Reversible acid-catalyzed hydration

You may have noticed that the acid catalyzed hydration of an alkene and the acid catalyzed dehydration of an alcohol are the reverse of each other... 

IS reversible with respect to reactants and products so each tiny increment of progress along the reaction coordinate is reversible Once we know the mechanism for the for ward phase of a particular reaction we also know what the intermediates and transition states must be for the reverse In particular the three step mechanism for the acid catalyzed hydration of 2 methylpropene m Figure 6 9 is the reverse of that for the acid catalyzed dehydration of tert butyl alcohol m Figure 5 6... 

Synthetic pine oil is produced by the acid-catalyzed hydration of a-pinene (Fig. 1). Mineral acids, usually phosphoric acid, are used in concentrations of 20—40 wt % and at temperatures varying from 30—100°C. Depending on the conditions used, alcohols, chiefly a-terpineol (9), are produced along with /)-menthadienes and cineoles, mainly limonene, terpinolene, and 1,4- and 1,8-cineole (46—48). Various grades of pine oil can be produced by fractionation of the cmde products. Formation of terpin hydrate (10) from a-terpineol gives P-terpineol (11) and y-terpineol (12) as a consequence of the reversible... 

This elimination reaction is the reverse of acid-catalyzed hydration, which was discussed in Section 6.2. Because a carbocation or closely related species is the intermediate, the elimination step would be expected to favor the more substituted alkene as discussed on p. 384. The El mechanism also explains the general trends in relative reactivity. Tertiary alcohols are the most reactive, and reactivity decreases going to secondary and primary alcohols. Also in accord with the El mechanism is the fact that rearranged products are found in cases where a carbocation intermediate would be expected to rearrange ... 

Note that these mechanisms are the reverse of those involved in the acid-catalyzed hydration of double bonds (15-3), in accord with the principle of microscopic reversibility. With anhydrides (e.g., P2O5, phthalic anhydride) as well as with some other reagents such as HMPA, it is likely that an ester is formed, and the leaving group is the conjugate base of the corresponding acid. In these cases, the mechanism can be El or E2. The mechanism with AI2O3 and other solid catalysts has been studied extensively but is poorly understood. 

The term acid catalysis is often taken to mean proton catalysis ( specific acid catalysis ) in contrast to general acid catalysis. In this sense, acid-catalyzed hydrolysis begins with protonation of the carbonyl O-atom, which renders the carbonyl C-atom more susceptible to nucleophilic attack. The reaction continues as depicted in Fig. 7. l.a (Pathway a) with hydration of the car-bonium ion to form a tetrahedral intermediate. This is followed by acyl cleavage (heterolytic cleavage of the acyl-0 bond). Pathway b presents an mechanism that can be observed in the presence of concentrated inorganic acids, but which appears irrelevant to hydrolysis under physiological conditions. The same is true for another mechanism of alkyl cleavage not shown in Fig. 7.Fa. All mechanisms of proton-catalyzed ester hydrolysis are reversible. 

Synthetic pine oil is produced by the acid-catalyzed hydration of mainly a-pinene derived from sulfate turpentine, followed by distillation of the crude mixture of hydrocarbons and alcohols. The predominant alcohol obtained is a-terpineol, although under the usual conditions of the reaction, reversible and dehydration reactions lead to multiple hydrocarbon and alcohol components (Fig. 1). 

This is the reverse of acid-catalyzed hydration of alkenes discussed previously (Section 10-3E) and goes to completion if the alkene is allowed to distill out of the reaction mixture as it is formed. One mechanism of dehydration involves proton transfer from sulfuric acid to the alcohol, followed by an E2 reaction of hydrogen sulfate ion or water with the oxonium salt of the alcohol ... 

There also exists an acid-catalyzed regioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291 f.). The condensation of secondary amines with aldehydes yields immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CH2-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,/3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercuryfll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

In all these cases it is possible to determine Kk directly by combining kn2o with ku, the rate constant for carbocation formation. The latter constant is readily determined spectrophotometrically by monitoring acid-catalyzed dehydration of the aromatic hydrate to the corresponding aromatic product. In principle, as we have seen, when the dehydration product is aromatic, carbocation formation is the rate-determining step of the reaction. However, the finite values of kp/kn2o for the phenanthrenonium ion and other areno-nium ions leading to moderately stable aromatic products imply a small correction for reversibility of this reaction step. 

