Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds

Chemistry of - unsaturated carbonyl compounds

1. Synthesis of unsaturated carbonyl compounds

2. Conjugate addition to carbonyl compounds
3. Michael addition
4. Robinson annulation- ①M i ehad
addition② intramolecularatdel condensation
5. Reduction reactions

1. Synthesis of unsaturated carbonyl compounds

a. From stabilized ylide

Horner Emmons reaction Eisemer only

Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 1

 roomtemp
b. Elimination of PhSe group

c. Aldol condensation

d. The Mannich reaction: It is a reaction between enol of ketone (nucleophile) with an iminium ion (electrophile). Iminium
ion is formed by reaction of formaldehyde with secondary amine in the presence of acid catalyst or by reaction of
formaldehyde with dialkylammonium chloride. The product is -dialkyl aminoketones - Mannich bases. Thermal
decomposition of Mannich bases and their conjugate acids yields unsaturated ketones called enones.
formaldehyd
e
workup

Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 2

 mechanism o n final ①NNuattack
② protonateo'
③ protenateOH
④eliminated
① malacnd
@ endNuattack
③Ndeprotonateott
④ deprotonaten

salt can also be used instead of an amine and formaldehyde to make iminium ion. This salt is particularly
useful under non-aqueous condition when enolate is formed with a strong base in polar aprotic solvent, like THF (no acid
is present in these conditions).

Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 3

Thermal decomposition of Mannich bases:

%
a

¥¥
Another useful method to prepare an enone is methylation of
Mannich base with methyl iodide followed by elimination with
weak bases like Ag2O, H2O, or HCO3

O photoH

¥1
Mme)a ¥¥
Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 4
2. Conjugate addition to carbonyl compounds
unsaturated carbonyls undergo nucleophilic
addition
Nucleophile can either adds to carbonyl carbon, (direct
addition or 1,2 addition) or at (conjugate
addition or 1,4 addition), both sites are electrophilic.

General mechanism:
fast

stable
substrate
Formation of 1, 2 addition or 1, 4 addition product depends on conditions of reaction, nature of , unsaturated carbonyl
compounds and type of nucleophile. Generally, more reactive carbonyl group, like unsaturated aldehydes and acid
chloride, favor 1, 2 addition whereas 1, 4 addition is favored by unsaturated ketones, esters, and amides.
Strongly basic nucleophiles, like RLi, RMgX, LiAlH4, adds irreversibly forming kinetically controlled product
(1, 2 addition).

Most of the nucleophiles adds reversibly and form thermodynamic (1,4 addition) product.

Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 5

# ←
ago ←
0%0

"
"I.jo#ttq+oxnwd.reetadditrn(b
2addihm)
"
"If.gg#HtgNufgonjugateadditrm(b4add
ihm)
A. Addition of water in acidic or basic condition
Hydration of unsaturated carbonyl compounds is the key step in
many biochemical processes. The conjugate addition of water takes 1
place in acidic or basic condition.

Mechanism (basic condition)

OH>H o
Na

Mechanism (acidic condition)

Hao>HzOt
(Step 4 in two steps, addition of H3O+ followed by deprotonation) Nu
Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 6
B. Addition of HCN
Cyanide ion (CN--) under basic conditions adds to unsaturated aldehydes to form 1, 2 addition products but with
unsaturated ketones and esters 1, 4 addition is major product.
'becauseo f hindrance

n e aldehydes f e r this
an exam

Hydrolysis and reduction of nitriles (CN group) form acid and amines respectively (as discussed earlier).

c h21
hydrolysis

0h21

Hz , Pd - c

Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 7

C. Addition of alcohols and thiols (ROH and RSH)

Alcohols and thiols undergo conjugate addition (1, 4 addition) in acidic or basic condition. Base catalyzed reactions
usually give higher yield.
'because o fendates

Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 8

D. Addition of amines
Amines undergo conjugate addition (1,4 addition) with unsaturated ketones.

Mechanism

①LD#THE,-782
@ phased
@ ③ Her,b
④ Howi o n
⑤ Ha,PI-C

Fees#
Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 9
Non-conjugated double bondsa r e nucleophilic, b u t conjugateddoublebonds a r e eketrophilic

Her, O H → H D t-OOH
E. Epoxidation of unsaturated ketones (enones)
Enones form epoxide on reaction with hydroperoxide ion. Unlike alkene, unsaturated ketones do not form epoxides with
peracids. Per acid selectively reacts with non-conjugated alkene. In epoxidation of alkene, bond is nucleophilic, and
oxygen is electrophilic (of per acid) whereas in enone hydroperoxide is nucleophilic and bond is electrophilic.

coniugated
nonsideni.
side
Mechanism:
n o to n e x a m

FEI
F-

g
A 0 I 0 FEI
Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 10

know where epoxide goes f o r reagent

Importantforsynthes, gaddinn
1.
yiraddihrn simplemenoaltylation

:
F. Reaction with organometallic reagents (RMgX, RLi, R2CuLi and other organocuprates)
Grignard reagents and organolithium compounds, strong base nucleophiles mostly form1,2 addition with unsaturated
carbonyl compounds whereas Gillman reagent and other higher order organocuprates form1,4 addition products.

Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 11

 ftp.grinliit#FIIIIsfIImenoalladatin
-

4¥ R e a l i t y ¥1, ¥ , §µ' Meneralkylatron

tendale addition

E#i ¥±I¥¥Ir
Fix@%I¥"#} Fig, dialladation
The enolate ion formed in conjugate addition of organocuprates (instead of acid work up) can be used to form
dialkylated carbonyls on reaction with alkyl halide(methyl,primary,allylic, benzylic).

no stereodrum o n exam

Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 12

The enolate ion can also regenerate conjugated carbnoyl back by suitable reagents. The conjugated carbonyl thus can
be diallkylated by conjugate addition.

o
①Etzculi ①E f f u l i
@ Hyot ②Meth
①Me.MU
§¥¥@ Phsea
①Exculi
@ pused
③11-202,0
¥uLi ④ Merculi
@ Hot
Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 13
3. Michael addition:

Conjugated addition of stabilized enolates to -unsaturated carbonyl compounds.

Mechanism:

no mechanism

Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 14

> To ten thee.
bee
stable →

1¥ Et

Ya
 The unsaturated component is called Michael
acceptor. The Michael acceptor can also be other
than carbonyl compounds. The active methylene
enolate is Michael donor which are -diester,
-diketone, -ketoester, -cyanoester, and nitro
compounds. (pKa < 14)

Simple ester or ketone enolates as nucleophiles:

A " "of allendates
base E
a r e moderate
Nu,prefer
conjugate
addition

§"' 'P-cerbend

Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 15

The enolate ion formed can react with alkyl halide to form -alkylated product.

O f throme

Me@Ilom e H o & m t
co,
A)
H
B
H

Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 16

 knowlanepairs, a r r o w s , charges f o r e x a m
Rewewcenefully
4. Robinson Annulation:
mirrosoprmersimpy
Michael addition followed by an intramolecular aldol
condensation forming cyclohexanone (a new 6 membered ring)

Mechanism:

't,}
N N

T T Omamendate
@ enolatenuattaele
Fe,
@protenateneuendate@mnke-
newadutegpotenateo.t. ¥,::inEi.

Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 17

Automaterxn, 2 electrophone-nueteophile interactions total

Retrosynthesis:

init'
o . IE
Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 18
If af c h Ey f ¥ Naoetgetotte,

Etta, →
i¥±¥¥§←siI¥'t
i*j¥fEf÷ pj@IfFnnw
HII'm
dadee.i'¥i÷:
aid
 h e mechanisms
5. Reduction Reactions:
Metal hydride, like: NaBH4 in MeOH, preferentially reduces aldehyde group in unsaturated aldehyde but with
ketones the reaction gives mixture of 1, 2 and 1, 4 addition products. In most cases reduces both double bond and
keto group.

aldehyde→ G -c
n o ttouched

ketene→ reduce both

Unsaturated ketones in the presence of CeCl3 preferentially reduce ketone only. The presence of CeCl3 reduces
the conjugated ketone much faster than the normal ketone.

Unsaturated esters can be selectively reduced by AlH3 or di-isobutyl aluminum hydride (DIBALH) to form allyl alcohol.

B t
ago → n o H

Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 19

 Catalytic hydrogenation: The product depends on the nature of catalyst. Hydrogenation with H2, Pd-C reduces
double bond, but homogenous ruthenium catalyst is especially useful for reducing only the carbonyl portion of
unsaturated ketone.

R n catalyst

¢
B therea diff btwn Its,Rucatalyst and Nabitybeds?

Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 20

 a radiala n n n reaction
v e r y important reaetren
Dissolving metal reduction: A method for conjugated reduction of
unsaturated ketones proceed by addition of an electron from metal like
Li, Na dissolved in liquid ammonia a dissolving metal reduction.
g o tot x tb a c kf e rmechanism

also v e r y important
Reduction with Li/NH3 in the presence of I equivalent of water or alcohol stops at enolate ion. The enolate ion
formed can be alkylated with methyl, 10, allylic or benzylic halide. The enolate formed under these conditions is
regioselective that is the enolate ion formed on the side of the ketone that has double bond. That means alkylation
only occurs at -carbon on that side.

Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 21

 ① LDHTHF,-78%
YER
HI → @ R-Br

Hu H&R ① l i e Mts, I H O
→
② R-Br
 O
¥ . E E MEE →

Skip section: 24.2 b, 24.3 f, 24.4

Suggested text book problems: All, except: 5, 26, 27

focus o n arrow pushing f o r mechanisms

Chapter 24 - Conjugate Addition Reactions of Unsaturated Carbonyl Compounds - (KSethi) Page 22

A,B-unsaturated carbonyl compounds a r e carbonyl compoundsw i t h a conjugated a
bond betweentheA and P carbons i n E R
synthesis
synthesize such compounds u s i n g stabilized glides and derivatic Horner Bonmens
reaction a s well a s phs e e n a n enda t e a n d aldd condensation
MannichReaction
which i sa n
Readinga 2 0a n i m e w/formaldehyde i n acid forms a n i minium ion,
electrophilet h a t reacts w i t h a nucleophilicend toa d dtot h e4 Positron(Mann,eh Base)
Heatingthe resultant producteliminates the a m i n e t o makea T L bonda t a,13carbons
Eschenmoser's salt c a n beusedt o maket h e immium i n in non-audio conditions
(Me)2 N= L H zI

using methyl iodideo n a Mann12hbasethen eliminatingw i t h a w e a k base such

a s Ag,O,H,O, H lo,-alsoworks to formunsaturated carbonyls
conjugateAddition
Nudeophiles c a n either add t o the carbonylcarbon (1,2addition/directaddition/lawn
product)o r t h e 13Carbon
(1,4addition/conjugateaddition/thermodynamic product)
stronglybas,2 N u such a s Rmgx, RLi,a n d L iAIHuformmerekineticproduct,while most
other N u form m o re thermodynamic product
morere a eh e (lesshindered)substrates reactfaster while mere stable substrates
form m o r e stable products
Reduction
Nanty reducesonlythe aldehydea n d leavesthe c a r bondi ntact but reduces both
theketone and bond
N aBHu w/Cella added reducesonlythe ketenea n d leavest h ec a r bondi ntact
A t I t , o r D I B A LI t reduces unsaturatedesters to ally1alcohols
Hz,Pd-Creducesonlythe E C bond,a n d thecatalyst reducesonlythecarbonyl
Li, NH,(l), Ro I t reducest h e E C bondt o makea r a v i n e m i x t u r e
L i , NH,( l ) i n 1 equiv. H e reduces to a n endate onlyo n thesidea t the E C bond,
makingi t useful f o r selectived alkylation

note: non-conjugated T L bends(such a sendates)a r e nucleophilic

Important bondsfuehat
and can
s o attack a t last/and halides, b u t conjugated i t
-

f - ① unsaturated carbonyls) a r e #electrophilic a n d m u s t b e attacked b y

meteorites for direct(1,2) o r conjugated 11,4) a d d i t i o n a l
Reactions
①Mean,A u t o , Itt@Ottworkup RmR→RmR¥t
Carbonyl → unsaturated carbonyl
MannionReaction
(Me)zN=cHaI(Eschenmeser'ssalt)canbeusednnonaundiconditrons
goeswaamannihbaseintermediate
UsingmeIthenaueakbasesuchasAgzoarltoiwerksthesameuay
Nu
unsaturated carbonyl → substitutedcarbonyl RInR→R"¥¥
REAR-7121%
1,9(animated)additional,z(direct) addition
m o s t Nuadd conjugated,'lystrongNuadddireet
17202,014
unsaturated carbonyl→ carbonylepoxide RNRTRMRJ.to
onlyaddstoconiugateducbond
organic peroxyandslmopBA)addtongularallanes
nannmenorito
unsat.aldehyde → allane i÷÷÷÷i±€
REAR RIER
→
unsat.la/ene-salkaneceUzaddedpreser-
vesthelutone'sC=cbond
DIBALHWAIH,
unsatiester-sally
carbonyl only
alcohol
Rmor→R##H
Ha,Pd - c RnR→Rn#¥
unsat. carbonyl → carbonyl
Hi,R u catalyst

÷÷÷÷
" ' " ' " ' " ' "'

L i , N H ,( l ) , ROHo r L i , Nits,ROH,-334 RmR→Rm#¥

i n s a t . carbonyl→ carbonyl
reduces double bond
makes a r a c e m i e(50:50)mixturev i a radiala n i o n

L i , N H ,(d), I equiv.H ,O o r L i ,NHs , I equiv.I t20,-334

unsat. carbonyl → e n da t e
endate c a n react f o ra substitution o n E c bendsideonly
÷i÷
H E ¥9 i s

I n ¥tg ~

e . negation
a h , Dimitry n o r

Hmpden,
Ann e n

n e
Fas .'