Download Carbonyl The carbonyl function, C=O, exists in a number of organic

Carbonyl
The carbonyl function, C=O, exists in a number of organic functional groups. These
groups are: aldehydes, ketones, acids, acid halides and anhydrides, esters and amids. And
there are still more. The nitrile group is closely related in its chemistry to the carbonyl
group.
C
O
C
O
C
O
The important feature of the carbonyl group is that the oxygen atom polarizes the double
bond such that the carbon atom has positive character and the oxygen atom has negative
character. The positive carbon atom is electrophilic and is responsible for much of the
observed chemistry, such as acidity of alpha hydrogens and nucleophic reactions at the
carbonyl. If florine atoms are located near the carbonyl function then their electronegativity
increases the positive character on the carbonyl carbon creating an even more electrophilic
center.
The types of reactions of carbonyl compounds falls into two main catagories. One is the
simple additions across the carbonyl observed for aldehydes and ketones to form an
alcohol. The reaction can be accelerated by acid-catalysis. The other, exemplified by the
ester family, RC=OX, is addition to the carbonyl group followed by elimination of the
heteroatom attachment, X, to give overall substitution. These reactions are also accelerated
by acid.
Aldehyde and Ketone reactions.
neutral
O
O
+
OH
H2O
Nu
Nu
Nu
acid-catalyzed
O
H+
OH
OH
OH
+ Nu
Nu
Reactions of RXC=O groups; Acid, ester, acid halide, anhydride, amide
The characteristic reaction of this class of carbonyl compounds is the first step of
addition of the nucleophile followed by elimination of the X function to give the final
product. In acid catalysis the carbonyl is first protonated to give a more electrophilic carbon
that adds the nucleophile. These functional groups have a great deal of difference in their
overall reactions depending on the relative ease of the loss of X. Thus in leaving group
ability, nuch like in nucleophilic substitution, Halide> OAc, > OH, OR, > NR2. Of course if
X = H or R then you have an aldehyde or ketone and there is no leaving group and only
addition occurse as shown above.
neutral
O
O
X
+
Nu
O
-X-
substitution
Nu
X
Nu
addition
elimination
tetrahedral intermediate
acid-catalyzed
O
H+
OH
+ Nu
X
-X-
OH
OH
X
OH
X
-H
Nu
X
Nu
O
substitution
Nu
Aldehyde and Ketone Examples
Oxygen, Nitrogen, Sulfur Nucleophiles
Water reacts with aldehydes or ketones under neutral or acid-catalyzed conditions to form
hydrates.
neutral
H2O
PhCH=O
OH2
OH
PT
PhCH
Hydrate
PhCH
O
OH
acid catalyzed
H+
Ph 2C=O
Ph 2C-OH
Ph 2C-OH
Ph 2C=OH
H2O
H2O
H+
OH2
Ph 2C-OH
OH
Hydrate formation is greater with low molecular weight compounds. Addition of fluorine to
the system greatly increses the hydrate content because the fluorine atoms make the
carbonyl carbon much more positive. Thus water adds more readily to the fluorinated
carbonyl group.
H+
Ph2C=O
HO
PT
HO
OH
Ph2C-OH 2
O
OH
- H2O
Ph2C-OH
Ph2C-OH
Ph2C=OH
H
O
Ph2
O
-H
OH HO
OH
O
Ph2
O
acetal
The dithiane molecules used as a source for carbanions can be seen to be thioacetals of
aldehydes or ketones from thiols, RSH. Glucose is a common compound which is a hemiacetal (half-acetal). If glucose is treated with acid and alcohol it is converted into an acetal.
K = hydrate/ketone
CH2O
100
CH3C=O
FCH2 C=OCH3 .11
PhCH=O
1
.008
(CH3)2 C=O
.001
(CF3)2 C=O
.00001
PhC=OCF3
PhC=OCH3
CF3C=OCH3
35
1,200,000
78
Alcohols react in a similar fashion to form acetals. The acetal derived from ethylene
glycol is very useful for protecting the aldehyde carbonyl. Of course the carbonyl group
can be recovered from the acetal by treatment with acid and water. These reactions are
reversible.
