As a nucleophilic catalyst

Acylation of alcohols is often performed in the presence of an organic base such as pyridine. The base serves two purposes. It neutralizes the protons generated in the reaction and prevents the development of high acid concentrations. Pyridine also becomes directly involved in the reaction as a nucleophilic catalyst (see Section 8.5). 

Sulfonic esters are most frequently prepared by treatment of the corresponding halides with alcohols in the presence of a base. The method is much used for the conversion of alcohols to tosylates, brosylates, and similar sulfonic esters. Both R and R may be alkyl or aryl. The base is often pyridine, which functions as a nucleophilic catalyst, as in the similar alcoholysis of carboxylic acyl halides (10-21). Primary alcohols react the most rapidly, and it is often possible to sulfonate selectively a primary OH group in a molecule that also contains secondary or tertiary OH groups. The reaction with sulfonamides has been much less frequently used and is limited to N,N-disubstituted sulfonamides that is, R" may not be hydrogen. However, within these limits it is a useful reaction. The nucleophile in this case is actually R 0 . However, R" may be hydrogen (as well as alkyl) if the nucleophile is a phenol, so that the product is RS020Ar. Acidic catalysts are used in this case. Sulfonic acids have been converted directly to sulfonates by treatment with triethyl or trimethyl orthoformate HC(OR)3, without catalyst or solvent and with a trialkyl phosphite P(OR)3. ... 

Complexes like 64 and 65 can act by two general ways either as a Br0nsted-base or as a nucleophilic catalyst, depending on the type of reaction and substrate. However, the exact mechanistic pathway is in a few cases speculative to some extent as the distinction between the two mechanistic routes is sometimes rather difficult. 

In a similar vein, antibody NPN43C9 appears to employ a catalytic histidine, HisL91, as a nucleophilic catalyst in the hydrolysis of a p-nitrophenyl phenylacetate ester, as discussed in detail below (Section 5 Appendix entry 2.8) (Gibbs et al., 1992a Chen et al., 1993). 

Oxime hgations can be significantly accelerated by using aniline as a nucleophilic catalyst . Rate enhancements are achieved by changing the electrophile from a weakly populated protonated carbonyl (Scheme 2a) to a more highly populated protonated aniline Schiff base (Scheme 2b). The transimination of the protonated aniline Schiff base to the oxime proceeds rapidly under aqueous acidic conditions. 

An even stronger catalytic effect is obtained when 4-dimethylaminopyridine (DMAP) is used as a nucleophilic catalyst.96 The dimethylamino group acts as an electron-donor... 

Tri-n-butylphosphine is also an effective catalyst for acylations by anhydrides. It is thought to act as a nucleophilic catalyst by generating an acylphosphonium ion.102... 

The key intermediate chloromethyloxadiazole 18 was prepared in two steps from inexpensive, commercially available materials as shown in Scheme 5.10. Bishydrazide 19 was prepared in a one-pot procedure by reaction of 35% aqueous hydrazine with ethyl trifluoroacetate in acetonitrile and subsequent addition of chloroacetyl chloride and base. This procedure affords the unsymmetrical bis(hydrazide) 19 in higher than 95% assay yield. While a number of dehydrating agents were found to be effective in the dehydration to prepare 18, phosphorus oxychloride was chosen because of its low cost and relatively benign waste stream. Sub-stoichiometric (0.3 equiv.) amounts were found to be as effective as full equivalents in the reachon when used in conjunction with catalyhc amounts of DMAP as a nucleophilic catalyst. The entire sequence was transformed into a one-pot through process in order to improve efficiency. Following the cyclization, an aqueous work-up was performed and the organic extracts carried directly into the next step. 

They suggested that the terra in [I-] in equation (61) corresponded to a mechanism in which the iodide ion acted as a nucleophilic catalyst. These results of Gielen and Nasielski have been disputed by Pilloni and Tagliavini51 who declare that in the iodinolysis of tetramethyllead in solvent acetonitrile. . the product /t°2bs-[r] is fairly constant within the limit of experimental error . Their results are given in Table 28. It may be seen that the values of A 5bs [I ] are not quite constant, and can be fitted to an expression of the same type as equation (61), viz. ... 

