Nucleophile-solvent attraction

In protic solvents, the allylic carbonium ion formed by acid-catalyzed alkyl carbon-oxygen bond fission can recombine either with the carboxylic acid molecule or with a solvent molecule. The electrostatic attraction between the carbonium and carboxylate ions, which is a major factor in isomerization of allylic esters by ion-pair internal return during solvolysis, is absent in the acid-catalyzed reaction. The more numerous, usually more nucleophilic, solvent molecules in the solvation shell of the carbonium ion should compete effectively with the departed carboxylic acid molecule and solvolysis rather than isomerization should be the predominant reaction. For example, in the presence of 0.05 M perchloric acid, solvolyses of cis- and //- //7.s-5-methyl-2-cyclohexenyl p-nitrobenzoates are not only very much faster than in the absence of the acid, but polarimetric and titrimetric rates of solvolysis of optically-active esters were identical within experimental error. For these esters, the acid-catalyzed solvolysis was not accompanied by a detectable amount of isomerization. Braude reported, on the basis of indirect evidence, that isomerization accompanies acid-catalyzed hydrolysis of a-ethynyl-y-methylallyl acetate in aqueous dioxane. It was shown that, under some experimental conditions, the spectrophotometrically determined rate of appearance of the rearranged 1 -yne-3-ene chromophore exceeds the titrimetrically determined rate of hydrolysis,... 

Finally, an ingenious synthetic sequence by Trost, Cossy and Burks201 includes a unique desulphonylation reaction that involves an electron-transfer process. The synthetic sequence uses 1, l-bis(phenylsulphonyl)cyclopropane as a source of three carbon atoms, since this species is readily alkylated even by weakly nucleophilic species. Given an appropriate structure for the nucleophile, Trost found that desulphonylation with lithium phenanthrenide in an aprotic solvent allowed for an efficient intramolecular trapping of the resultant carbanion (equation 88). This desulphonylation process occurs under very mild conditions and in high yields it will undoubtedly attract further interest. 

The subsequent reaction of the pure 1-nitroanthraquinone to 1-aminoan-thraquinone used to be carried out mainly by reaction with sodium sulfides in an alkaline medium and is now performed by nucleophilic replacement of the nitro group with ammonia in organic solvents, affording up to 98% yield. The overall reaction affords approximately 70% yield, in comparison to the roughly 50% yielded by the classical method which proceeds via the 1-sulfonic acid. Moreover, the newer method is also superior to the old one because recyclization of the solvent makes it ecologically more attractive. 

The affinity of the polymer-bound catalyst for water and for organic solvent also depends upon the structure of the polymer backbone. Polystyrene is nonpolar and attracts good organic solvents, but without ionic, polyether, or other polar sites, it is completely inactive for catalysis of nucleophilic reactions. The polar sites are necessary to attract reactive anions. If the polymer is hydrophilic, as a dextran, its surface must be made less polar by functionalization with lipophilic groups to permit catalytic activity for most nucleophilic displacement reactions. The % RS and the chemical nature of the polymer backbone affect the hydrophilic/lipophilic balance. The polymer must be able to attract both the reactive anion and the organic substrate into its matrix to catalyze reactions between the two mutually insoluble species. Most polymer-supported phase transfer catalysts are used under conditions where both intrinsic reactivity and intraparticle diffusion affect the observed rates of reaction. The structural variables in the catalyst which control the hydrophilic/lipophilic balance affect both activity and diffusion, and it is often not possible to distinguish clearly between these rate limiting phenomena by variation of active site structure, polymer backbone structure, or % RS. 

The nucleophile for which increased reactivity is most critical is the fluoride ion [3,4], Water molecules bind tightly to this ion, and their presence dramatically reduces its effective nucleophilicity. A variety of fluoride ion sources have been used in an effort to improve product yields in deoxyfluoro sugar synthesis [26,34]. The yields of substitution and elimination products generated from reactions with fluoride ion from several sources are listed in Table 2 [26]. Currently, the most attractive source of fluoride ion is tris(dimethylanuno)-5ulfur (trimetbylsilyl)difluoride (TASF), which is soluble in a variety of oiganic solvents and produces an anhydrous fluoride ion [33]. 

The concept of in situ liberation of carbon monoxide would be even more attractive if a metal-free material could serve as the carbon monoxide source. In the ideal carbonylation method, the organic solvent itself could be exploited for controlled generation of carbon monoxide. In 2002, Wan et al. addressed this issue and developed a microwave-promoted carbamoylation process based on the commonly used solvent dimethylformamide (DMF) as the carbon monoxide precursor75. Firstly, it was discovered that aryl dimethyl amides were accessible from the corresponding bromides in the presence of a nucleophilic catalyst, imidazole (Scheme 2.34). Secondly, tertiary benzamides other than dimethylamides were synthesised by addition of 3 equiv of an external amine (Scheme 2.34). 

Phosphoromorpholidate intermediates, initially developed by Khorana and Moffatt,19 have been widely used for the construction of nucleoside diphosphates. The construction of the diphosphate linkage typically involves exposure of a carbohydrate-derived phosphate nucleophile to phosphoromorpholidate electrophile in pyridine solvent. This protocol was attractive from the point of view that it can be executed on completely deprotected precursors. This method suffers, however, from the lengthy reaction times required for reasonable conversion, although a tetrazole modification, introduced by Wong, had been shown to shorten reaction times considerably. The major drawback of this method, for our own purposes, is that it would require construction of either a carbohydrate-derived phosphoromorpholidate or the preparation of a phosphoromorpholidate intermediate deriving from our rather expensive undecaprenyl monophosphate precursor. 

Addition of nucleophiles to electrophilic glycine templates has served as an excellent means of synthesis of a-amino acid derivatives [2c, 4—6]. In particular, imines derived from a-ethyl glyoxylate are excellent electrophiles for stereoselective construction of optically active molecules [32], This research and retrosyn-thetic analysis led us to believe that amine-catalyzed asymmetric Mannich-type additions of unmodified ketones to glyoxylate derived imines would be an attractive route for synthesis of y-keto-ce-amino acid derivatives [33], Initially, L-proline-catalyzed direct asymmetric Mannich reaction with acetone and N-PMP-protected a-ethyl glyoxylate was examined in different solvents. The Mannich-type reaction was effective in all solvents tested and the corresponding amino acid derivative was isolated in excellent yield and enantioselectivity (ee >95 %). Direct asymmetric Mannich-type additions with other ketones afford Mannich adducts in good yield and excellent regio-, diastereo- and enantioselectivity (Eq. 8). 

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