Thermodynamic control, nucleophilic

An interesting case are the a,/i-unsaturated ketones, which form carbanions, in which the negative charge is delocalized in a 5-centre-6-electron system. Alkylation, however, only occurs at the central, most nucleophilic position. This regioselectivity has been utilized by Woodward (R.B. Woodward, 1957 B.F. Mundy, 1972) in the synthesis of 4-dialkylated steroids. This reaction has been carried out at high temperature in a protic solvent. Therefore it yields the product, which is formed from the most stable anion (thermodynamic control). In conjugated enones a proton adjacent to the carbonyl group, however, is removed much faster than a y-proton. If the same alkylation, therefore, is carried out in an aprotic solvent, which does not catalyze tautomerizations, and if the temperature is kept low, the steroid is mono- or dimethylated at C-2 in comparable yield (L. Nedelec, 1974). 

Unsaturated sugars are useful synthetic intermediates (11). The most commonly used are the so-called glycals (1,5- or 1,4-anhydroalditol-l-enes). In the presence of a Lewis-acid catalyst, 3,4,6-tri-0-acetyl-l,5-anhydro-2-deoxy-D-arabinohex-l-enitol [2873-29-2] commonly called D-glucal triacetate, adds nucleophiles in both kineticaHy controlled and thermodynamically controlled (soft bases predominately at C-3 and hard bases primarily at C-1) reactions (11,13). 

For the other broad category of reaction conditions, the reaction proceeds under conditions of thermodynamic control. This can result from several factors. Aldol condensations can be effected for many compounds using less than a stoichiometric amount of base. Under these conditions, the aldol reaction is reversible, and the product ratio will be determined by the relative stability of the various possible products. Conditions of thermodynamic control also permit equilibration among all the enolates of the nucleophile. The conditions that permit equilibration include higher reaction temperatures, protic solvents, and the use of less tightly coordinating cations. 

Specific alterations of the relative reactivity due to hydrogen bonding in the transition state or to a cyclic transition state or to electrostatic attraction in quaternary compounds or protonated azines are included below (cf. also Sections II, B, 3 II, B, 5 II, C and II, F). A-Protonation is often reflected in an increase in JS and therefore the relative reactivity can vary with the significance of JS in controlling the reaction rate. Variation can also result from rate determination by the second stage of the SjjAr2 mechanism or from the intervention of thermodynamic control of product formation. Variation in the rate and in the reactivity pattern of polyazanaph-thalenes will result when nucleophilic substitution [Eq. (10)] occurs only on a covalent adduct (408) of the substrate rather than on its aromatic form (400). This covalent addition is prevented by any 4-... 

In comparing nucleophiles whose attacking atom is in the same row of the periodic table, nucleophilicity is approximately in order of basicity, though basicity is thermodynamically controlled and nucleophilicity is kinetically controlled. So an approximate order of nucleophilicity is NH2 >RO > OH > R2NH > ArO > NH3 > pyridine > F > H2O > CIO4, and another is R3C > R2N > RO > F (see Table 8.1). This type of correlation works best when the structures of the nucleophiles being compared are similar, as with a set of substituted phenoxides. Within such a series, linear relationships can often be established between nucleophilic rates and pAT values. 

The fundamental aspects of the structure and stability of carbanions were discussed in Chapter 6 of Part A. In the present chapter we relate the properties and reactivity of carbanions stabilized by carbonyl and other EWG substituents to their application as nucleophiles in synthesis. As discussed in Section 6.3 of Part A, there is a fundamental relationship between the stabilizing functional group and the acidity of the C-H groups, as illustrated by the pK data summarized in Table 6.7 in Part A. These pK data provide a basis for assessing the stability and reactivity of carbanions. The acidity of the reactant determines which bases can be used for generation of the anion. Another crucial factor is the distinction between kinetic or thermodynamic control of enolate formation by deprotonation (Part A, Section 6.3), which determines the enolate composition. Fundamental mechanisms of Sw2 alkylation reactions of carbanions are discussed in Section 6.5 of Part A. A review of this material may prove helpful. 