Triphenylphosphine was employed as a nucleophilic catalyst for the umpolung addition of azoles (225) to the electron-deficient allenes (226 R1 = H, R2 = OEt, R3 = H, Et) to afford the addition products (227). This organocatalytic methodology has been extended to addition-cyclization reactions between electron-deficient allenes or alkynes and pyrrole-2-carboxaldehyde in the presence of a catalytic amount of tri-butylphosphine, giving the substituted indolizine-7-carboxylates (228 R2 = OEt, Me R3 = H, Et).265... 

In addition to phosphines and pyridines, N-alkylated imidazoles are also known to act as a nucleophilic catalysts in acylation reactions [1], In the approach by Miller et al. short oligopeptides incorporating N-alkylhistidine derivatives were used as enantioselective acylation catalysts [27]. The design of, e.g., the tripeptide... 

Fife and co-workers described a macromolecule, 5 containing 4-DAAP and a bis-(trimethylene) disiloxane backbone that exhibited enzyme-like substrate selectivity for the esterolysis of p-mtrophenyl alkanoates, 6 (Scheme 5.2). This synthetic polymer showed highest levels of activity toward substrate 6 (n = 14), when it was used as a nucleophilic catalyst for the solvolysis of a series of... 

The iodide reacts as a better nucleophile than Ph3P and then as a better leaving group than Br. Each iodide ion goes round and round many times as a nucleophilic catalyst. 

The answer is to protect the hydroxyl group, and the group chosen here was a silyl ether. Such ethers are made by reacting the alcohol with a trialkylsilyl chloride (here f-butyl dimethyl silyl chloride, or TBDMSCl) in the presence of a weak base, usually imidazole, which also acts as a nucleophilic catalyst (Chapter 12). 

Pyridine is a reasonable nucleophile for carbonyl groups and is often used as a nucleophilic catalyst in acylation reactions. Esters are often made in pyridine solution from alcohols and acid chlorides (die full mechanism is onp. 281 of Chapter 12). 

An equally serious problem is that the nitrogen lone pair is basic and a reasonably good nucleophile—this is the basis for its role as a nucleophilic catalyst in acylations. The normal reagents for electrophilic substitution reactions, such as nitration, are acidic. Treatment of pyridine with the usual mixture of HN03 and H2SO4 merely protonates the nitrogen atom. Pyridine itself is not very reactive towards electrophiles the pyridinium ion is totally unreactive. 

This is how the N-Boc pyrrole was made for use in the synthesis of epibatidine. The base used was the pyridine derivative DMAP, which you met earlier in the chapter. It has a p Tan of 9.7 and so produces small, equilibrating amounts of the anion as well as acting as a nucleophilic catalyst. Boc anhydride is used as the acylating agent. 

The serine enzymes have a serine residue vital for catalysis. The serine OH group is known to act as a nucleophilic catalyst. Draw out the mechanism for the hydrolysis of p-nitrophenyl acetate. 

First of all, a photochemical ring opening of the chinolacetate to the ketene occurs in the subsequent thermic cyclization the tertiary amine serves as a nucleophilic catalyst to form the lactone. 

It must be pointed out, however, that the catalytic role ( yed by the imidazole group at the active site of serine esterases is different frimi that of Eq. (4—1). The imidazole group at the active ate helps acyiatifH) and deaQdation at the seiyl 1 -droxyl group as general base (see Fig. 2—1), whereas in Eq. (4—1) imidazde acts as a nucleophilic catalyst. 

Mechanism The experimental evidence supports the nucleophilic catalysis mechanism as discussed in Scheme 3.11. The amine is acting as a nucleophilic catalyst rather than a base... 

In outline, the mechanism of the enzyme catalysed hydrolysis must use the serine OH as a nucleophilic catalyst to form the known intermediate and then hydrolyse that intermediate with water, Lhe intermediate is an ordinary ester rather than a lactone so its hydrolysis will need help from the cnzvme too. 

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