Water, acyl addition reactions

If the solvent is water, or contains water, the bimolecular (collision) processes between a neutral substrate and a charged nucleophile (such as nucleophilic acyl addition reactions and nucleophilic displacement with alkyl halides) are generally slow due to solvation effects and unimolecular processes may be competitive. A H unimolecular process involves ionization of the substrate, usually to a carbocation (sec. 2.7.B.1). If the solvent is anything but water, the faster bimolecular processes probably dominates., which is obviously an assumption. 

If the solvent is water or if it contains water, the bimolecular (collision) processes between a neutral substrate and a charged nucleophile (such as nucleophilic acyl addition reactions and nucleophilic displacement with alkyl hahdes) are slower due to solvation effects. On the other hand, water is an excellent solvent for the solvation and separation of ions, so unimolecular processes (which involve ionization to carbocations see Chapter 11, Section 11.6) may be competitive. If the solvent is protic (ethanol, acetic acid, methanol), ionization is possible, but much slower than in water. However, ionization can occiu- if the reaction is given sufficient time to react. In other words, ionization is slow, but not impossible. An example of this statement is the solvolysis of alcohols presented in Chapter 6 (Section 6.4.2). Based on this observation, assume that ionization (unimolecular reactions) will be competitive in water, but not in other solvents, leading to the assumption that bimolecular reactions should be dominant in solvents other than water. This statement is clearly an assumption, and it is not entirely correct because ionization can occur in ethanol, acetic acid, and so on however, the assumption is remarkably accurate in many simple reactions and it allows one to begin making predictions about nucleophilic reactions. 

With respect to this sequence of observed reactions, experimental evidence shows that 21 reacts with the base (NaOEt) to form an enolate anion, and the nucleophilic carbon atom of that enolate anion attacks the carbonyl of a second aldehyde to give the alkoxide of 22. This is a normal acyl addition reaction, and the nucleophile is the a-carbon of the enolate anion. Treatment of this initial alkoxide product with aqueous acid under mild conditions simply generates alcohol 22, as with all other acyl addition reactions (see Chapter 18). Product 22 is called an alilol or an aldolate. The reaction of an aldehyde or a ketone with a base generates an aldol product. Vigorous acid hydrolysis led to protonation of the OH unit in 22 by the strong acid (to form an oxonium ion), which eliminated a molecule of water (dehydration) to give the alkene unit in 23. 

The Hell-Volhard-Zelinskii reaction is a bit more complex than it looks and actually involves substitution of an acid bromide enol rather than a carboxylic acid enol. The process begins with reaction of the carboxylic acid with PBr3 to form an acid bromide plus HBr (Section 21.4). The HBr then catalyzes enolization of the acid bromide, and the resultant enol reacts with Br2 in an cr-substitution reaction to give an cv-bromo acid bromide. Addition of water hydrolyzes the acid bromide in a nucleophilic acyl substitution reaction and yields the a-bromo carboxylic acid product. 

In addition, at very low water contents, ampicillin accumulation curves do not exhibit a clear-cut maximum, inherent in the enzymatic acyl transfer reactions in aqueous medium (including quite concentrated heterogeneous aqueous solution-precipitate systems), because of the secondary hydrolysis of the target product by penicillin acylase (Figure 12.6) [84]. 

A Japanese group have been investigating the use of readily accessible dihydrocinnoline derivatives of the type 1 (R = alkyl, aryl, styryl, ethoxy X = H or methoxy) as novel precursors for the synthesis of other types of heterocycles. The following synthesis of 2-acetyl-3-cyanoindole is representative of a new general method (22-88% for 10 examples) for the preparation of 2-acyl- and 2-ethoxycarbonyl-3-cyanoindoles from 1 a mixture of 1 (R = Me, X = H 1 eq.) and powdered potassium cyanide (2 eq.) was stirred overnight in aqueous DMF at room temperature. Addition of water to the reaction mixture precipitated 2-acetyl-3-cyanoindoIe, which was obtained in 54% yield after recrystallisation. 

Wells (1971) showed through the addition of oxygen-18-labeled water to the reaction mixture that the point of attack occurs at the O-acyl bond as shown by the arrows in Figure 4-5. This conclusion was supported by the finding that oxygen-18 was found only in the liberated fatty acid. Though no direct evidence for the occurrence of an acyl-enzyme intermediate could be obtained, formation of such a complex could not be completely excluded. 

Dithioacetals are useful in organic synthesis as protective groups for carbonyl compounds, as precursors of acyl carbanion equivalents or as electrophiles under Lewis acidic conditions. The DBSA-catalysed system was also found to be applicable to dithioacetal-ization in water. In addition, easy work-up has been realized without the use of organic solvents when the products are solid and insoluble in water. In fact, the dithioacetaliza-tion of cinnamaldehyde on 10 mmol-scale with 1 mol% of DBSA proceeded smoothly to deposit crystals. The pure product was obtained in excellent yield after the crystals were filtered and washed with water (Equation (8)). This simple procedure is one of the advantages of the present reaction system. 

