Conjugate addition thermodynamic control

Conjugated dienes undergo several reactions not observed for nonconjugated dienes. One is the 1,4-addition of electrophiles. When a conjugated diene is treated with an electrophile such as HCl, 1,2- and 1,4-addition products are formed. Both are formed from the same resonance-stabilized allylic carbocation intermediate and are produced in varying amounts depending on the reaction conditions. The L,2 adduct is usually formed faster and is said to be the product of kinetic control. The 1,4 adduct is usually more stable and is said to be the product of thermodynamic control. 

Both primary and secondary amines add to a /S-unsaturated aldehydes and ketones to yield /3-amino aldehydes and ketones rather than the alternative imines. Under typical reaction conditions, both modes of addition occur rapidly. But because the reactions are reversible, they generally proceed with thermodynamic control rather than kinetic control (Section 14.3), so the more stable conjugate addition product is often obtained to the complete exclusion of the less stable direct addition product. 

The general mechanistic features of the aldol addition and condensation reactions of aldehydes and ketones were discussed in Section 7.7 of Part A, where these general mechanisms can be reviewed. That mechanistic discussion pertains to reactions occurring in hydroxylic solvents and under thermodynamic control. These conditions are useful for the preparation of aldehyde dimers (aldols) and certain a,(3-unsaturated aldehydes and ketones. For example, the mixed condensation of aromatic aldehydes with aliphatic aldehydes and ketones is often done under these conditions. The conjugation in the (3-aryl enones provides a driving force for the elimination step. 

Scheme 2.11 shows some examples of Robinson annulation reactions. Entries 1 and 2 show annulation reactions of relatively acidic dicarbonyl compounds. Entry 3 is an example of use of 4-(trimethylammonio)-2-butanone as a precursor of methyl vinyl ketone. This compound generates methyl vinyl ketone in situ by (3-eliminalion. The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of product from the more stable enolate, as in Entry 3. The C(l) enolate is preferred because of the conjugation with the aromatic ring. For monosubstituted cyclohexanones, the cyclization usually occurs at the more-substituted position in hydroxylic solvents. The alternative regiochemistry can be achieved by using an enamine. Entry 4 is an example. As discussed in Section 1.9, the less-substituted enamine is favored, so addition occurs at the less-substituted position. 

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. 

In order to obtain adiponitrile, 2 should isomerize to 4, and not to the thermodynamically more stable 3 (stabilised by the energy of conjugation). The thermodynamic ratio is 2 3 4 = 20 78 1.6 [6], The isomerization of 2 to 4 happens to be favorably controlled by the kinetics of the reactions the reaction 2 to 4 reaches equilibrium, but the reaction 2 to 3 does not. Note that the nickel complex not only is responsible for the addition of HCN but that it is also capable of catalysing selectively the isomerisation. The final step is the addition of HCN to 4 to give 5, adiponitrile. 

Such equilibria are governed by thermodynamics, and so the abundances of the different species in solution are dependent on their relative thermodynamic stabilities. If, however, such a mixture of species is applied in, for example, a conjugate addition reaction, the product formation will be controlled by kinetics, and it is most likely that Cu2Li2Mc4 would be kinetically the most active species present. 

The and spectroscopy of a solution of 2-chloro-3,5-dinitropyridine in liquid ammonia at-40°C showed the formation of the C-6 adduct (10). This adduct is rather stable, since after 1 hr standing, no change in the spectrum was observed. It is interesting that at a somewhat lower temperature (-60°C) the addition takes place at C-4, i.e., formation of (9). Apparently one deals with the interesting concept of kinetically and thermodynamically controlled covalent adduct formation. At -60°C the addition is kinetically controlled, and at -40°C the addition is thermodynamically favored. The higher stability of the C-6 adduct compared to the C-4 adduct is probably due to the more extended conjugate resonance system (Scheme II.9). 

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... 

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... 

Conjugate addition. In the presence of 1 equivalent of triethylaluminum, cyanotrimethylsilane undergoes conjugate addition to a,/ -enones in high yield. The products arc converted into /J-cyano ketones by acid hydrolysis. The addition is kinetically controlled in toluene at room temperature, but thermodynamically controlled in refluxing THF (equation I). 

