774 CHAPTER 18 Carbonyl Compounds II
ENZYME-CATALYZED CIS–TRANS
INTERCONVERSION
Enzymes that catalyze the interconversion of cis
and trans isomers are called cis–trans isomerases. These
isomerases are all known to contain thiol (SH) groups. Thiols
are weak bases and therefore add to the b-carbon of ancarbonyl compound (conjugate addition). The
resulting carbon–carbon single bond rotates before the enol is able
to tautomerize to the ketone. When tautomerization occurs, the
thiol is eliminated. Rotation results in cis–trans interconversion.a,b-unsaturatedcis double bondtrans double bondOOCOO−−OOCenzyme–SHOH OCOO−−OOCenzyme–S
rotationOO− COO−
OOC enzyme–SHOH OCOO−
−OOCenzyme–SSummary
Aldehydesand ketonesare Class II carbonyl compounds;
they have an acyl group attached to a group or
that cannot be readily replaced by another group.
Aldehydes and ketones undergo nucleophilic addition
reactions with C and H nucleophiles and nucleophilic
addition–elimination reactionswith O and N nucleophiles.
With the exception of amides, carboxylic acid derivatives
(Class I carbonyl compounds) undergo nucleophilic acyl
substitutionreactions with C and H nucleophiles to form a
Class II carbonyl compound, which then undergoes a
nucleophilic additionreaction with a second equivalent of
the C or H nucleophile. Notice that the tetrahedral interme-
diate formed by attack of a nucleophile on a carbonyl
compound is stable if the newly formed tetrahedral carbon is
not bonded to a second electronegative atom or group and
is generally unstable if it is.
Electronic and steric factors cause an aldehyde to be
more reactive than a ketone toward nucleophilic attack.
Aldehydes and ketones are less reactive than acyl halides
and acid anhydrides and are more reactive than esters, car-
boxylic acids, and amides.
Grignard reagents react with aldehydes to form sec-
ondary alcohols, with ketones and acyl halides to form ter-
tiary alcohols, and with carbon dioxide to form carboxylic
acids. Aldehydes are reduced to primary alcohols, ketones
to secondary alcohols, and amides to amines.
Aldehydes and ketones undergo acid-catalyzed addition
of water to form hydrates. Electron donation and bulky
substituents decrease the percentage of hydrate present at
equilibrium. Most hydrates are too unstable to be isolated.
Acid-catalyzed addition of alcohol to aldehydes forms
hemiacetalsand acetals, and to ketones forms hemiketals
¬Ar)(¬H, ¬R,and ketals. Acetal and ketal formation are reversible.
Cyclic acetals and ketals serve as protecting groupsfor
aldehyde and ketone functional groups. Aldehydes and ke-
tones react with thiols to form thioacetals and thioketals;
desulfurization replaces the bonds with
bonds.
Aldehydes and ketones react with primary amines to
form iminesand with secondary amines to form enamines.
The mechanisms are the same, except for the site from
which a proton is lost in the last step of the reaction. Imine
and enamine formation are reversible; imines and enam-
ines are hydrolyzed under acidic conditions back to the
carbonyl compound and amine. A pH-rate profileis a
plot of the observed rate constant as a function of the pH
of the reaction mixture. Hydroxide ion and heat differ-
entiate the Wolff–Kishner reduction from ordinary
hydrazoneformation.
An aldehyde or a ketone reacts with a phosphonium
ylide in a Wittig reactionto form an alkene. A Wittig reac-
tion is a concerted cycloaddition reaction; it is
completely regioselective. Stabilized ylides form primarily
Eisomers; unstabilized ylides form primarily Zisomers.
A prochiral carbonyl carbonis a carbonyl carbon that
is bonded to two different substituents. The Reface is the
one closest to the observer when decreasing priorities are in
a clockwise direction; the Siface is the opposite face. At-
tack by a nucleophile on either the Reface or the Siface
forms a pair of enantiomers.
A useful step in a retrosynthetic analysis is a disconnect-
ion—breaking a bond to produce two fragments. Synthons
are fragments of a disconnection. A synthetic equivalentis
the reagent used as the source of the synthon.[2+2]C¬S C¬H