Overview of the Reactions of Carbonyl Compounds

• Topical Outline of Coverage– I. Kinds of Carbonyl Compounds.– II.Polarity of the Carbonyl Functional

Group.– III.General Reactions of Carbonyl

Compounds• A.     Nucleophilic Addition Reactions• B.     Nucleophilic Substitution Reactions

Kinds of Carbonyl Compounds • All carbonyl compounds contain the acyl group

• where the (R) residue bonded to the carbonyl maybe alkyl, aryl, alkenyl, or alkynyl. The different kinds of carbonyl compounds arise from the nature of the other residue bonded to the carbonyl group.

CR

O

Kinds of Carbonyl Compounds

CR

O

X

X = H then aldehydeX= R then ketoneX = OH then carboxylic acidX = Cl then acid chlorideX = OR then ester (cyclic esters = lactones)X = OCOR then acid anhydrideX = N then amide (cyclic amides = lactams)

Categories of Carbonyl Compounds• Carbonyl

Compounds may be grouped into two broad categories based upon whether or not they take part in Nucleophilic Substitution Reactions

Aldehydes and Ketones

• Aldehydes and Ketones - X = H and R respectively ; these carbonyl compounds do not undergo nucleophilic substitution reactions. That is to say, the H and R groups are never substituted by other groups. Both H- and R- make poor leaving groups.

CR

O

XR X

Carboxylic Acids and their Derivatives

• Carboxylic acids and their derivatives – X = some heteroatom (O, Cl, or N). Nucleophilic substitution reactions are possible for these carbonyl compounds because the electronegative heteroatom can stabilize a negative charge and form good Leaving Groups.

CR

O

X

Polarity of the Carbonyl Groups

• The carbon-oxygen double bond of the carbonyl group is extremely polarized in the direction of the highly electronegative oxygen. This polarization is responsible for the characteristic reactions of carbonyl compounds

C

O:: nucleophilic oxygen reacts with acid and other electrophiles

electrophilic carbon reacts withbases and other nucleophiles

+

-

General Reactions Of Carbonyl Compounds

• Nucleophilic Addition Reactions

• Nucleophilic Acyl Substitution

Nucleophilic Addition Reactions – Chapter 09

• There are two different ways in which a nucleophile can add to a carbonyl compound. Each way leads to a different nucleophilic addition reaction but the mechanisms for both reactions involves the same 1st step.

• In this step, the nucleophile bonds to the carbonyl carbon and thereby causes a carbon-oxygen bond to break. The carbonyl carbon rehybridizes from sp2 to sp3 and the carbonyl oxygen becomes negatively charged. At this point the tetrahedral intermediate can either be protonated to form an alcohol (NaBH4, LiAlH4, or Grignard Reduction) or a non-bonded e- pair on the nucleophile can be used to form a second bond to the carbonyl carbon. The new bond formation causes expulsion of the carbonyl oxygen as H2O.

First Type of Nucleophilic Addition

• Alcohol Formation – Ketones and Aldehydes react with NaBH4, LiAlH4, and Grignard reagents to form alcohols

Second Type of Nucleophilic Addition

• Imine formation - Ketones and Aldehydes react with 1o amines to form imines .

Nucleophilic Acyl Substitution –

• Theses reactions do not apply to aldehydes and ketones. These reactions involve the substitution of the nucleophile for the X residue of the carbonyl compound.

CR

O

X

Nu-

CR

O

Nu+ X-

Nucleophilic Acyl Substitution

CR

O

X

X = H then aldehydeX= R then ketoneX = OH then carboxylic acidX = Cl then acid chlorideX = OR then ester (cyclic esters = lactones)X = OCOR then acid anhydrideX = N then amide (cyclic amides = lactams)

Carboxylic Acid Derivatives

Carboxylic Acid Derivatives• These all have an acyl group bonded to Y, an

electronegative atom or leaving group• Includes: Y = halide (acid halides), acyloxy

(anhydrides), alkoxy (esters), amine (amides).