The 1,4-addition (or conjugate addition) of resonance-stabilized carbanions. The Michael Addition is thermodynamically controlled the reaction donors are active methylenes such as malonates and nitroalkanes, and the acceptors are activated olefins such as a,P-unsaturated carbonyl compounds. 

The partial steps of the conjugate addition in aminocatalytic reactions are in dynamic equilibrium, and thus products are formed under thermodynamic control. This fact is translated also in the geometry of the enamine intermediates, leading to the product, which can be either E or Z (Fig. 2.9). The geometry of the enamine depends on the catalyst structure and also on the substrate. Whilst proline-catalyzed reactions form preferentially, with a-alkyl substituted ketones, the. E-isomer, enamines derived from pipecolic acid afford an approximate 1 1 mixture of the E and Z isomers [6], In turn, small- and medium-sized cyclic ketones afford the E isomer. 

We will return to kinetic and thermodynamic control in Chapter 13, where we will analyse the rates and energies involved a little more rigorously, but for now here is an example where conjugate addition is ensured by thermodynamic control. Note-the temperature ... 

The cyanide group is a typical group for promoting conjugate addition. It is possible for nucleophiles to attack directly at,the CN group but it is not very electrophilic so that these reactions tend to be thermodynamically controlled and attack is preferred in the conjugate position. 

This principle can be extended to ketones whose enolates have less dramatic differences in stability. We said in Chapter 21 that, since enols and enolates are alkenes, the more substituents they carry the more stable they are. So, in principle, even additional alkyl groups can control enolate formation under thermodynamic control. Formation of the more stable enolate requires a mechanism for equilibration between the two enolates, and this must be proton transfer. If a proton source is available— and this can even be just excess ketone—an equilibrium mixture of the two enolates will form. The composition of this equilibium mixture depends very much on the ketone but, with 2-phenylcyclo-hexanone, conjugation ensures that only one enolate forms. The base is potassium hydride it s strong, but small, and can be used under conditions that permit enolate equilibration. 

Conjugate addition of enolates is the result of thermodynamic control... 

Na, and K) enolates. Lithium enolates are not ideal nucleophiles for thermodynamically controlled conjugate addition. Better results are... 

The thermodynamic control of conjugate addition allows even enals that are very electrophilic at the carbonyl carbon to participate successfully. Any aldol reaction, which must surely occur, is reversible and 1,4-addition eventually wins out Acrolein combines with this five-membered diketone under very mild conditions to give a quantitative yield of product, The mechanism is analogous to that shown above,... 

The 1,4 conjugate addition of HCN to a, d-unsaturated ketones has received partictUar attention, because of its selectivity in the steroid field [2S). Alkyl aluminum cyanides are used as catalysts in these reactions. Two methods have been developed which allow either thermodynamic (Equation (39 or kinetic control (Equation (40)) of the addition stereochemistry (Nagata reaction). 

Since the base-catalyzed conjugate addition is a reversible process, reactions of this type are usually thermodynamically controlled. Nevertheless, pronounced selectivities may be observed. For example, when the alcohols 2 were added to the enoate 1, the addition products rat-3 were formed with diastereomeric ratios (d.r.) of up to 100 02 3. Unfortunately, the relative configurations of the products were not determined2. 

As mentioned at the beginning, base-catalyzed conjugate additions usually proceed by thermodynamic control. Thus, if the cyclic acceptor carries a substituent, the incoming nucleophile is usually added trans to this substituent. This general rule persists, with only few exceptions, as shown by the examples presented below. 

As already mentioned, the steric course of acid- or base-catalyzed conjugate additions is usually subject to thermodynamic control. An interesting example of how hydrogen bonding in the product(s) may affect the stereochemical outcome of the addition reaction is provided by ajmalicine (25). When the enoate 25 was treated with 5% aqueous sulfuric acid, the 17-hydroxy-derivative 26 was obtained as a single diastereomer in 40% yield20. The configuration of the... 

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