HO
S
S
HO
O
HO
OH
HO
dithane
glucose
hemi-acetal
Reactions with ammonia, hydrazine: Wolff Kishner reduction
Aldehydes and ketones undergo addition reaction with ammonia and with hydrazine
derivatives. These reactions do not produce alcohols, but instead product imines and
hydrazones from loss of water.
O
NH3
O
HO
-OH
PT
+ NH3
NH2
NH2
NH
-H+
imine
Reaction of an aldehyde or ketone with ammonia in the presence of hydrogen and a catalyst
results in hydrogenation of the intermediate imine to give an amine. This process is known
as reductive amination.
reductive amination
O
NH2
NH
H2
+ NH3
Pd
Aldehydes and ketones readily form hydrazones on reaction with hydrazine and hydrazine
compounds. The example below is with 2,4-dinitrophenylhydrazine because the final
product hydrazone is always a nice solid.
O2N
PhCH=O
+
NH2NH
H+
NO2
O2N
PhCH=OH
PhCH NH2NH
NO2
OH
O2N
O2N
PhCH NHNH
NO2
PhCH NHNH
NO2
OH2
O2N
- H+
PhCH
NNH
NO2
2,4-dinitrophenylhydrazone
An old but useful reaction, known as Wolff Kishner reduction, is the reduction of the
carbonyl group to a CH2 by reaction of the carbonyl with hydrazine and KOH at high
temperature in ethylene glycol. The intermediate hydrazone is converted to intermediate
carbanions that are protonated by the water formed in the reaction.
Wolff-Kishner Reduction
O
Ph
Ph
N=NH
Ph
NNH 2
NH2 NH2
KOH
Ph
ethylene glycol
Ph
-H2O
N=NH
H2O
Ph
KOH
Ph
H
Ph
-H2O
H
H2O
KOH
Ph
H
Ph
Ph
H
Ph
Addition of Carbon Nucleophiles
The addition of Grignard reagents, RMgX, and organolithium reagents, RLi, to carbonyl
groups to form alcohols constitute a major process in organic chemical synthesis. These
reagents add easily to the carbonyl group but as strong bases they can also form alphacarbanions that give aldol reactions. The aldol reactions are minimized by working at cold
temperatures. The reaction is exemplified with cyclohexanone. All of these addition
reactions require a second step reaction with dilute acid to neutralize the alkoxide formed in
the first step addition. Ketones give secondary alcohol, and aldehydes give primary
alcohols.
O
O
PhMgBr
Ph
or PhLi
H3O
OH
Ph
Whan the carbonyl component contains a chiral center, diasteriomeric products are possible.
The size of the groups attached to the chiral center have significant influence on the
diastereomeric mixture.
RS
RS
OH
RS
CH3
O
RL
RL
RL
CH3
OH
CH3MgBr
+
RM
R
H3O
RM
R
RM
R
Cornforth
Nu
Nu
O
RS
Cl
OM
RM
RS
RM
Cl
RX
RX
For alphal-halo compounds. Halogen and carbonyl are anti. Nu
attacks over the Rs.
Karabotsos
RM
RL
O
RL
RS
O
RX
RS RS
O
RM RM
RX
RX
RL
Favored
Of the three conformations possible, the one with the carbonyl and Rm eclipsed is
the most stable. Nu attacks over the Rs.
Felkin-Ahn
O
RL
Nu
RX
RS
RM
RS
O
RL
Nu
RM
RX
Nu attacks between Rm and Rs. Least interaction between Rx
and Rm or Rs is preferred.
Cram
Nu
O
RS
Nu
RM
OM
RM
RS
RL R
X
RL R
X
RL and Rs are eclipsed. Nu attacks over the Rs group.
Cram Chelate Model
R
O
M
O
OR
OM
Nu
Nu
RS
RM
RS
RX
RM
RX
For alpha-oxygenated carbonyl compounds. Bothy oxygens are eclipsed in
complex with a metal. Nu attacks over the Rs.
