Thermodynamic and Kinetic Control of Addition Reactions

The addition reactions in the previous sections allow us to look at general properties of chemical reactions and to address fundamental issues of reactivity. Just what are the factors that influence the direction a reaction takes Why is one product formed more than another Is it because of the energies of the products themselves, or something else  

There are curious effects of temperature and time on the addition reactions of HX and X2 with conjugated dienes. If the reactions are run at low temperature, it is the product of 1,2-addition that is generally favored. The warmer the reaction conditions, the more product of 1,4-addition is formed. At high temperature (25 °C) the product of 1,4-addition is favored (Fig. 12.39). 

The effect of time is seen in the observation that the products shown in Rgure 12.39 will equilibrate if allowed to stand in solution. As Rgure 12.40 shows, the same mixture of 1,2- and 1,4-addition products is formed from each compound, and the product of 1,4-addition is favored. 

Several questions now confront us (1) Why is the product of 1,4-addition favored (2) How do the products of 1,2- and 1,4-additions equilibrate (3) Why is the 1,2-addition product favored at low temperatures  

The first question is easy. The product of 1,4-addition contains a disubstituted double bond, whereas the 1,2-product has only a monosubstituted double bond, and is therefore less stable (Rg. 12.41). Remember. The more substituted an alkene, the more stable it is (p. 115). 

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An important fundamental concept in this chapter involves the difference between thermodynamic and kinetic control of a reaction. Conjugated dienes will react with HX or X2 to give 1,2-addition products when kinetic conditions are used. The use of thermodynamic conditions will favor formation of the most stable product, usually the 1,4-addition product. 

The competition between redox reaction and anodic dissolution became very important in the development of stable regenerative solar cells on the basis of semiconductor-liquid junctions. As shown in the previous section, it is determined by the thermodynamic and kinetic properties of the processes involved. Information on the competitions between these reactions cannot be obtained entirely from current-potential curves, because in many cases they do not look very different upon addition of a redox system, especially if the current is controlled by the light intensity. Therefore, a rotating ring disc electrode (RRDE) assembly consisting of a semiconductor disc and a Pt ring is usually applied, i.e. a technique which makes it possible to determine separately the current corresponding to the oxidation of a redox system [62, 63]. 

In 1994, Diederich and co-workers reported a very important approach for the regioselective formation of multiple adducts of Cjq by tether-directed remote functionalization [75]. This technique allows for the synthesis offullerene derivatives with addition patterns that are difficult to obtain by thermodynamically or kinetically controlled reactions with free untethered addends. This important subject has been extensively reviewed [26, 76, 77]. 

In addition of organometallic reagents to some arynes, prior counterion complexation with the substituent can direct the incoming group to the ortho position (kinetic control). Addition of alkyllithiums to oxazolinyl (OXZ) aryne (51) to give the ortho product (52) is explained in this manner. In contrast, lithium dialkylcuprates add to the aryne (51) exclusively at the meta position. This is ascribed to thermodynamic control of the reaction, which results in the formation of the more ligated and stable adduct (S3).i2 Control of nucleophilic addition to arynes by complex-induced proximity effects has not been explored with substituents other than OXZ,83 but has considerable synthetic potential if it can be achieved, say through solvent manipulation. 

The initial products of organic reactions are formed under conditions of kinetic control - the products are formed in proportions governed by the relative rates of the parallel (forward) reactions leading to their formation. Subsequently, product composition may become thermodynamically controlled (equilibrium controlled), i.e. when products are in proportions governed by the equilibrium constants for their interconversion under the reaction conditions. The reaction conditions for equilibrium control could involve longer reaction times than those for kinetic control, or addition of a catalyst. The mechanism of equilibrium control could simply involve reversal of the initial product-forming reactions (as in Scheme 2.4, see below), or the products could interconvert by another process (e.g. hydrolysis of an alkyl chloride could produce a mixture of an alcohol and an alkene, and the HsO"1" by-product could catalyse their interconversion). 

Formation of a highly electrophilic iodonium species, transiently formed by treatment of an alkene with iodine, followed by intramolecular quenching with a nucleophile leads to iodocyclization. The use of iodine to form lactones has been elegantly developed. Bartlett and co-workers216 reported on what they described as thermodynamic versus kinetic control in the formation of lactones. Treatment of the alkenoic acid 158 (Scheme 46) with iodine in the presence of base afforded a preponderance of the kinetic product 159, whereas the same reaction in the absence of base afforded the thermodynamic product 160. This approach was used in the synthesis of serricorin. The idea of kinetic versus thermodynamic control of the reaction was first discussed in a paper by Bartlett and Myerson217 from 1978. It was reasoned that in the absence of base, thermodynamic control could be achieved in that a proton was available to allow equilibration to the most stable ester. In the absence of such a proton, for example by addition of base, this equilibration is not possible, and the kinetic product is favored. 

