John E. McMurry Paul D. Adams University of Arkansas PREVIEW TO CARBONYL CHEMISTRY

 Much of organic chemistry involves the chemistry of carbonyl compounds  Next five Chapters discusses the Chemistry of the carbonyl group  We look at Kinds of Carbonyl Compounds; Nature of Carbonyl group; General reactions of Carbonyl compounds Why this Chapter?

 All carbonyl compounds contain the carbonyl functional group or acyl group (C=O)  The R part of the acyl group can be any organic part- structure  It is useful to classify carbonyl compounds into two categories: 1) Aldehydes and Ketones and 2) Carboxylic acid and derivatives Kinds of Carbonyl Compounds

 1) Aldehydes and Ketones and 2) Carboxylic acid and derivatives  The presence or absence of a leaving group on the carbonyl determines the type of reactions the carbonyl compound will undergo. Categories of Carbonyl Compounds

Carbonyl carbons are sp 2 hybridized, trigonal planar, and have bond angles that are ~ In these ways, the carbonyl group resembles the trigonal planar sp 2 hybridized carbons of a C=C. Nature of the Carbonyl Group

In one important way, the C=O and C=C are very different. The electronegative oxygen atom in the carbonyl group means that the bond is polarized, making the carbonyl carbon electron deficient.  Thus, carbonyl C atom carries a partial positive charge (i.e electrophilic site) and reacts with nucleophiles  The carbonyl O atom carries a partial negative charge (i.e. nucleophilic site) and reacts with electrophiles Nature of the Carbonyl Group

Using a resonance description, the carbonyl group is represented by two resonance structures. Nature of the Carbonyl Group

Reactions of carbonyl compounds take place by one of four general mechanisms: 1) nucleophilic addition 2) nucleophilic acyl substitution 3) alpha substitution 4) carbonyl condensation General Reactions of Carbonyl Compounds

In general, carbonyls react with nucleophiles General Reactions of Carbonyl Compounds

Most common reaction of Aldehydes and Ketones is the Nucleophilic Addition Reaction - the nucleophile adds to the electrophilic carbon atom of the carbonyl group. 1. Nucleophilic Addition Reactions

Once formed and depending on the nature of the Nu:, the tetrahedral alkoxide intermediate can undergo either of two reactions: 1. alkoxide protonated by water or acid to form an alcohol 2. alkoxide protonated and expel the oxygen to form a new double bond 1. Nucleophilic Addition Reactions

1. Alkoxide protonated by water or acid to form an alcohol:  Also achieved through the reduction of aldehydes and ketones with hydride reagents such as NaBH 4 and LiAlH 4 and use of Grignard reagents. 1. Nucleophilic Addition Reactions

2. Alkoxide protonated & expel of O atom to form new π bond:  Often occurs with amine nucleophiles, where aldehydes and ketones react with primary amines (RNH 2 ) to form imines (R 2 C=NR’) and loss of H 2 O 1. Nucleophilic Addition Reactions

Aldehydes are more reactive than ketones towards nucleophilic attack for both steric and electronic reasons. 1. Nucleophilic Addition Reactions

Nucleophilic acyl substitution occurs only with carboxylic acid derivatives Carbonyl group reacts with Nu:, but the initially formed alkoxide intermediate is not isolated. Due to presence of leaving group, the tetrahedral alkoxide react further, expelling the leaving group (LG) and forming a new carbonyl compound (i.e. replace LG with Nu:) 2. Nucleophilic Acyl Substitution

Alpha substitution occurs at the position next to the carbonyl group – the alpha (α) position The reaction takes place with all carbonyl compounds regardless of structure Results in the substitution of an α hydrogen by an electrophile through the formation of an enol or enolate ion intermediate. 3. Alpha Substitution

The presence of the carbonyl makes the hydrogens on the α carbon acidic. Thus, carbonyl compounds react with strong bases to yield enolate ions 3. Alpha Substitution

Since enolate ions are negatively charged, they act as nucleophiles and undergo many reactions e.g. react with primary alkyl halides in the S N 2 reaction S N 2 alkylation rxn between an enolate ion and alkyl halide is a powerful method of making C-C bonds, building larger molecules 3. Alpha Substitution

Carbonyl Condensation takes place when two carbonyl compounds react with each other, with loss of H 2 O. E.g. treatment of acetylaldehyde with a base, two molecules combine to form the hydroxy aldehyde product, known as the Aldol (aldehyde + alcohol) 4. Carbonyl Condensation

Carbonyl Condensation is simply a combination of a nucleophilic addition step and an α-substitution step The initially formed enolate ion of one acetylaldehyde molecule acts as a Nu: and adds to the carbonyl group of the other acetylaldehyde 4. Carbonyl Condensation