Tetrahedral carbonyl addition intermediate

The partially positive charge on the carbonyl carbon (Section 12.3) is the cause of the most common reaction theme of the carbonyl group, the addition of a nucleophile to form a tetrahedral carbonyl addition intermediate. In the following general reaction, the nucleophilic reagent is written as Nu to emphasize the presence of its unshared pair of electrons ... 

STEP 2 Reaction of an electrophile and a nucleophile to form a new covalent bond. Addition of the alkoxide ion to the carbonyl gives a tetrahedral carbonyl addition intermediate ... 

STEP 3 Add a proton. Proton transfer from water to the tetrahedral carbonyl addition intermediate gives the hemiacetal and regenerates the hydroxide ion catalyst ... 

The key step in the metal hydride reduction of an aldehyde or a ketone is the transfer of a hydride ion from the reducing agent to the carbonyl carbon to form a tetrahedral carbonyl addition intermediate. In the reduction of an aldehyde or a ketone to an alcohol, only the hydrogen atom attached to carbon comes from the hydride-reducing agent the hydrogen atom bonded to oxygen comes from the water added to hydrolyze the metal alkoxide salt. 

Nucleophiles react with aldehydes and ketones to form tetrahedral carbonyl addition intermediates. (12.4)... 

The addition of ammonia or a primary amine to the carbonyl group of an aldehyde or a ketone forms a tetrahedral carbonyl addition intermediate. Loss of water from this intermediate gives an imine (a Schiff base) ... 

STEP 3 Take a proton away. Proton transfer from the oxonium ion to a second molecule of alcohol gives a tetrahedral carbonyl addition intermediate (TCAI) ... 

STEP 5 Collapse of the tetrahedral carbonyl addition intermediate to eject a leaving group and regenerate the carbonyl group. Loss of water from this oxonium ion gives the ester and regenerates the acid catalyst ... 

The most common reaction theme of acid halides, anhydrides, esters, and amides is the addition of a nucleophile to the carbonyl carbon to form a tetrahedral carbonyl addition intermediate. To this extent, the reactions of these functional groups are similar to nucleophilic addition to the carbonyl groups in aldehydes and ketones (Section 12.4). The tetrahedral carbonyl addition intermediate (TCAI) formed from an aldehyde or a ketone then adds H". The result of this reaction is nucleophilic addition to a carbonyl group of an aldehyde or a ketone ... 

The key step in a basealdol reaction is nucleophilic addition of the enolate anion from one carbonyl-containing molecule to the carbonyl group of another carbonyl-containing molecule to form a tetrahedral carbonyl addition intermediate. This mechanism is illustrated by the aldol reaction between two molecules of acetaldehyde. Notice that OH is a true catalyst An OH is used in Step 1, but another OH is generated in Step 3. Notice also the parallel between Step 2 of the aldol reaction and the reaction of Grignard reagents with aldehydes and ketones (Section 12.5) and the first step of their reaction with esters (Section 14.7). Each type of reaction involves the addition of a carbon nucleophile to the carbonyl carbon of another molecule. 

STEP 2 Reaction of an electrophile and a nucleophile to form a new covalent bond. Because the equilibrium favors the left in Step 1, there is plenty of unreacted aldehyde (or ketone) remaining in the reaction mixture. Nucleophilic addition of the enolate anion to the carbonyl carbon of an unreacted molecule of aldehyde (or ketone) gives a tetrahedral carbonyl addition intermediate the newly formed... 

As you study this mechanism, note how closely its first two steps resemble the first steps of the aldol reaction (Section 15.1). In each reaction, base removes a proton from an a-carbon in Step 1 to form a resonance-stabilized enolate anion. In Step 2, the enolate anion attacks the carbonyl carbon of another ester molecule to form a tetrahedral carbonyl addition intermediate. 

The mechanism of a Dieckmann condensation is identical to the mechanism we described for the Claisen condensation. An anion formed at the a-carbon of one ester in Step 1 adds to the carbonyl of the other ester group in Step 2 to form a tetrahedral carbonyl addition intermediate. This intermediate ejects ethoxide ion in Step 3 to regenerate the carbonyl group. Cyclization is followed by formation of the conjugate base of the j8-ketoester in Step 4, just as in the Claisen condensation. The j8-ketoester is isolated after acidification with aqueous acid. 

In the Claisen condensation catalyzed by the enzyme thiolase, acetyl-CoA is converted to its enolate anion, which then attacks the carbonyl group of a second molecule of acetyl-CoA to form a tetrahedral carbonyl addition intermediate. Collapse of this intermediate by the loss of CoAnSH gives acetoacetyl-CoA. The mechanism for this condensation reaction is exactly the same as that of the Claisen condensation (Section 15.3A) ... 

A key step in the Claisen condensation is the addition of an enolate anion of one ester to a carbonyl group of another ester to form a tetrahedral carbonyl addition intermediate, followed by the collapse of the intermediate to give a /3-ketoester. 

STEP 3 Reaction of the thioester with phosphate ion gives a tetrahedral carbonyl addition intermediate, which then collapses to regenerate the enzyme and give a mixed anhydride of phosphoric acid and glyceric acid ... 

The mechanism of this reaction involves attack by the fatty acid carboxylate anion on P = 0 of a phosphoric anhydride group of ATP to form an intermediate analogous to the tetrahedral carbonyl addition intermediate formed in C=0 chemistry. In the intermediate formed in the fatty acid-ATP reaction, the phosphorus attacked by the carboxylate anion becomes bonded to five groups. The collapse of this intermediate gives an acyl-AMP, which is a highly reactive mixed anhydride of the carboxyl group of the fatty acid and the phosphate group of AMP ... 

This mixed anhydride then undergoes a carbonyl addition reaction with the sulfhydryl group of coenzyme A to form a tetrahedral carbonyl addition intermediate, which collapses to give AMP and an acyl-CoA (a fatty acid thioester of coenzyme A) ... 

STEP 1 A sulfhydryl group of the enzyme thiolase attacks the carbonyl carbon of the ketone to form a tetrahedral carbonyl addition intermediate. 

The mechanism for the reaction of thionyl chloride with a carboxylic acid to form an acid chloride is similar to that presented in Section 10.5C for the conversion of an alcohol to a chloroalkane and involves initial chlorosulfite formation, followed by nucleophilic attack of chloride ion on the carbonyl carbon to give a tetrahedral carbonyl addition intermediate, which decomposes to give the acid chloride, SO2, and chloride ion. 

---