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electrophilic nitration of benzene by acetyl nitrate (CH₃CO₂NO₂) involves substitution of the aromatic C─H bond by a nitro (–NO₂) group (Reaction 1.72) [3]:

(1.72)

Overall, the reaction has the second‐order rate law, first order in benzene and first order in acetyl nitrate (rate = k[C₆H₆][CH₃CO₂NO₂]). Study of the kinetic isotope effect using fully deuterated benzene C₆D₆ shows k_H/k_D = 1 [3]. The data indicate that the C─H bond cleavage is not involved in the rate‐determining step. Instead, the rate‐determining step is the electrophilic attack of the nitrating agent on benzene, which is supported by the observed overall second‐order rate law. Mechanism for the reaction is shown in Figure 1.20. The aromatic nitration and related electrophilic substitution reactions of arenes will be studied in Chapter 5.

FIGURE 1.20 Reaction mechanism for nitration of benzene by acetyl nitrate.

      

1.11 ENZYMES: BIOLOGICAL CATALYSTS

      Biochemistry is the study of life at the molecular level. Among main types of biomolecules are carbohydrates (including monosaccharides, disaccharides, and polysaccharides), lipids (including triacylglycerols, phospholipids, and steroids), proteins, and nucleotides (e.g., ATP) and nucleic acids (including RNA and DNA). Most of the biochemical reactions that occur in vivo (in the living systems such as animals and plants) are catalyzed by enzymes, which are also called biological catalysts. Almost all the enzymes are protein molecules which are composed of α‐amino acid residues linked by peptide bonds. There are six types of enzymes classified on the basis of the types of reactions that the enzymes catalyze. They are oxidoreductases (the enzymes catalyzing oxidation–reduction reactions), transferases (the enzymes catalyzing group transfers, namely to substitute one functional group for another), lyases (the enzymes catalyzing elimination of two groups from adjacent carbon atoms to form a C=C double bond), hydrolases (the enzymes catalyzing hydrolysis of biomolecules), isomerases (the enzymes catalyzing isomerization reactions), and ligases (the enzymes catalyzing bond formation coupled with ATP hydrolysis) [8].

An enzyme contains an active site which is the catalytic center where a biochemical reaction takes place. The active site is usually composed of functional groups from side chains of some α‐amino acid residues in the protein (enzyme) molecule. The biological reactant molecule(s) [often termed substrate(s), one or more] enters the structure of the enzyme and loosely binds to the enzyme usually by hydrogen bonding, hydrophobic interactions, and/or ionic bonding to form an intermediate enzyme–substrate complex (ES complex). Then various chemical processes take place in the ES complex to lead to the formation of the product. Finally, the product departs from structure of the enzyme to regenerate a free enzyme molecule. The enzyme catalyzed biochemical reactions are generalized as follows (Eq. 1.73):

(1.73)

      In Equation 1.73, S and E represent the biological substrate and enzyme, respectively. ES is the intermediate enzyme–substrate complex. P is the reaction product. The formation of the ES complex is usually reversible, while the conversion of ES to the final product is irreversible.

      An enzyme catalyzes a biochemical reaction by lowering activation energy of the reaction. On the basis of the types of interactions between the enzyme and the biological substrate in the transition state of a biochemical reaction, there are in general three types of catalytic mechanisms.

      1 The acid–base catalysis. Hydrogen bonds are formed in the transition state, which stabilize the transition state (decrease the level of its free energy) to lower the activation energy (ΔGǂ). As a result, the reactivity of the substrate is enhanced and the reaction goes faster.

      2 The metal–ion catalysis. The catalytic center is a metal ion which is attached to functional groups of some side chains of α‐amino acid residues of the enzyme. A coordination bond between the substrate and the metal ion is formed (or partially formed) in the transition state to stabilize the transition state and activate the substrate.

      3 The covalent catalysis. A covalent bond between the substrate and the enzyme is formed (or partially formed) in the active site in the transition state to stabilize the transition state and activate the substrate.

      A remarkable feature for enzymatic reactions is that the enzyme and substrate are both structurally and electronically complementary (also called key‐to‐lock model). As a result, the catalytic efficiency is extremely high. An enzymatic reaction is often 10⁶–10¹² times as fast as the uncatalyzed reaction [8]. In addition, most of the enzymatic reactions are highly selective and stereospecific due to the enzyme–substrate complementarity.

Many common enzymatic reactions follow mechanisms of the acid–base catalysis. The catalysis is usually concerted and achieved by proton transfer between the enzyme and substrate. The general principle for this type of catalysis can be illustrated using a generalized keto–enol tautomerization (Fig. 1.21).

      Figure 1.21a shows an uncatalyzed, concerted keto–enol tautomerization taking place via a single transition state. The transition state is greatly destabilized (with a high level in free energy) by the formation of partial electric charges in different atoms. Figure 1.21b and c show acid‐ and base‐catalyzed tautomerization, respectively. The acid H–A and base :B⁻ represent acidic and basic functional groups, respectively, in the active sites of enzymes. In the acid catalysis (Fig. 1.21b), a hydrogen bond is formed in the transition state on the carbonyl of the keto substrate to stabilize the partial negative charge on oxygen (via the electrostatic attraction to the partial positive charge on the HA proton). This stabilization leads to decrease in the energy level (in the free energy term) of the transition state and the activation energy (ΔG^ǂ) is lowered. In the base catalysis (Fig. 1.21c), a partial deprotonation on α‐carbon by the basic group occurs in the transition state. As a result, the partial positive charge developed on the α‐hydrogen of the keto substrate is stabilized (via the electrostatic attraction to the negative charge in the basic group B⁻). This stabilization leads to decrease in the free energy level of the transition state and the activation energy is lowered. In both acid‐ and base‐catalyzed tautomerization (Fig. 1.21b and c), the formations of the enol and regeneration of the free enzymes from the transition states (TS1 and TS2) proceed via additional proton transfer steps. However, these steps are spontaneous and fast and do

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