Reaction Type 2 - Solvolysis

The solvolysis of 2-chloro-2-methylpropane is 335000 times faster in water than in the less polar solvent ethanol [40] cf. reaction type (a) in Table 5-4. 

Reaction type 3 in Table 5-25 is best represented by the SnI solvolysis of 2-chloro-2-methylpropane cf. Eq. (5-13) in Section 5.3.1. Considering the heterolysis of the C—Cl bond, one would expect the activation volume to be positive because of the C—Cl stretching during the activation process. However, a negative activation volume of AF = —22.2 cm mol has been found for this solvolysis at 30 °C in ethanol/ water (80 20 cL/L), indicating a strong volume contraction due to solvation of the dipolar activated complex (electrostriction) [756]. Typical activation volumes for halo-alkane solvolyses in pro tic solvents are in the range of —15... —30 cm mol ... 

A-Homocholestane derivatives have been obtained by the Demjanov ring-enlargement reaction. Transannular solvolysis reactions have been observed in seco-steroids of type (393) containing a ten-membered ring. Thus, treatment of (393) in aqueous acetone solution produced 5(10—> l H)abeo-5fi-cholest-10(19)-ene 3/8-acetate (394) in high yield. ... 

The relative strengths of weakly basic solvents are evaluated from the extent of protonation of hexamethylbenzene by trifluoro-methanesulfonic acid (TFMSA) in those solvents or from the effect of added base on the same protonation in solution in trifluoroacetic acid (TFA), the weakest base investigated. The basicity TFA < di-fluoroacetic acid < dichloroacetic acid (DCA) < chloroacetic acid < acetic acid parallels the nucleophilicity. 2-Nitropropane appears to be a significantly stronger base than DC A by the first approach, although in the second type of measurement, the two have essentially equal basicity. The discrepancy is due to an interaction, possible for hydroxylic solvents such as DC A, with the anion of TFMSA. This anion stabilization is a determining factor of carbocationic reactivity in chemical reactions, including solvolysis. A distinction is made between carbocation stability, determined by structure, and persistence (existence at equilibrium, e.g., in superacids), determined by environment, that is, by anion stabilization. 

Describe what is meant by each of the following reaction types, and illustrate with an example from the text (a) dehydration (b) hydrolysis (c) solvolysis (d) hydration of an alkene. 

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

An example of a reaction series in which large deviations are shown by — R para-substituents is provided by the rate constants for the solvolysis of substituted t-cumyl chlorides, ArCMe2Cl54. This reaction follows an SN1 mechanism, with intermediate formation of the cation ArCMe2 +. A —R para-substituent such as OMe may stabilize the activated complex, which resembles the carbocation-chloride ion pair, through delocalization involving structure 21. Such delocalization will clearly be more pronounced than in the species involved in the ionization of p-methoxybenzoic acid, which has a reaction center of feeble + R type (22). The effective a value for p-OMe in the solvolysis of t-cumyl chloride is thus — 0.78, compared with the value of — 0.27 based on the ionization of benzoic acids. 

Deuterium isotope effects have been found even where it is certain that the C—H bond does not break at all in the reaction. Such effects are called secondary isotope effectsf" the term primary isotope effect being reserved for the type discussed previously. Secondary isotope effects can be divided into a and P effects. In a P secondary isotope effect, substitution of deuterium for hydrogen p to the position of bond breaking slows the reaction. An example is solvolysis of isopropyl bromide ... 

Kinetic studies also provide other evidence for the SnI mechanism. One technique used F NMR to follow the solvolysis of trifluoroacetyl esters. If this mechanism operates essentially as shown on page 393, the rate should be the same for a given substrate under a given set of conditions, regardless of the identity of the nucleophile or its concentration. In one experiment that demonstrates this, benzhy-dryl chloride (Ph2CHCl) was treated in SO2 with the nucleophiles fluoride ion, pyridine, and triethylamine at several concentrations of each nucleophile. In each case, the initial rate of the reaction was approximately the same when corrections were made for the salt effect. The same type of behavior has been shown in a number of other cases, even when the reagents are as different in their nucleophilicities (see p. 438) as H2O and OH . 

In an elegant summary, Bly and Koock (95) explain the diverse products and results observed in the solvolysis of all homoallenic systems as shown in Scheme VI. Upon reaction, homoallenic derivatives which solvolyze with TT-electron participation form an initial cyclopropylcarbinyl-type ion, 127. 

In this type of reaction the active drug undergoes decomposition following reaction with the solvent present. Usually the solvent is water, but sometimes the reaction may involve pharmaceutical cosolvents such as ethyl alcohol or polyethylene glycol. These solvents can act as nucleophiles, attacking the electropositive centers in drug molecules. The most common solvolysis reactions encountered in pharmaceuticals are those involving labile carbonyl compounds such as esters, lactones, and lactams (Table 1). 

Another reaction mechanism that occurs in some chain-growth polymers is solvolysis. In this type of reaction, a species reacts with a C-X bond, where X represents a halogen, and breaks it. Specifically, this becomes important when describing the degradation of polyvinyl chloride. Acidic species act to remove the chlorine atom, forming hydrochloric acid. 

The chemical nature of the main-chain linkages of step-growth polymers makes this class of polymers particularly reactive to a wide variety of chemical species. Solvolysis reactions break the C-X bond at the polymer linkage bonds. These types of reactions are often pH-dependent, so the stability of the polymer is highly dependent on the acidity or basicity of the prodegradant. 

Simple kinetic measurements can, however, be an inadequate guide to which of the above two mechanisms, SN1 or SN2, is actually operating in, for example, the hydrolysis of a halide. Thus, as we have seen (p. 45), where the solvent can act as a nucleophile (solvolysis), e.g. H20, we would expect for an S 2 type reaction,... 

Thus solvolysis of (+)C6HsCHMeCl, which can form a stabilised benzyl type carbocation (cf. p. 84), leads to 98% racemisation while (+)C6H13CHMeCl, where no comparable stabilisation can occur, leads to only 34% racemisation. Solvolysis of ( + )C6H5CHMeCl in 80 % acetone/20 % water leads to 98 % racemisation (above), but in the more nucleophilic water alone to only 80% racemisation. The same general considerations apply to nucleophilic displacement reactions by Nu as to solvolysis, except that R may persist a little further along the sequence because part at least of the solvent envelope has to be stripped away before Nu can get at R . It is important to notice that racemisation is clearly very much less of a stereochemical requirement for S l reactions than inversion was for SN2. 

The discovery of carbene and carbenoid additions to olefins was the major breakthrough that initiated the tapping of this structural resource for synthetic purposes. Even so, designed applications of cyclopropane chemistry in total syntheses remain limited. Most revolve around electrophilic type reactions such as acid induced ring opening or solvolysis of cyclopropyl carbinyl alcohol derivatives. One notable application apart from these electrophilic reactions is the excellent synthesis of allenes from dibromocyclopropanes 2). 

A similar vinylic cation was once claimed to be formed during the solvolysis of cyclohexylidenemethyl triflate in aqueous methanol at 140 °C (eq 9),13 but this reaction could occur via participation and SN2-type reaction. Solvolysis of the optically active 4-methyl-substituted triflate under the same reaction conditions took place with complete retention of the optical purity.14... 

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