Modeling hydrogeochemical processes requires a detailed and accurate water analysis, as well as thermodynamic and kinetic data as input. Thermodynamic data, such as complex formation constants and solubility products, are often provided as data sets within the respective programs. However, the description of surface-controlled reactions (sorption, cation exchange, surface complexation) and kinetically controlled reactions requires additional input data. 

The choice of the solvent and of the electrophile is very important since the reaction can be carried out under kinetic or thermodynamic control. The possibility of equilibrating a cyclic intermediate strongly influences the regio- and stereochemistry of the reaction. The presence of a base in an aqueous medium generally results in kinetic control of the cyclization process18, while reversible conditions are favored by iodine in acetonitrile19. In addition, A -iodosuccin-imide in chloroform, iodine in chloroform and iodine in tetrahydrofuran/pyridine are considered to give cyclizations under kinetic control. On the other hand, the use of AT-bromosuccin-imide or bromine affords lower selectivity. 

The isolation of the oxides (58) and (59) from the addition reactions of the allene (60) has been shown to depend upon whether or not the reaction is under kinetic control, which leads to (58), or thermodynamic control, which leads to (59). ... 

The versatility of this mode of operation has made it extremely powerful for fabrication of microstructures. In the feedback mode an ultramicroelectrode is held close above a substrate in a solution containing one form of electroactive species, either reduced or oxidized, that serves as a mediator (Fig. 1). The latter is usually used both as a means of controlling the distance between the UME and the surface and to drive the microelectrochemical process on the surface. This poses a number of requirements that must be taken into account when configuring the system. The basic limitation stems from the requirement that the electrochemical reaction be confined only to the surface. This means that the electroactive species generated at the UME will react with the surface or with other species attached to it. In addition, it is preferable in most cases that the redox couple used should exhibit chemical and electrochemical reversibility, so that it is effectively regenerated on the surface. The regeneration of the redox couple on the surface is required for controlling the UME-substrate distance. Finally, the thermodynamics and kinetics of the electrochemical process on the surface will dictate the choice of the redox couple introduced. 

Identification of an efficient metal chelate for optimum absorption of NO requires knowledge of the thermodynamics and kinetics of the coordination of NO to various metal chelates. Knowledge is also needed of the kinetics and mechanisms of the reaction between nitrosyl metal chelates and absorbed SO2 in solution to calculate the regeneration rate of metal chelates and to control the products of reaction by adjusting the scrubber operating conditions. Not much of this information is available in the literature, although several ferrous and cobalt chelates have been used as additives for testing in bench-scale wet flue gas simultaneous desulfurization and denitrification scrubbers. 

The bulk of this chapter has dealt with kinetically controlled aldol addition processes. However, one of the characteristics of aldol reactions involving Group I and Group II enolates is that they are frequently subject to ready reversibility (see Volume 2, Chapter 1.5). Under appropriate conditions, aldol reactions can be carried out under conditions of thermodynamic control. Furthermore, it is usually found that the stereoisomer ratio formed under equilibrating conditions is quite different from the kinetic isomer mixture. 

In addition to the methods described for controlling the ratio of thermodynamic and kinetic products, other techniques have been developed to trap the enolate, based on reactions with reagents that prefer O-alkylation. Reaction of a ketone with acetic anhydride, usually in the presence of a catalytic amount of perchloric acid, generates the thermodynamic enol acetate When this is treated with methyllithium, the... 

The high-temperature addition of hydrogen bromide to 2-bromo-2-butene has been classified as being nonstereospecific, (ref. 11, pp. 436-437) because both cis and trans reactants give identical product mixtures - 75%-dl and 25%-meso. This is not necessarily so. By our new definition for stereospecificity, given above, this reaction is not nonstereospecific - a nonstereospecific reaction would have given a 50 50 dhmeso mixture. The above kinetically-controlled HBr addition involves latent thermodynamic equilibration - hence, the non-50 50 75%-dl and 25%-meso) mixture. Ideally, the stereospecificity should be determined for transformations under kinetic control, and not, under thermodynamic control. 

Related Mannich reactions have been reported by Holy and Wang. These chemists generated the silyl enol ethers under either thermodynamic or kinetic control, but cleaved the ether with methyllithium to the same lithium enolate and then added the Mannich salt. Product distributions demonstrated that the addition reaction is regiospecific. They also found that the reaction can be conducted by the trapping technique of conjugate addition of dimethylcopper-lithium to cyclohexenone followed by addition of the immonium salt (equation I.)... 

The nature of the base can profoundly influence the regiochemistry of the reaction. f-BuOK favors kinetic control in the reaction shown in eq 16 and the product derived from cyclization of the enolate having a /3-amino group is obtained. However, when EtONa/EtOH is employed, the more stable /3-keto ester enolate resulting from thermodynamic control is obtained. In addition to diesters, dinitriles, e-keto esters, e-cyano esters, e-sulfinyl esters, and -phosphonium esters may participate in these reactions. 

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