The case is illustrated with 3-phenylbutanone below. Addition of ethyl magnesium bromide
follows the model of Felkin-Ahn to give 88% of the diasterioisomer shown. The Cram
model gives the same result.
CH3
O
H3 C
Ph
CH3CH2MgBr
H3O
H
CH3
Et
OH
88%
Ph
H
CH3
CH3CH2MgBr
There are many other carbon nucleophiles that add to the carbonyl of aldehydes and
ketones, and these reactions makeup a major synthetic arsenal in organic chemistry. Thus
reactions that are known as the aldol condensation, the Reformatsky reaction, Knovenagel
Condensation are among the many reactions. Another important reaction shown below is
the Wittig reaction. The Wittig reaction is very useful because the position of the double
bond in the product is determined from the position of the carbonyl group. Cis and trans
isomers constitution can be influenced by the addition of other reagents.
Wittig and Related Reactions
A very nice procedure for the preparation of alkenes from aldehydes and ketones is
known as the Wittig reaction, or Wittig-olefination. Phosphonium salt, prepared from a
triarylphosphine or a trialkylphosphine and an alkyl halide, is treated with a moderately
strong base to form a zwitterion known as an ylide. The ylide is formed in the presence of
the carbonyl compound and the resulting product is an alkene. The position of the alkene
function is always at the spot of the carbonyl. Thus problems associated with the isomers
found in elimination reactions are not present here. The Wittig olefiniation has complete
regioselectivity.
Ph3P+-CH3 IPh3P + CH3I
NaH
Ph3P+-CH2-
O
Ph3P=CH2
Ylide
CH2
The mechanism of the reaction is shown below. The ylide adds to the carbonyl group much
like many other nucleophiles, but the newly formed intermediate called a betaine cyclizes to
a oxphospetane that collapses to the alkene. The driving force for this process is the
ultimate formation of the very strong phosphorus to oxygen bond. An alternative to this
mechanism has the oxaphosphetane being formed first.
_
Ph3P+-CH2-
Ph3 P
O
O
+
Ph3P-CH 2
O
Oxaphosphetane
betaine
A related alternative to the Wittig olefination is know as the Horner-Wadsworth-Emmons
olefination. The reaction utilizes a phosphine oxide, formed from an Arbusov reaction
involving an alpha haloester, as a carbanion source. The carbanion adds to the carbonyl
group much in the same manner as shown above.
Arbusov Reaction
OCH2 CH3
(EtO)2 PCH2 CO2 Et + Br-
(EtO)3 P + BrCH2CO2Et
O
(EtO)2 PCH2 CO2 Et
Horner-Wadsworth-Emmons Olefination
O
(EtO)2 PCH2 CO2 Et
O
(EtO)2 PCHCO2Et
n-BuLi
O=CHPh
O
(EtO)2 PCHCO2Et
O
(EtO)2 P-CHCO2Et
O-CHPh
O
(EtO)2 P-CHCO2Et
O-CHPh
PhCH=CHCO2 Et + (EtO)2 P=O
O
The stereochemistry of Wittig reactions is very interesting, and the detailed mechanisms
involved are somewhat cloudy. As shown below the reagents add in a fast step to form an
eclipsed betaine (or goes directly to the oxaphosphetane). The oxaphosphetane breaks
down by syn elimination to give the trans (E) product. In a slower step the staggered more
stable betaine is formed that leads to the cis (Z) isomer. Most Wittig reactions give the
trans alkene (E isomer), but in some cases the cis isomer is formed (Z isomer). A number
of parameters affect the outcome, such as added metal ions (Li+ ), solvents, the size of the R
groups, and the functions attached the phosphorus atom (aryl, alkyl, alkylcarbonyl).
R3 P+ CH- R + R'CHO
slow
fast
R3 P O
H
O
H
R'
R
R
H
H
R'
PR3
R3 P O
H
R
R3 P O
H
R'
H
R
R'
H
R
R
cis
trans
R'
R'
An interesting case with a fluorine attachment is shown below. The organic substituents are
in the trans position in the absence of fluorine but are in the cis position in the presence of
fluorine. Is it possible that the small fluorine atom is large enough to inhibit the formation
of the eclipsed betaine.