The mechanisin of alcohol oxidation with NAD has several analoge in laboratory chemistry A base removes the O-TC proton from the alcohol and Keaerates an allcoxide ion, which expels a hydride ion leaving group as in the Cannizzaro reaction tSection 19.13>> The nucleophilic hydride ion dacn adds to the Cs=C-C=N part of NAD in a conjugate addition reaction, much the same as water adds to the C=C-C=0 part of the tt,p-unsaturated acyl CoA in step 2. 

The first step in the Hell-Volhard-Zelinskii reaction takes place bet PBra and a carboxylic acid to yield an intermediate acid bromide plus] (Section 21.4). The HBr thus formed catalyzes enolization of the acid I mide, and the resultant enol reacts rapidly with Brg in an a-substittttif reaction. Addition of water results in hydrolysis of the a-bromo acid 1 mide (a nucleophilic acyl substitution reaction) and gives the n-bromo< boxylic acid product. 

When the enzyme is used to catalyse the synthesis of a peptide bond, the solvent is either non-aqueous or contains only a low concentration of water. In addition, of course, an amino component such as an amino acid or peptide ester replaces the water in the second step. Obviously, the amino component must be unprotonated for reaction to succeed. Synthesis is favoured over hydrolysis of the resultant peptide because an amide is kinetically a much worse substrate for a proteinase than is an ester. The rapid acylation of a proteinase by an TV-protected amino acid or peptide aryl ester can be demonstrated experimentally using a stopped-flow apparatus with spectrophotometric facilities. A rapid burst of phenol is followed by steady-state release, showing that acylation of the enzyme is faster than hydrolysis of the acy-lated enzyme. No such burst is detectable if, for example, an TV-acylated amino acid anilide is used as substrate. In fact, acylation is the rate-determining step with amide substrates. 

Evidence for the mechanism was obtained by looking at a variety of alcohols. The addition of alcohols to the cyano group is also catalyzed by metals (Equation 1). Ethanol had the normal reactivity of free ethanol in solution. That is, the ratio of reactivity of alcohol to water in mixed reactions was of the order of ten to one. This is characteristic of attack of external ethanol in many acylation reactions and consistent with the second mechanism. Ethanol in the coordination sphere of nickel, as in the first mechanism, would be selected against. We also tried to put ligands into the coordination sphere of nickel, as in the case of ethanolamine or hydroxyethylethylenediamine, and these did not show any selective reactivity, excluding the possibility that it was a nickel-bound ligand which was attacking. 

For the acylation, additional amounts (50% molar excess) of pyridine and acid chloride are beneficial. The reaction takes from hours to days at room temperature. The triacylglycerol product can be crystallized with good purity in some cases but in others it is necessary to use an alumina column in addition. Jensen and Pitas (1976) emphasize that, for the latter to be used efficiently, the triacylglycerol must be soluble in hexane-anhydrous diethyl ether (9 1) at room temperature. Many saturated triacylglycerols are not thus soluble and, so, have to be purified by crystallization alone. When the latter is used then ethanol is included in the crystallization solvent so that excess acid chloride is converted to the ester which remains in solution. When alumina columns are employed, care must be taken to eliminate all traces of alcohol, chloroform or water from the eluting solvents, since these can ruin the separation. Alumina columns can be run rapidly and recoveries are 80-90% (Jensen etaL, 1966). 

Stereospecific Michael addition reactions also may be catalyzed by hydrolytic enzymes (Scheme 2.205). When ot-trifluoromethyl propenoic acid was subjected to the action of various proteases, lipases and esterases in the presence of a nucleophile (NuH), such as water, amines, and thiols, chiral propanoic acids were obtained in moderate optical purity [1513]. The reaction mechanism probably involves the formation of an acyl enzyme intermediate (Sect. 2.1.1, Scheme 2.1). Being an activated derivative, the latter is more electrophilic than the free carboxylate and undergoes an asymmetric Michael addition by the nucleophile, directed by the chiral environment of the enzyme. In contrast to these observations made with crude hydrolase preparations, the rational design of a Michaelase from a lipase-scaffold gave disappointingly low stereoselectivities [1514-1517]. 

Lipases are able to catalyse the acylation of alcohols in addition to the hydrolysis of esters. For acylations, the reactions are typically carried out in low-water systems (water activity (a ) < 1)), to minimize hydrolysis, and with a suitably reactive acyl donor to ensure high rates of reaction and efficient conversions. Suitable acyl donors include oximes, vinyl esters and anhydrides (Scheme 4.5). 

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