Nucleophilic reactions 1,2 versus 1,4 addition

Aldehydes are generally more reactive than ketones in nucleophilic addition reactions for both steric and electronic reasons. Sterically, the presence of only one large substituent bonded to the C=0 carbon in an aldehyde versus two large substituents in a ketone means that a nucleophile is able to approach an aldehyde more readily. Thus, the transition state leadingto the tetrahedral intermediate is less crowded and lower in energy for an aldehyde than for a ketone (Figure 19.3). 

Additional experimental, theoretical, and computational work is needed to acquire a complete understanding of the microscopic dynamics of gas-phase SN2 nucleophilic substitution reactions. Experimental measurements of the SN2 reaction rate versus excitation of specific vibrational modes of RY (equation 1) are needed, as are experimental studies of the dissociation and isomerization rates of the X--RY complex versus specific excitations of the complex s intermolecular and intramolecular modes. Experimental studies that probe the molecular dynamics of the [X-. r - Y]- central barrier region would also be extremely useful. 

The complementary approach, activation of unsaturated hydrocarbons toward electrophilic attack by complexation with electron-rich metal fragments, has seen limited investigation. Although there are certainly opportunities in this area which have not been exploited, the electrophilic reactions present a more complex problem relative to nucleophilic addition. For example, consider the nucleophilic versus electrophilic addition to a terminal carbon of a saturated 18-electron metal-diene complex. Nucleophilic addition generates a stable 18-electron saturated ir-allyl complex. In contrast, electrophilic addition at carbon results in removal of two valence electrons from the metal and formation of an unstable ir-allyl unsaturated 16-electron complex (Scheme 1). 

Kinetic data show that in seawater medium S42 reacts about 20-30 times faster than HS with acrylic acid, whereas the reaction of S42 with acrylonitrile is only about 4-6 times higher than with HS. However, in any environment, the importance of polysulfide versus bisulfide reactions is also dependent on their relative concentrations. In a situation where polysulfide and bisulfide ions are present in similar concentrations, our results imply that polysulfide ions, rather than bisulfide, are the important sulfur nucleophiles for reactions with activated unsaturated molecules having a terminal carboxyl group (e.g. acrylic acid, cinnamic acid). However, for neutral molecules such as fucoxanthin, in addition to polysulfide ions, reactions with bisulfide ions will also be of importance. 

An enantioselective intermolecular Michael addition of aldehydes (138) to enones (139), catalysed by imidazolidinones (140), has been reported. Chemoselectivity (Michael addition versus aldol) can be controlled through judicious choice of hydrogen bond-donating co-catalysts. The optimal imidazolidinone-hydrogen bond donor pair affords Michael addition products in <90% ee. Furthermore, the enamine intermediate was isolated and characterized and its efficacy as a nucleophile in the observed Michael addition reactions was demonstrated.172... 

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. 

Examples of the solvent-dependent competition between nucleophilic substitution and / -elimination reactions [i.e. SnI versus Ei and Sn2 versus E2) have already been given in Section 5.3.1 [cf. Table 5-7). A nice example of a dichotomic y9-elimination reaction, which can proceed via an Ei or E2 mechanism depending on the solvent used, is shown in Eq. (5-140a) cf. also Eqs. (5-20) and (5-21) in Section 5.3.1. The thermolysis of the potassium salt of racemic 2,3-dibromo-l-phenylpropanoic acid (A), prepared by bromine addition to ( )-cinnamic acid, yields, in polar solvents [e.g. water), apart from carbon dioxide and potassium bromide, the ( )-isomer of l-bromo-2-phenylethene, while in solvents with low or intermediate polarity e.g. butanone) it yields the (Z)-isomer [851]. 

The addition of a C-2 (equation 1 R = H > alkyl, aryl > OMe NR2), C-3, or C-4 electron-donating substituent to a 1 -oxa-1,3-butadiene electronically decreases its rate of 4ir participation in a LUMOdiene-controlled Diels-Alder reaction (c/. Table 5). Nonetheless, a useful set of C-3 substituted l-oxa-l,3-buta-dienes have proven to be effective dienes ° and have been employed in the preparation of carbohydrates (Table 6). The productive use of such dienes may be attributed to the relative increased stability of the cisoid versus transoid diene conformation that in turn may be responsible for the Diels-Alder reactivity of the dienes. Clear demonstrations of the anticipated [4 + 2] cycloaddition rate deceleration of 1-oxa-1,3-butadienes bearing a C-4 electron-donating substituent have been detailed (Table 6 entry 4). >> "3 In selected instances, the addition of a strong electron-donating substituent (OR, NR2) to the C-4 position provides sufficient nucleophilic character to the 1-oxa-1,3-butadiene to permit the observation of [4 + 2] cycloaddition reactions with reactive, electrophilic alkenes including ketenes and sul-fenes, often in competition with [2 + 2] cycloaddition reactions. ... 

In addition to the nature of the donor atom (e.g., sulfur in bisulfide versus oxygen in hydroxide), other features that govern the hardness of a nucleophile—and thus the rates and mechanisms of its reaction with pesticide compounds— include the oxidation state of the donor atom... 

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