oxygen gives rise to a positively charged sulfonium ion. Addition of an elec- tron to the oxygen would break the S–O bond to form the sulfide and hydroxyl radical. This can add one more electron to form hydroxide anion which would be protonated to form water. An example of metabolic sulf- oxide reduction occurs with the NSAID Sulindac (Figure 7.39). Sulindac is a prodrug with a sulfoxide group. The sulfoxide, which is inactive, under- goes both metabolic oxidation to form a sulfone, which is also inactive, and reduction to form the methyl sulfide, which is active as an antiinflammatory agent.
the carboxylic acid group and the alcohol remain attached as part of the same molecule. Amides also undergo hydrolysis to form two molecules, one of which is again a carboxylic acid, while the other is a primary or second- ary amine. As with lactones, hydrolysis of lactams produces only a single molecule that contains a carboxylic acid group and an amine that are joined by a chain of atoms. The ring-opened hydrolysis products of lactones and lactams may recyclize with elimination of water if conditions are favorable.
The mechanism of a hydrolysis reaction requires attack by water (a nucleophile) at the carbonyl carbon, which is an electrophilic site. Remem- ber that in a carbonyl group the carbon carries a partial positive charge (see Chapter 3). With functional groups such as aldehydes and ketones the charge on that carbon is not counter-balanced by any sources of electron density and is subsequently highly electrophilic. This means that nucleo- philes, including water, will readily attack at this position. Reaction of water with an aldehyde for example (Figure 7.41) creates a new C–OH bond and transfers electron density from the π bond onto the existing oxygen, which then becomes protonated. The result is a functional group known as a hydrate, which has two OH groups attached to a single carbon. Hydrates, however, exist in equilibrium with their original aldehyde forms via elimi- nation of a water molecule. That is because breaking a C–OH bond is much easier than breaking an attached C–C or C–H bond, especially when the OH group is protonated so that it can be eliminated as water.
With esters and amides, however, the heteroatom attached to the car- bonyl carbon can donate electrons which has the effect of decreasing the charge on the carbon and reducing its electrophilicity (Figure 7.42). In order for water to successfully attack the carbon the amount of charge
O
H R
δ+ δ–
H2O
H2O
H R
O OH2
H R
HO OH
Proton transfer
Hydrate
Figure 7.41 Aldehydes and ketones are sufficiently electrophilic so that nucleophiles such as water can attack the carbonyl to give rise to hydrates. While the reactions are reversible, it is only the OH group that can be eliminated because it is weaker than the C–C or C–H bonds.
needs to be increased. This is achieved by having an enzyme coordinate with one of the lone pairs on the carbonyl oxygen. The resonance struc- ture with a formal positive charge on carbon is more stable than that bear- ing a positive charged on oxygen. Now water can attack to form a tetrahedral intermediate, with carbon attached to an R group, alkoxy group, OH2+ (the attacking water), and an O-enzyme. Formation of this intermediate is reversible. However, transfer of a proton from OH2+ to the OR group can also occur. Now the tetrahedral intermediate has an OH and a HOR+ in addition to the other two groups. If the enzyme dissoci- ates away from the oxygen, those electrons will be released back toward carbon and the protonated alkoxy group will be forced out—that is, the HOR+ becomes what is known as a leaving group. Thus an alcohol is pro- duced along with a carboxylic acid. The mechanism for amide hydrolysis is identical except that the nitrogen is a much better electron-donating group which decreases the electrophilicity of the carbon to a greater extent than did the ester alkoxy group. This is because nitrogen can better tolerate having a positive charge than the more electronegative oxygen. Thus the hydrolysis of amides tends to be much slower than that of esters. Both processes, however, are common metabolic pathways. The enzymes that
O
OR' R
δδ+ Enzyme
O
OR' R
Enzyme
H2O
OR' R
O OH2
Enzyme
OR' R
O OH Enzyme
–R'OH H –Enzyme O
OH R
Proton transfer
Figure 7.42 Esters and amides have a heteroatom with lone pair electrons attached to the carbonyl group. This diminishes the amount of positive charge on the carbon mak- ing it less electrophilic. For a nucleophile such as water to attack a catalyst is required to bind to the oxygen, resulting in an increase in positive charge on the carbon. Metaboli- cally this is achieved with a hydrolase enzyme acting as the catalyst. Again the attack of water is reversible. A proton, however, can be transferred to the OR (or NR2) group, which converts it into a good leaving group. When the enzyme dissociates from the oxygen the electrons help push out the leaving group to form a carboxylic acid and an alcohol (or amine).
catalyze these processes are called, respectively, esterases and amidases, and are prevalent in plasma and other body tissues. Figure 7.43 shows two examples of metabolic hydrolysis.
Ester and amide hydrolysis are strongly influenced by steric factors.
From the mechanism of hydrolysis shown above it is seen that while the parent carbonyl derivatives are sp2 hybridized at the carbon, hydrolysis proceeds through a tetrahedral intermediate. Thus bond angles go from a nominal 120° in the ester or amide to about 109° in the intermediate.
Crowding therefore increases before one group gets eliminated and the hybridization returns to sp2. Large substituents that are close to the car- bonyl group can influence the rate at which metabolic hydrolysis occurs.
This is often used to advantage in drug design to modify the duration of action of ester- and amide-containing drugs. If a long duration is required then bulky groups are used on the alkoxy portion or adjacent to the car- bonyl group, whereas if only a short duration is desired, then small groups
Esterase OCH2CH3
O
H2N
O
H2N
OH
HOCH2CH3 +
Benzocaine 4-Aminobenzoic acid Ethanol
CH3
CH3 HN
O N
CH2CH3
CH2CH3
O N
CH2CH3
CH2CH3
CH3
CH3 NH2 HO
+ Amidase
Lidocaine
2,6-Dimethylaniline 2-Diethylaminoacetic acid Figure 7.43 Top: benzocaine, a local anesthetic, is an example of an ester-containing drug that is metabolized by hydrolysis. Bottom: lidocaine, another anesthetic, contains an amide group and is metabolized by amidase to 2,6-dimethylaniline and 2-diethyl- aminoacetic acid.
and easy accessibility to the ester groups ensure that rapid hydrolysis will occur (Figure 7.44).