The anti addition is a kinetically controlled process that results from irreversible backside opening of an iodonium ion intermediate by the carboxylate nucleophile. Bartlett and co-workers showed that the more stable trans product was obtained under acidic conditions in which there is acid-catalyzed equilibration (thermodynamic control).74... 

Given their extraordinary reactivity, one might assume that o-QMs offer plentiful applications as electrophiles in synthetic chemistry. However, unlike their more stable /tora-quinone methide (p-QM) cousin, the potential of o-QMs remains largely untapped. The reason resides with the propensity of these species to participate in undesired addition of the closest available nucleophile, which can be solvent or the o-QM itself. Methods for o-QM generation have therefore required a combination of low concentrations and high temperatures to mitigate and reverse undesired pathways and enable the redistribution into thermodynamically preferred and desired products. Hence, the principal uses for o-QMs have been as electrophilic heterodienes either in intramolecular cycloaddition reactions with nucleophilic alkenes under thermodynamic control or in intermolecular reactions under thermodynamic control where a large excess of a reactive nucleophile thwarts unwanted side reactions by its sheer vast presence. 

The first silicon-organophosphorus betaine with a thiolate center (15a) was synthesized by the reaction of stable silanethione (14) with trimethyl-methylenephosphorane (Scheme 8) and characterized by multinuclear NMR spectroscopy.14 Compound 15a is formed under kinetic control and is transformed, under the thermodynamically controlled conditions, into the silaacenaphthene salt (16). The processes presented in this scheme reflect the competition of the basicity and nucleophilicity of phosphorus ylides. Betaine 15b prepared from less nucleophilic and less basic ylide with phenyl substituents at the phosphorus atom is much less resistant toward retro-decomposition compared to the alkyl analog. Its equilibrium concentration does not exceed 6%. 

The orbital coefficients obtained from Hiickel calculations predict the terminal position to be the most reactive one, while the AMI model predicts the Cl and C3 positions to be competitive. In polyenes, this is true for the addition of nucleophilic as well as electrophilic radicals, as HOMO and LUMO coefficients are basically identical. Both theoretical methods agree, however, in predicting the Cl position to be considerably more reactive as compared to the C2 position. It must be remembered in this context that FMO-based reactivity predictions are only relevant in kinetically controlled reactions. Under thermodynamic control, the most stable adduct will be formed which, for the case of polyenyl radicals, will most likely be the radical obtained by addition to the C1 position. 

Although addition of activated phosphoramidite to hemiacetals of manno-pyranoses under thermodynamic control has been reported to deliver exclusively a-phosphates in some cases,43 anomeric mixtures with preponderance of a-anomer have been reported in other examples.10,44 Since formation of phosphorotetrazolidite is a rate-limiting step of the process, initial activation of phosphoramidite followed by addition of nucleophilic hemiacetal should accelerate condensation and favour the formation of the thermodynamic a-product. Indeed, reaction of hemiacetal 101 with dibenzyl phosphorotetrazolidite assured exclusive a-selectivity of the resulting glycosyl phosphate 102.43 The accumulation in the reaction mixture of mildly acidic 1H-tetrazole, which is liberated upon reaction of tetrazolidite with hydroxylic component, could also favour predominant formation of the a-phosphate (Scheme 18, A). Conventional hydrogenolysis afforded the a-mannosyl phosphate 103. 

Reverse hydrolysis a thermodynamically controlled equilibrium process, in which a free monosaccharide reacts with a nucleophile under exclusion of a water molecule and hence chemically, can be considered a condensation reaction. 