O
(EtO)2 PCHCO2Et
EtO2 C
OHC
+
O
O
O
O
F
O
(EtO)2 PCFCO2Et +
OHC
O
O
EtO2 C
O
O
The Wittig reaction with α− fluoro α,β unsaturated aldehydes is a convenient method for
the production of fluorinated dienes.
CHO
+ Ph P=CHOCH
3
3
F
F
55 %
Sulfur Ylides
Sulfur ylides contain a carbanion next to a positively charged sulfur atom. The
ylides that contain a sulfur to oxygen bond are called sulfoxonium ylides and those without
the oxygen are called sulfonium ylides.
O
CH3-S-CH2
CH3
CH3
sulfoxonium ylide
SPh2
CH3-S-CH2
sulfonium ylide
(CH3)2S-CH-CO2Et
Ph2S-C(CH3)2
These ylides add to the carbonyl group of aldehydes and ketones to give epoxides
as shown below. The larger sulfoxonium ylide adds from the equitorilal direction on a
cyclohexanone ring to leave the carbon atom equatorial and the oxygen atom axial. The
smaller sulfonium ylide adds to form an expoxide from the axial direction.
axial
(H3C)2S
O
t-Bu
CH3-S-CH2
t-Bu
O
CH3
O
t-Bu
+
15% equitorial
85%
O
CH3-S-CH2
0%
+
100%
CH3
The cyclopropyl sulfonium ylide adds to carbonyl groups to give cyclopropyl
epoxides. On treatment with acid the epoxides rearrange to cyclobutanones. (Trost
reaction).
O
O
SPh2
+
O
H+
The addition of sulfur ylides to α, β-unsaturated systems offers an excellent
procedure for the preparation of cyclopropane compounds. In these reactions the ylide may
also add to the carbonyl but the thermodynamics of the addition favor the 1,4 addition.
O
O
CO2Et
(CH3)2S-CH-CO2Et
O
O
S(CH3)2
CO2Et
CO2Et
Simple dimethyl cyclopropanes my be prepared as well.
CN
CN
+
Ph2S-C(CH3)2
+ Ph2S
O
CH3-S-CH 2
CH3-S-CH 2
CH3
CH3
sulfonium ylide
sulfoxonium ylide
(CH3)2 S-CH-CO2Et
SPh2
Ph2S-C(CH 3)2
axial
(H 3C) 2S
O
t-Bu
CH3-S-CH 2
t-Bu
O
CH3
O
t-Bu
+
15% equitorial
85%
O
CH3-S-CH 2
0%
+
100%
CH3
The reduction of the carbonyl group of aldehydes or ketones is usually a simple matter.
The most common reagents are sodium borohydride (or it derivatives) and lithium
aluminum hydride (or it derivatives). The derivatives are reagents in which the reducing
power has been reduced by replacing a hydrogen atom by a cyano or alkoxy group. In
most cases sodium borohydride is the reagent of choice because of its ease in handling and
simple reaction workup.
PhCH=O
NaBH4
or LiAlH4
2) H3O+
RCH2OH
Reaction of Carboxylic Acid Derivatives
The types of molecules in this class have the general structure of R(C=O)L, where L is a
leaving groups such as Cl, OAc, OR, NR2 These substrates all follow the additionelimination path mostly to give the substitution product. But the rate of the reaction and the
final outcome depend largely on the ability of the leaving group, L, to leave. The reactions
being considered are hydrolysis or alcoholysis, reaction with grignard or RLi, and
reduction.
