Carbonyl

The carbonyl function, C=O, exists in a number of organic functional groups. Thesegroups are: aldehydes, ketones, acids, acid halides and anhydrides, esters and amids. Andthere are still more. The nitrile group is closely related in its chemistry to the carbonylgroup.

C O C O C O

The important feature of the carbonyl group is that the oxygen atom polarizes the doublebond such that the carbon atom has positive character and the oxygen atom has negativecharacter. The positive carbon atom is electrophilic and is responsible for much of theobserved chemistry, such as acidity of alpha hydrogens and nucleophic reactions at thecarbonyl. If florine atoms are located near the carbonyl function then their electronegativityincreases the positive character on the carbonyl carbon creating an even more electrophiliccenter.

The types of reactions of carbonyl compounds falls into two main catagories. One is thesimple additions across the carbonyl observed for aldehydes and ketones to form analcohol. The reaction can be accelerated by acid-catalysis. The other, exemplified by theester family, RC=OX, is addition to the carbonyl group followed by elimination of theheteroatom attachment, X, to give overall substitution. These reactions are also acceleratedby acid.

Aldehyde and Ketone reactions.

O+ Nu

O

Nu

H2OOH

Nu

O H+ OH OHNu+

OH

Nu

neutral

acid-catalyzed

Reactions of RXC=O groups; Acid, ester, acid halide, anhydride, amide The characteristic reaction of this class of carbonyl compounds is the first step ofaddition of the nucleophile followed by elimination of the X function to give the finalproduct. In acid catalysis the carbonyl is first protonated to give a more electrophilic carbonthat adds the nucleophile. These functional groups have a great deal of difference in theiroverall reactions depending on the relative ease of the loss of X. Thus in leaving groupability, nuch like in nucleophilic substitution, Halide> OAc, > OH, OR, > NR2. Of course ifX = H or R then you have an aldehyde or ketone and there is no leaving group and onlyaddition occurse as shown above.

X

O+ Nu

X

O

NuNu

O

X

O H+

X

OH

X

OHNu+ X

OH

Nu

neutral

acid-catalyzed

-X-

addition elimination

substitution

tetrahedral intermediate

Nu

OH-X- -H

Nu

Osubstitution

Aldehyde and Ketone Examples

Oxygen, Nitrogen, Sulfur Nucleophiles

Water reacts with aldehydes or ketones under neutral or acid-catalyzed conditions to formhydrates.

PhCH=OH2O

PhCH

O

OH2PT

PhCH

OH

OH

Hydrate

neutral

acid catalyzed

Ph2C=OH+

H2OPh2C=OH Ph2C-OH

H2OPh2C-OH

OH2H+

Ph2C-OH

OHHydrate formation is greater with low molecular weight compounds. Addition of fluorine tothe system greatly increses the hydrate content because the fluorine atoms make thecarbonyl carbon much more positive. Thus water adds more readily to the fluorinatedcarbonyl group.

-H

Ph2C=OH+

Ph2C=OH Ph2C-OH Ph2C-OH

HO OH HO OHHO OH

PTPh2C-OH2

O OH Ph2

O

OH

- H2O Ph2

O

O

acetal

The dithiane molecules used as a source for carbanions can be seen to be thioacetals ofaldehydes or ketones from thiols, RSH. Glucose is a common compound which is a hemi-acetal (half-acetal). If glucose is treated with acid and alcohol it is converted into an acetal.

K = hydrate/ketone

CH2O

CH3C=O

PhCH=O

(CH3)2C=O

FCH2C=OCH3

CF3C=OCH3

(CF3)2C=O

PhC=OCH3 PhC=OCF3

100

1.008

.001

.11

35

1,200,000

.00001 78

Alcohols react in a similar fashion to form acetals. The acetal derived from ethyleneglycol is very useful for protecting the aldehyde carbonyl. Of course the carbonyl groupcan be recovered from the acetal by treatment with acid and water. These reactions arereversible.

S SO

HO

HOHO

HOOH

dithane glucose hemi-acetal

Reactions with ammonia, hydrazine: Wolff Kishner reduction

Aldehydes and ketones undergo addition reaction with ammonia and with hydrazinederivatives. These reactions do not produce alcohols, but instead product imines andhydrazones from loss of water.

O

NH3+

O NH3

PT

HO NH2

-OH

NH2

-H+NH

imine

Reaction of an aldehyde or ketone with ammonia in the presence of hydrogen and a catalystresults in hydrogenation of the intermediate imine to give an amine. This process is knownas reductive amination.

O

NH3+H2

Pd

NH NH2

reductive amination

Aldehydes and ketones readily form hydrazones on reaction with hydrazine and hydrazinecompounds. The example below is with 2,4-dinitrophenylhydrazine because the finalproduct hydrazone is always a nice solid.