General Reaction Pattern

• Nucleophilic acyl substitution

Nucleophilic Acyl Substitution-The Mechanism

• Carboxylic acid derivatives have an acyl carbon bonded to an electronegative group Y that can leave

• A tetrahedral intermediate is formed, then the leaving group is expelled to generate a new carbonyl compound, leading to substitution

Substitution in Synthesis• We can readily convert a more reactive acid derivative into a

less reactive one• Reactions in the opposite sense are possible but require more

complex approaches

Found in Nature

Reactions of Acid Halides• Nucleophilic acyl substitution• Halogen replaced by OH, by OR, or by NH2

• Reduction yields a primary alcohol• Grignard reagent yields a tertiary alcohol

Reactions of Acid Anhydrides

• Similar to acid chlorides in reactivity

Reactions of Esters• Less reactive toward nucleophiles than are acid chlorides or

anhydrides• Cyclic esters are called lactones and react similarly to acyclic

esters

Chapter 09. Aldehydes and Ketones: Nucleophilic Addition Reactions

Aldehydes• Aldehydes are carbonyl compounds having at least

one hydrogen attached to the carbonyl carbon.

propanal

CHCH2CH3

O

Benzaldehyde

C

O

H

formaldehyde

C

O

H H

Ketones• Ketones are carbonyl compounds having two

alkyl fragments attached to the carbonyl carbon.

2-propanone

CH3CCH3

O

acetophenone

CH3

O

2-butanone

CH3 C CH2 CH3

O

Naming Aldehydes and Ketones• Aldehydes are named by replacing the terminal -e of the

corresponding alkane name with –al• The parent chain must contain the CHO group

– The CHO carbon is numbered as C1• If the CHO group is attached to a ring, use the suffix

carbaldehyde

Names of more Complex Aldehydes

Naming Ketones• Replace the terminal -e of the alkane name with –one• Parent chain is the longest one that contains the

ketone group– Numbering begins at the end nearer the carbonyl carbon

Ketones with Common Names• IUPAC retains well-used but unsystematic names for a

few ketones

Preparation of Aldehydes and Ketones• Preparing Aldehydes

• We have already discussed two of the best methods of aldehyde synthesis. These are oxidation of primary alcohols, and oxidative cleavage of alkenes. Oxidize primary alcohols using pyridinium chlorochromate

Preparing Ketones• Ketones may be prepared by the oxidation of secondary

alcohols. A wide range of oxidizing can accomplish this purpose. Some of these are: Jones reagent (CrO3 in aqueous sulfuric acid), sodium chromate (Na2CrO4) and potassium permanganate (KMnO4).

4-tert-butylcyclohexanol

OH

C(CH3)3

Na2CrO4

acetic acid

4-tert-butylcyclohexanone

O

C(CH3)3

(90%)

Prep. Of Ketones by Ozonolysis of Alkenes

• Ozonolysis of alkenes yields ketones if one of the doubly bonded carbons is itself bonded to two alkyl groups.

Prep. Of Ketones by Hydration of Terminal Alkynes

• Methyl ketones can be prepared by the Markovnikov addition of water to a terminal alkyne. The reaction needs to be catalyzed by Hg+2 ion. See Section 4.13 of text.

Aryl Ketones by Acylation

• Friedel–Crafts acylation of an aromatic ring with an acid chloride in the presence of AlCl3 catalyst (see Section 5.6)

Oxidation of Aldehydes and Ketones• Aldehydes are readily oxidized to carboxylic acid but

ketones are unreactive towards oxidation except under the most vigorous conditions. This difference in reactivity towards oxidation lies in the structural difference between the two types of carbonyl compounds. Aldehydes are more easily oxidized because they posses a hydrogen atom bonded to the carbonyl carbon. This hydrogen atom can be removed as a proton with the final result being the oxidation (loss of hydrogen) from the original aldehyde. Ketones have no expendable carbonyl-hydrogen bond.

Oxidation of Aldehydes and Ketones• Many oxidizing agents will convert aldehydes to carboxylic acids.

Some of these are Jones reagent, hot nitric acid and KMnO4.

• One drawback to the Jones reagent is that it is acidic. Many sensitive aldehydes would undergo acid - catalyzed decomposition before oxidation if Jones reagent was used

CCH3(CH2)4

O

H CCH3(CH2)4

O

OHJones

A Milder Oxidizing Agent• For acid sensitive molecules a milder oxidizing

agent such as the silver ion (Ag+) may be used. A dilute ammonia solution of silver oxide, Ag2O, (Tollens reagent) oxidizes aldehydes in high yield without harming carbon-carbon double bonds or other functional groups.

•Note; In this reaction the oxidizing agent is Ag+ and it is ultimately reduced to Ag(s).