Very different solvent deuterium isotope effects (SDIE) of (/ch)/( d) = 0.42 and 1.66, respectively, are observed for acid-catalyzed addition of solvent to o-l and 81.50,58 The inverse SDIE for hydration of o-1 is consistent with initial fast and reversible protonation of substrate followed by rate-determining addition of solvent to the protonated benzylic carbocation o-H-l +. The normal primary SDIE on acid-catalyzed hydration of 81 is consistent with a change in mechanism from stepwise, for acid-catalyzed addition of water o-l,50 to concerted for the acid-catalyzed reaction of 81, where the addition of water and hydron occurs at a single reaction stage (kcon, Scheme 47). 

The mechanism of the formation of the tetrahydropyranyl ether (see Figure 23.1) is an acid-catalyzed addition of the alcohol to the double bond of the dihydropyran and is quite similar to the acid-catalyzed hydration of an alkene described in Section 11.3. Dihydropyran is especially reactive toward such an addition because the oxygen helps stabilize the carbocation that is initially produced in the reaction. The tetrahydropyranyl ether is inert toward bases and nucleophiles and serves to protect the alcohol from reagents with these properties. Although normal ethers are difficult to cleave, a tetrahydropyranyl ether is actually an acetal, and as such, it is readily cleaved under acidic conditions. (The mechanism for this cleavage is the reverse of that for acetal formation, shown in Figure 18.5 on page 776.)... 

As was already mentioned, the standard procedure for acid catalyzed alkene hydration exhibits a rather low selectivity. On the other hand, the use of a hydroxymercuration-reduction sequence leads to the exclusive formation of Markovnikov s alcohols. A nearly exclusive anti-Markovnikov s hydration is achieved via a hydroboration-oxidation reaction (see Section 2.4). The result in both these cases is the net addition of H2O, but the basic differences in the reaction mechanisms unambiguously determine a reversed regioselectivity pattern. 

The acid-catalyzed condensation of 2-bromopyridines with o-aminoace-tophenone in dilute acids afforded the pseudobases 299. These pseudobases underwent dehydration in concentrated sulfuric acid to give the pyr-ido[2,l-6]quinazolinium salts 300, but on dilution of the acid covalent hydration occurred, causing reversion to the pseudobases. 

In acidic media, polarized multiple bonds often undergo acid catalyzed addition, and a common mode of addition is the Ad 2. Deprotonation of the nucleophile by solvent gives the neutral compound. Common examples of this easily reversible Adg2 reaction are the formation of hydrates (NuH is H2O) and, if NuH is ROH, hemiacetals (from aldehydes) and hemiketals (from ketones). Usually this reaction favors reactants. 

At the time when the Ase2 mechanism of the acid-catalyzed hydration of alkenes was finnly established , the reaction of conjugated dienes was also investigated. It was shown that the same mechanism also applietl to dienes (equation 2). The first step is generally reversible but, under well-chosen reaction conditions, the formation of an allylic carbocation by proton addition to one of the two double bonds is rate-limiting. The fast trapping of the carbocation by water in the second step affords the two allylic alcohols conesponding either to a 1,2-addition or to a 1,4-addition. Several pieces of evidence supported this mechanism. 

Addition and elimination processes are the formal reverse of one another, and in some cases the reaction can occur in either direction. For example, acid-catalyzed hydration of alkenes and dehydration of alcohols are both familiar reactions that constitute an addition-elimination pair. 

The mechanistic pattern of hydration and alcohol addition reactions of ketones and aldehydes is followed in reactions of carbonyl compounds with amines and related nitrogen nucleophiles. These reactions involve addition and elimination steps proceeding through tetrahedral intermediates. These steps can be either acid catalyzed or base catalyzed. The rates of the reactions are determined by the energy and reactivity of the tetrahedral intermediates. With primary amines, C=N bond formation ultimately occurs. These reactions are reversible and the position of the overall equilibrium depends on the nitrogen substiments and the structure of the carbonyl compound. 

In Section 4.5, we saw that an alkene is hydrated (adds water) in the presence of an acid catalyst, thereby forming an alcohol. The hydration of an alkene is the reverse of the acid-catalyzed dehydration of an alcohol. 

After dehydrogenation to 234, X = SCoA, the catabolism of leucine 205 (Scheme 62c) differs from that of the other branched-chain amino acids. A biotin-dependent carboxylation leads to the acid 236, X = SCoA, which is hydrated to HMG-CoA 237, a compound involved in isoprenoid biosynthesis. Feeding stereospecifically labeled samples of leucine in studies of terpenoid biosynthesis indicated that the ( )-methyl group was carboxylated without isomerization of the double bond (181, 182). Messner, Cornforth et al. (215) investigated the hydration 236 = 237 catalyzed by the enzyme 3-methyl-glutaconyl-CoA hydratase (EC 4. 2. 1. 18) and showed that the reversible reaction had syn stereospecificity. 

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