NH2NH

O2N

NO2PhCH=O + H+

PhCH=OH NH2NH

O2N

NO2PhCH

OH

NHNH

O2N

NO2PhCH

OH2

NHNH

O2N

NO2PhCH

H+-NNH

O2N

NO2PhCH 2,4-dinitrophenylhydrazone

An old but useful reaction, known as Wolff Kishner reduction, is the reduction of thecarbonyl group to a CH2 by reaction of the carbonyl with hydrazine and KOH at hightemperature in ethylene glycol. The intermediate hydrazone is converted to intermediatecarbanions that are protonated by the water formed in the reaction.

Ph Ph

O NH2NH2

KOHethylene glycol

Ph Ph

NNH2

Ph Ph

N=NH

Ph Ph

N=NH

HPh Ph

HPh Ph

H

H

KOH

-H2O

KOH

-H2O

H2O H2O

Wolff-Kishner Reduction

Addition of Carbon NucleophilesThe addition of Grignard reagents, RMgX, and organolithium reagents, RLi, to carbonylgroups to form alcohols constitute a major process in organic chemical synthesis. Thesereagents add easily to the carbonyl group but as strong bases they can also form alpha-carbanions that give aldol reactions. The aldol reactions are minimized by working at coldtemperatures. The reaction is exemplified with cyclohexanone. All of these additionreactions require a second step reaction with dilute acid to neutralize the alkoxide formed inthe first step addition. Ketones give secondary alcohol, and aldehydes give primaryalcohols.

OPhMgBr

O

Phor PhLi

H3OOH

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 thediastereomeric mixture.

O

R

RL

RM

RSCH3MgBr

H3O R

RL

RM

RS

R

RL

RM

RSCH3 OH

OH CH3

+

RMRSO

Cl

RMRS

Cl

OM

O O O

Of the three conformations possible, the one with the carbonyl and Rm eclipsed isthe most stable. Nu attacks over the Rs.

Cornforth

For alphal-halo compounds. Halogen and carbonyl are anti. Nu attacks over the Rs.

Karabotsos

RX RX

NuNu

RL RMRS RS RM

RL

RX RX RL

RSRM

RX

Favored

O O

Felkin-Ahn

Nu attacks between Rm and Rs. Least interaction between Rxand Rm or Rs is preferred.

RS

RL

RX RX

RL

RS

RM

RM

Nu Nu

RMRSO

RL

RMRS

RL

OM

RMRS

O

RO

RMRS

Cram

For alpha-oxygenated carbonyl compounds. Bothy oxygens are eclipsed incomplex with a metal. Nu attacks over the Rs.

OR

Cram Chelate Model

OMNu

RL and Rs are eclipsed. Nu attacks over the Rs group.

RX

Nu

RX

Nu

RXRX

Nu

M

The case is illustrated with 3-phenylbutanone below. Addition of ethyl magnesium bromidefollows the model of Felkin-Ahn to give 88% of the diasterioisomer shown. The Crammodel gives the same result.

CH3CH2MgBr

H3O

O

CH3

CH3

OHEt

CH3

PhH

88%Ph

H3C

H

CH3CH2MgBr

There are many other carbon nucleophiles that add to the carbonyl of aldehydes andketones, and these reactions makeup a major synthetic arsenal in organic chemistry. Thusreactions that are known as the aldol condensation, the Reformatsky reaction, KnovenagelCondensation are among the many reactions. Another important reaction shown below isthe Wittig reaction. The Wittig reaction is very useful because the position of the doublebond in the product is determined from the position of the carbonyl group. Cis and transisomers 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 isknown as the Wittig reaction, or Wittig-olefination. Phosphonium salt, prepared from atriarylphosphine or a trialkylphosphine and an alkyl halide, is treated with a moderatelystrong base to form a zwitterion known as an ylide. The ylide is formed in the presence ofthe carbonyl compound and the resulting product is an alkene. The position of the alkenefunction is always at the spot of the carbonyl. Thus problems associated with the isomersfound in elimination reactions are not present here. The Wittig olefiniation has completeregioselectivity.

Ph3P CH3I Ph3P+-CH3 I-

Ph3P+-CH2- Ph3P=CH2

+

NaH

O

CH2

Ylide

The mechanism of the reaction is shown below. The ylide adds to the carbonyl group muchlike many other nucleophiles, but the newly formed intermediate called a betaine cyclizes toa oxphospetane that collapses to the alkene. The driving force for this process is theultimate formation of the very strong phosphorus to oxygen bond. An alternative to thismechanism has the oxaphosphetane being formed first.