•A shiny mirror of metallic silver is deposited on the inside walls of the flask during a Tollens oxidation: observation of such a mirror forms the basis of an old qualitative test for the presence of an aldehyde functional group in a molecule of unknown structure.

Tollens Oxidation

Nucleophilic Addition Reactions of Aldehydes and Ketones

• Nu- approaches 45° to the plane of C=O and adds to the Carbonyl Carbon

• A tetrahedral alkoxide ion intermediate is produced and ultimately protonated

Nucleophiles• Nucleophiles can be negatively charged ( : Nu) or neutral ( : Nu-H)• If neutral, the nucleophile usually carries a hydrogen atom that can

subsequently be eliminated and carry away the positive charge.

Relative Reactivity of Aldehydes and Ketones• Aldehydes are generally much more reactive than ketones. There are two reasons for this;

– Aldehydes are less sterically hindered than ketones. In other words the carbonyl carbon of aldehydes is more accessibly to attack. The presence of two relatively large substituents in ketone hinders the attacking nucleophile from reaching the carbonyl carbon .

– The + on the carbonyl carbon is reduced in ketones because of the ability of the extra alkyl group to stabilize a + charge. This ability is emphasized in the stability order of carbocations. 3o>2o>1o

Aldehydes Have A Greater Electrophilicity Than Do Ketones

• Aldehyde C=O is more polarized than ketone C=O• As in carbocations, more alkyl groups stabilize + character• Ketone has more alkyl groups, stabilizing the C=O carbon

inductively

Addition of H-Y to C=O• Reaction of C=O with H-Y, where Y is electronegative, gives an

addition product (“adduct”) and the reaction is readily reversible because the electronegative Y is a good leaving group.

Nucleophilic Addition of Alcohols: Acetal Formation

• Two equivalents of ROH in the presence of an acid catalyst add to C=O to yield acetals, R2C(OR)2

• Alcohols, ROH, fall under the category of Y-H and therefore the reaction is reversible.

• Mechanism for Formation of Acetals

Uses of Acetals• Acetals can serve as protecting groups for aldehydes and

ketones-remember the rxn. is reversible.• It is convenient to use a diol, to form a cyclic acetal (the

reaction goes even more readily)

Nucleophilic Addition of Grignard Reagents and Hydride Reagents: Alcohol Formation

• Treatment of aldehydes or ketones with Grignard reagents yields an alcohol– Nucleophilic addition of the equivalent of a carbon

anion, or carbanion. A carbon–magnesium bond is strongly polarized in the direction of the carbon atom, so a Grignard reagent reacts for all practical purposes as R: and MgX +.

Mechanism of Addition of Grignard Reagents

• R- attacks the carbonyl carbon. The alkoxide anion is then protonated by dilute acid.

• Grignard additions are irreversible because a carbanion is not a leaving group

Hydride Addition• H- attacks the carbonyl carbon. The alkoxide anion is then protonated by dilute acid.• Hydride additions are irreversible because a hydride is not a good leaving group• LiAlH4 and NaBH4 react as donors of hydride ion (H-)

Nucleophilic Addition of Amines: Imine Formation

Primary amines (RNH2) add to C=O to form imines, R2C=NR (after loss of HOH)

• Mechanism of Imine Formation

Imine Derivatives• Addition of amines that have an adjacent atom containing a

lone pair of electrons occurs very readily, giving useful, stable imines

• For example, hydroxylamine forms oximes and 2,4-dinitrophenylhydrazine readily forms 2,4-dinitrophenylhydrazones – These are usually solids and help in characterizing liquid ketones

or aldehydes by melting points

Spectroscopy of Aldehydes and Ketones

• Infrared Spectroscopy• Aldehydes and ketones show a strong C=O peak 1660 to 1770

cm1

• aldehydes show two characteristic C–H absorptions in the 2720 to 2820 cm1 range.

C=O Peak Position in the IR Spectrum

• The precise position of the peak reveals the exact nature of the carbonyl group

Summary• Aldehydes are from oxidative cleavage of alkenes

or oxidation of 1° alcohols• Ketones are from oxidative cleavage of alkenes or

oxidation of 2° alcohols.• Aldehydes and ketones are reduced to yield 1° and

2° alcohols , respectively• Grignard reagents also gives alcohols • 1° amines add to form imines• Alcohols add to yield acetals