Hydrolysis and Alcohlysis
The example below shows the hydrolysis (reaction with water) of an acid chloride
under both neutral and acid-catalyzed reactions. Acid chlorides (and acid anhydrides) react
very fast with water because of the highly positive carbonyl group and by the good leaving
avilibility of the chloride (or OAc in the case of acetic anhydride).
acid chloride
O
O
+
R
Cl
OH2
O
-Cl-
R
R
Cl
O
OH2
R
OH
OH2
acid-catalyzed
O
R
H+
Cl
OH
R
Cl
OH
R
+ H2O
Cl
OH
R
Cl
OH2
O
-H
-HCl
R
OH
OH
substitution
R
OH
Esters are hydrolyzed in the presence of acid catalysts to give carboxylic acids. The
addition-elimination mechanism accounts for the process. The steps are all equilibrium
steps and the reaction is thus reversible. Thus a carboxylic acid reacts with an alcohol in the
presence of an acid catalyst to give an ester. The process is the important Fischer
esterification. By using an excess of alcohol (about 10 fold) the reaction is driven to the
ester product in very good yield.
Ester Hydrolysis (Fischer Esterification)
O
R
H+
OH
OH
OR'
R
OR'
+ H2O
R
OH2
OH
O
OH
R
OHR'
R
OH
PT
OR'
OH
+
R'OH
R
OH
+ H+
Basic hydrolysis of esters occurs on reaction of the ester with hydroxide. The mechanism
is addition -elimination to give the carboxylate salt and an alcohol. Acidification of the
reaction mixture gives the free carboxylic acid.
Saponification
O
R
O
OH
OR'
R
O
OR'
OH
+
R
OH
OR'
O
R
O-
+
HOR'
Acid hydrolysis of amides occurs at low pH. During the elimination step enough acid must
be present to give the quaternary nitrogen ion which is lost as ammonia. Basic hydrolysis is
very difficult because the leaving group in the elimination step is amide ion, a very poor
leaving group. To achieve basic hydrolysis long times and high temperatures are required.
Amide Hydrolysis
O
H+
R
NH2
OH
OH
R
NH2
+ H2O
O
OH
NH3
R
OH
NH2
OH2
OH
R
PT
R
OH
+ NH3
R
NH4 +
+
OH
Saponification
O
O
OH
R
NH2
R
O
+
NH2
R
OH
OH
NH2
Nitriles produce amides on hydrolysis. Acid hydrolysis goes further to the carboxylic acid
while basic hydrolysis gives the amide.
Grignard reagents and organolithium reagents react with acid chlorides, anhydrides and
esters in the same manner. First an addition-elimination sequence occurs to give an
aldehyde or ketone, depending on R, and then the Grignard reagent does a simple addition
to the ketone. The product is a tertiary alcohol that contains two molecules of the Grignard
reagent. The reaction is very difficult to control to get just the aldehyde or ketone because
the Grignard reagent is very reactive and reacts with both the acid chloride or ketone.
O
Mg+Br
O
R
Cl
+
R'MgBr
R
Cl
O
R
R'MgBr
R'
R'
O
R
R'
R'
OH
2) H3O
R
R'
R'
An organocadmium reagent, prepared from a Grignard reagent and cadmium chloride, adds
to an acid chloride to give a ketone. The cadmium reagent is not reactive enough to add to
the ketone, and thus the final product in this procedure is the ketone.
CdCl2
R'MgBr
O
R
O
R'2 Cd
Cl
R
R'2 Cd
NR
R'
Amides and nitriles undergo addition reactions with Grignard reagents but not the
elimination step because the amide fuction, -NR2, is a poor leaving group. Thus after
hydrolysis of the reaction mixture an aldehyde or ketone is produced. Since the carbonyl
compound is produced after hydrolysis there is no further reaction with the Grignard
reagent, as it has also been hydrolyzed.
amide
O
R
O
NR2
+ R'MgBr
OH
2) H3O+
R
R
NR2
NHR 2
R'
R'
O
-HNR2
R
R'
nitrile
R C N
R C
+ R'MgBr
N
2) H3O+
R
R'
O
R'
Thus very common reagents can be used to deliver a carbonyl group from an amide or a
nitrile. N,N-dimethylformamide is equivalent to an aldehyde function, and acetonitrile is
equivalent to an acetyl group.
O
O
H-C-N(CH3)2
H-C-R
O
H3 C C
N
H3 C
R'
Trifluoromethyl amides react in the Wittig reaction to produce enamines.
CHPh
O
F3C
+
N
O
Ph3P=CHPh
F3C
N
60 %
O