Ph3P+-CH2-O

Ph3P-CH2

O+

_

OPPh3

betaine

Oxaphosphetane

A related alternative to the Wittig olefination is know as the Horner-Wadsworth-Emmonsolefination. The reaction utilizes a phosphine oxide, formed from an Arbusov reactioninvolving an alpha haloester, as a carbanion source. The carbanion adds to the carbonylgroup much in the same manner as shown above.

(EtO)3P BrCH2CO2Et+ (EtO)2PCH2CO2Et Br-OCH2CH3

+

(EtO)2PCH2CO2EtO

Arbusov Reaction

Horner-Wadsworth-Emmons Olefination

(EtO)2PCH2CO2EtO n-BuLi

(EtO)2PCHCO2EtO

(EtO)2PCHCO2EtO O=CHPh

(EtO)2P-CHCO2EtO

O-CHPh

(EtO)2P-CHCO2EtO

O-CHPh

PhCH=CHCO2Et (EtO)2P=OO

+

The stereochemistry of Wittig reactions is very interesting, and the detailed mechanismsinvolved are somewhat cloudy. As shown below the reagents add in a fast step to form aneclipsed betaine (or goes directly to the oxaphosphetane). The oxaphosphetane breaksdown by syn elimination to give the trans (E) product. In a slower step the staggered morestable betaine is formed that leads to the cis (Z) isomer. Most Wittig reactions give thetrans alkene (E isomer), but in some cases the cis isomer is formed (Z isomer). A numberof parameters affect the outcome, such as added metal ions (Li+), solvents, the size of the Rgroups, and the functions attached the phosphorus atom (aryl, alkyl, alkylcarbonyl).

R3P+ CH- R R'CHO

O

R'HH

R

R3PR

O

H R'

H

PR3

O

R'HH

R

R3P O

R'HR

H

R3P

+

fastslow

R'

R

R'

R

trans cis

An interesting case with a fluorine attachment is shown below. The organic substituents arein the trans position in the absence of fluorine but are in the cis position in the presence offluorine. Is it possible that the small fluorine atom is large enough to inhibit the formationof the eclipsed betaine.

(EtO)2PCHCO2EtO

OOOHC

OO

EtO2C

+

(EtO)2PCFCO2EtO

OOOHC

+O

OEtO2C

F

The Wittig reaction with α− fluoro α,β unsaturated aldehydes is a convenient method forthe production of fluorinated dienes.

Ph3P=CHOCH3+

CHO

F F 55 %

Sulfur Ylides

Sulfur ylides contain a carbanion next to a positively charged sulfur atom. Theylides that contain a sulfur to oxygen bond are called sulfoxonium ylides and those withoutthe oxygen are called sulfonium ylides.

CH3 CH3

O

sulfoxonium ylide sulfonium ylide

SPh2 Ph2S-C(CH3)2

CH3-S-CH2 CH3-S-CH2

(CH3)2S-CH-CO2Et

These ylides add to the carbonyl group of aldehydes and ketones to give epoxidesas shown below. The larger sulfoxonium ylide adds from the equitorilal direction on acyclohexanone ring to leave the carbon atom equatorial and the oxygen atom axial. Thesmaller sulfonium ylide adds to form an expoxide from the axial direction.

t-BuO

CH3

t-Bu O

(H3C)2S

t-Bu O

axial

+ 15% equitorial

CH3

O

85%

0% + 100%

CH3-S-CH2

CH3-S-CH2

The cyclopropyl sulfonium ylide adds to carbonyl groups to give cyclopropylepoxides. On treatment with acid the epoxides rearrange to cyclobutanones. (Trostreaction).

SPh2 +

H+O

OO

The addition of sulfur ylides to α, β-unsaturated systems offers an excellentprocedure for the preparation of cyclopropane compounds. In these reactions the ylide mayalso add to the carbonyl but the thermodynamics of the addition favor the 1,4 addition.

(CH3)2S-CH-CO2Et

OO CO2Et

O

S(CH3)2

CO2Et

O

CO2Et

Simple dimethyl cyclopropanes my be prepared as well.

Ph2S-C(CH3)2

CN+

CN

+ Ph2S

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 lithiumaluminum hydride (or it derivatives). The derivatives are reagents in which the reducingpower has been reduced by replacing a hydrogen atom by a cyano or alkoxy group. Inmost cases sodium borohydride is the reagent of choice because of its ease in handling andsimple reaction workup.

PhCH=ONaBH4

or LiAlH4

RCH2OH

2) H3O+

CH3-S-CH2

CH3

CH3-S-CH2

CH3

O

sulfoxonium ylide sulfonium ylide

SPh2 (CH3)2S-CH-CO2Et Ph2S-C(CH3)2

t-BuO CH3-S-CH2

CH3

t-Bu O

(H3C)2S

t-Bu O

axial

+ 15% equitorial

CH3-S-CH2

CH3

O

85%

0% + 100%

Reaction of Carboxylic Acid DerivativesThe types of molecules in this class have the general structure of R(C=O)L, where L is aleaving groups such as Cl, OAc, OR, NR2 These substrates all follow the addition-elimination path mostly to give the substitution product. But the rate of the reaction and thefinal outcome depend largely on the ability of the leaving group, L, to leave. The reactionsbeing considered are hydrolysis or alcoholysis, reaction with grignard or RLi, andreduction.