It was recognized in early examples of nucleophilic addition to acceptor-substituted allenes that formation of the non-conjugated product 158 is a kinetically controlled reaction. On the other hand, the conjugated product 159 is the result of a thermodynamically controlled reaction [205, 215]. Apparently, after the attack of the nucleophile on the central carbon atom of the allene 155, the intermediate 156 is formed first. This has to execute a torsion of 90° to merge into the allylic carbanion 157. Whereas 156 can only yield the product 158 by proton transfer, the protonation of 157 leads to both 158 and 159. 

The latter results have been explained on the basis of the following reaction scheme. The 1,2-regioisomers derived from butadiene are obtained through a non-symmetrical iodonium ion intermediate. The subsequent nucleophilic attack on the allylic position gives, under kinetic control, 1,2-derivatives. Nevertheless, when poorer nucleophiles such as benzene or acetonitrile are employed, the conversion of the initially formed iodonium ion into the allylic cation has been suggested to give 1,4-products, under thermodynamic control. However, other alternatives like nucleophilic attack involving allylic participation have not been excluded for the formation of 1,4-derivatives. 

The product distribution may depend on the reaction conditions if the nucleophilic attack is reversible (kinetic vs. thermodynamic control). An additional complication arises from... 

If tlie 1,2-addition is reversible (the nucleophile is a good leaving group), then we get thermodynamic control and the conjugate addition product predominates. When the 1,2-addition is not reversible (the nucleophile is a poor leaving group), we get kinetic control and simple addition. Stereochemical considerations are also partly responsible, since it will be easier for larger nucleophiles, especially enolate... 

When a catalytic amount of base is used, the reaction proceeds with thermodynamic control of enolate formation. The most effective nucleophiles under these conditions are carbanions derived from relatively acidic compounds such as /i-kctocstcrs or malonate esters. The adduct anions are more basic and are protonated under the reaction conditions. Scheme 1.11 provides some examples. 

When H2O deacetylates the acyl-enzyme, phenylacetic acid is formed. When nucleophiles other than H2O deacylate the acyl-enzyme, a new condensation product, in this case phenylacetyl-O-R or phenylacetyl-NH-R is formed. By definition the hydrolysis of these condensation products can be catalyzed by the same enzyme that catalyzes their formation in equation 10.1. Thus, when the acyl-enzyme is formed from phenylacetyl-glycine or phenylacetyl-O-Me, this gives rise to an alternative process to produce Penicillin G, in addition to the thermodynamically controlled (= equilibrium controlled) condensation of phenylacetic acid and 6-aminopenicillanic acid (6-APA). This reaction that involves an activated side chain is a kinetically controlled (= rate controlled) process where the hydrolase acts as a transferase (Kasche, 1986 1989). 

The heterocyclic equivalent of the benzoin condensation offers a route to the important herbicide paraquat (Scheme 128) (73JOC3993) (see also Section 2.05.7). N- Alkylnicotinic acid and its derivatives readily undergo addition of cyanide and many other nucleophiles (see Section 2.05.4.8). In the example shown in Scheme 129, 1,2-addition is subject to kinetic, and 1,4-addition to thermodynamic, control. 

Dimethylpyrimido[4,5-f]pyridazine-5,7-dione 23 and its derivatives undergo attack at both C-3 and C-4. Under conditions of kinetic control, addition occurs preferentially at the more electron-deficient C, whereas thermodynamic control conditions, or the use of bulkier nucleophiles, favor addition at the less hindered position 3. This duality is illustrated by the addition of Grignard and organolithium reagents to C of 3-chloro analogue 24 (Equation 9), whereas stabilized nucleophiles such as the anion of nitromethane add at C-3 (Scheme 10) <2000CHE975>. Displacement of the 3-chloride occurs also upon treatment of 24 with amines (Equation 10) <2000CHE1213>. 

Many of these reactions support a measure of thermodynamic control in nucleophilic capture Conjugated radicals or products formed with release of ring strain are favored. For example, the addition of ethanol to radical cation 110 + is regiospecific, forming the more stable (benzylic) intermediate 111 + the capture of 112 + likewise forms a benzylic radical (113 ). Radical cation 48 + generates a... 

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