is there still starting ester in second step?)
O
EtO
O
NaOEt
CH3
EtO
CH2 EtO
O
O
O
CH3
O
CH3
CH2 OEt
EtO
EtO
O
CH2
O
EtO
CH3
O
CH
EtO
A. alkoxide is not a good leaving group, assisted by CO double bond formation
B. equilibrium favors -keto enolate
C. neutralize to obtain product
D. Dieckmann - intramolecular condensation
OEt
O
O
O
OEt
EtO
OEt
O
OEt
O
O
XIII. Wittig reaction (phosphonium and ylid are stable salt)
H
H
Br
Ph3P + C
R R
R
R
Ph3P
C
O
Ph3P
C
R
Ph3P
R'
C
R
Ph3P
R
C
Ph3P
C
R
R
O
R'
PhLi
R
R
R'
R'
Ph3P
O
R
C
R
R
R'
R'
R'
O
R'
EtOH
CH3
CHEM 73/8311 CS7 Reactions of carbonyls.doc
2012March 9
8
XIV. phosgene and primary amine
H Cl
Cl
H
R N
R N
C O
+
Cl
H
Cl
H
C O
R N
H Cl
C
H
N
O
H
C O
R
Cl-
XV. reductive amination
O
-
+
OH
O
Base
+ HNR2
BH
2 steps
+
HN R2
H2O
OH2
+
NR2
Ni
NR2
Ni Ni Ni Ni Ni
NR2
NR2
H2
+ others
NR2
NHR2
Base
H
NR2
H
Ni Ni Ni Ni Ni
Ni Ni Ni Ni Ni
NR2
H
H
H
Ni Ni Ni Ni Ni
H
NR2 H H
Ni Ni Ni Ni Ni
Ni Ni Ni Ni Ni
A
NR2
Ni Ni Ni Ni Ni
H
XVI. Mannich reaction p901 in March
O
+ NH3
H
O
H
H
as above
NH
H
O H
NH
H
H
H
O
O
-
O
R
NH2
H2O
O
OH
CH3
R
R
R
-
CH2
XVII. Benzoin reaction (carbene catalysis)
O
O
+ CNAr
H
-
2 steps
C
Ar
XVIII. cyanogen bromide
CN
H
O
OH
Ar
OH O
O
-
-
CN
H
Ar
Ar CN H
Ar
Ar
-
OH
H Ar
CN
O
Ar
OH
H Ar
CHEM 73/8311 CS7 Reactions of carbonyls.doc
N C
R
O
-
N C
Br
R
-
Br
Br
N C
R
O
O
O
R
-
N C
R
O
O
9
O
Br
N C
-
O
O
2012March 9
O
O
N C
O
R
O
N
C
C
O
R
XIX. Wolff rearrangement – migrating group retains configuration
O
O
+
Cl CH2 N N
Me
-
O
CH2 N
Me
+
N
Me
Cl
O
Me
O
O
CH N
+
C
N
N2
CH
CHMe
HO
H2O
HO
C
A. bimolecular: addition/elimination, favored by electron withdrawing group
O
O
Cl
Cl
Cl
O
Cl
Nu
Cl
Nu Cl
Cl
O
B. unimolecular: vinyl cation formation, unfavorable
1. facilitated by -aryl group, ArXC=CR2
2. occurs with very good leaving group such as OSO2CF3
L
X
Hofmann, Schmidt, Lossen, Curtius Rearrangement
X
CH2Me
HO
XX. vinyl substitution
Cl
Ag2O
O
C
Me
+
CH2 N N
HO