Hydrolysis and AlcohlysisThe example below shows the hydrolysis (reaction with water) of an acid chloride

under both neutral and acid-catalyzed reactions. Acid chlorides (and acid anhydrides) reactvery fast with water because of the highly positive carbonyl group and by the good leavingavilibility of the chloride (or OAc in the case of acetic anhydride).

R Cl

O+

R Cl

O

OH2

R OH2

O

R Cl

O H+

R Cl

OH

R Cl

OH+ R Cl

OH

OH2

acid-catalyzed

R OH

OH-H

R OH

Osubstitution

OH2-Cl-

R OH

O

acid chloride

H2O

-HCl

Esters are hydrolyzed in the presence of acid catalysts to give carboxylic acids. Theaddition-elimination mechanism accounts for the process. The steps are all equilibriumsteps and the reaction is thus reversible. Thus a carboxylic acid reacts with an alcohol in thepresence of an acid catalyst to give an ester. The process is the important Fischeresterification. By using an excess of alcohol (about 10 fold) the reaction is driven to theester product in very good yield.

R OR'

O H+

R OR'

OHR OR'

OH

OH2

R OH

OH

H2O

R OHR'

OH

OH+ R'OH

R OH

O+ H+

Ester Hydrolysis (Fischer Esterification)

+PT

Basic hydrolysis of esters occurs on reaction of the ester with hydroxide. The mechanismis addition -elimination to give the carboxylate salt and an alcohol. Acidification of thereaction mixture gives the free carboxylic acid.

+R OR'

OOH

R OR'

O

OHR OH

OOR'

+R O-

OHOR'

Saponification

Acid hydrolysis of amides occurs at low pH. During the elimination step enough acid mustbe present to give the quaternary nitrogen ion which is lost as ammonia. Basic hydrolysis isvery difficult because the leaving group in the elimination step is amide ion, a very poorleaving group. To achieve basic hydrolysis long times and high temperatures are required.

R NH2

O H+

R NH2

OHR NH2

OH

OH2

R OH

OH

H2O

R NH3

OH

OH+

R OH

O

+

NH4+

Amide Hydrolysis

+PT

R NH2

OOH

R NH2

O

OHR OH

O

NH2

Saponification

NH3 +

Nitriles produce amides on hydrolysis. Acid hydrolysis goes further to the carboxylic acidwhile basic hydrolysis gives the amide.

Grignard reagents and organolithium reagents react with acid chlorides, anhydrides andesters in the same manner. First an addition-elimination sequence occurs to give analdehyde or ketone, depending on R, and then the Grignard reagent does a simple additionto the ketone. The product is a tertiary alcohol that contains two molecules of the Grignardreagent. The reaction is very difficult to control to get just the aldehyde or ketone becausethe Grignard reagent is very reactive and reacts with both the acid chloride or ketone.

R'MgBrR Cl

O+

R Cl

O

R'

Mg+Br

R R'

O R'MgBr

R R'

O

R'

2) H3OR R'

OH

R'

An organocadmium reagent, prepared from a Grignard reagent and cadmium chloride, addsto an acid chloride to give a ketone. The cadmium reagent is not reactive enough to add tothe ketone, and thus the final product in this procedure is the ketone.

R'MgBrCdCl2

R'2CdR Cl

O

R R'

O R'2CdNR

Amides and nitriles undergo addition reactions with Grignard reagents but not theelimination step because the amide fuction, -NR2, is a poor leaving group. Thus afterhydrolysis of the reaction mixture an aldehyde or ketone is produced. Since the carbonylcompound is produced after hydrolysis there is no further reaction with the Grignardreagent, as it has also been hydrolyzed.

R'MgBrR NR2

O

+ R NR2

O

R'

2) H3O+

R NHR2

OH

R'

-HNR2 R

O

R'

R C N R'MgBr R C N

R'

2) H3O+

R

O

R'+

amide

nitrile

Thus very common reagents can be used to deliver a carbonyl group from an amide or anitrile. N,N-dimethylformamide is equivalent to an aldehyde function, and acetonitrile isequivalent to an acetyl group.

H-C-N(CH3)2

O

H-C-RO

H3C C N H3C

O

R'

Trifluoromethyl amides react in the Wittig reaction to produce enamines.

F3C N

O

O

Ph3P=CHPh+ F3C N

CHPh

O60 %