Nucleophilic addition reactions stereochemistry

Since the nucleophilic addition reactions consist of two distinct stages, the stereochemistry of each stage has to be considered. On the basis of the scarce amount of data available, it seems that nucleophiles, like electrophiles, approach bicyclobutane from an equatorial direction. This is an expected path since, viewed as an Sj 2 reaction, the nucleophile approaches the substrate anti to the leaving group (the central bond). This has been experimentally demonstrated by the reaction of thiolate anions with 38. In these reactions, RS was found to assume only an endo position (equation 77) . This was also... 

Nucleophilic addition reactions occur by electron donation from the nucleophile to the IT antibonding orbital of the ketone. If the faces of the ketone are different, addition happens faster at the more accessible orbital lobe. Use SpartanView to display mesh electron-density surfaces of 2-norbomanone and camphor, and simultaneously display the tt antibonding orbital (LUMO) surface of each. Which face of each ketone is more reactive What is the stereochemistry of the alcohol produced by reaction of each with NaBH4 ... 

Section 18.11 Stereochemistry of Nucleophilic Addition Reactions Re and S Faces... 

Nucleophilic Additions. MgBr2 has been shown to form discrete bidentate chelates with various species, particularly a-and/or a,3-alkoxy carbonyl compounds, and thus functions as a diastereofacial control element in many nucleophilic addition reactions. In many cases, its inclusion completely reverses the nonchelation-controlled stereochemistry observed with nonchelating Lewis acids such as Boron Trifluoride Etherate. Highest diastereoselectivity is observed with a-substituted aldehydes (eq 1). High selectivities are observed for p-alkoxy aldehydes as well, including cases where three contiguous chiral centers are defined during the reaction (eq 2). ... 

A very important relationship between stereochemistry and reactivity arises in the case of reaction at an 5 carbon adjacent to a chiral center. Using nucleophilic addition to the carbonyl group as an example, it can be seen that two diastereomeric products are possible. The stereoselectivity and predictability of such reactions are important in controlling stereochemistry in synthesis. 

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

HC1, HBr, and HI add to alkenes by a two-step electrophilic addition mechanism. Initial reaction of the nucleophilic double bond with H+ gives a carbo-cation intermediate, which then reacts with halide ion. Bromine and chlorine add to alkenes via three-membered-ring bromonium ion or chloronium ion intermediates to give addition products having anti stereochemistry. If water is present during the halogen addition reaction, a halohydrin is formed. 

I-Oialkoxy carbonyl compounds are a special class of chiral alkoxy carbonyl compounds because they combine the structural features, and, therefore, also the stereochemical behavior, of 7-alkoxy and /i-alkoxy carbonyl compounds. Prediction of the stereochemical outcome of nucleophilic additions to these substrates is very difficult and often impossible. As exemplified with isopropylidene glyceraldehyde (Table 15), one of the most widely investigated a,/J-di-alkoxy carbonyl compoundsI0S, the predominant formation of the syn-diastereomer 2 may be attributed to the formation of the a-chelate 1 A. The opposite stereochemistry can be rationalized by assuming the Felkin-Anh-type transition state IB. Formation of the /(-chelate 1C, which stabilizes the Felkin-Anh transition state, also leads to the predominant formation of the atm -diastereomeric reaction product. 

If the carbanion has even a short lifetime, 6 and 7 will assume the most favorable conformation before the attack of W. This is of course the same for both, and when W attacks, the same product will result from each. This will be one of two possible diastereomers, so the reaction will be stereoselective but since the cis and trans isomers do not give rise to different isomers, it will not be stereospecific. Unfortunately, this prediction has not been tested on open-chain alkenes. Except for Michael-type substrates, the stereochemistry of nucleophilic addition to double bonds has been studied only in cyclic systems, where only the cis isomer exists. In these cases, the reaction has been shown to be stereoselective with syn addition reported in some cases and anti addition in others." When the reaction is performed on a Michael-type substrate, C=C—Z, the hydrogen does not arrive at the carbon directly but only through a tautomeric equilibrium. The product naturally assumes the most thermodynamically stable configuration, without relation to the direction of original attack of Y. In one such case (the addition of EtOD and of Me3CSD to tra -MeCH=CHCOOEt) predominant anti addition was found there is evidence that the stereoselectivity here results from the final protonation of the enolate, and not from the initial attack. For obvious reasons, additions to triple bonds cannot be stereospecific. As with electrophilic additions, nucleophilic additions to triple bonds are usually stereoselective and anti, though syn addition and nonstereoselective addition have also been reported. 

If the substituents are nonpolar, such as an alkyl or aryl group, the control is exerted mainly by steric effects. In particular, for a-substituted aldehydes, the Felkin TS model can be taken as the starting point for analysis, in combination with the cyclic TS. (See Section 2.4.1.3, Part A to review the Felkin model.) The analysis and prediction of the direction of the preferred reaction depends on the same principles as for simple diastereoselectivity and are done by consideration of the attractive and repulsive interactions in the presumed TS. In the Felkin model for nucleophilic addition to carbonyl centers the larger a-substituent is aligned anti to the approaching enolate and yields the 3,4-syn product. If reaction occurs by an alternative approach, the stereochemistry is reversed, and this is called an anti-Felkin approach. 

There have been several studies of the stereochemistry of conjugate addition reactions. If there are substituents on both the nucleophilic enolate and the acceptor, either syn or anti adducts can be formed. 

The kinetics, products, and stereochemistry of the addition of HC1, HBr, and HI to propiolic acid in water have been studied.28 The addition is predominantly trans to give the cz s-3-haloacrylic acid. Both the rate of addition and the selectivity giving trans-addition increase with the nucleophilicity of the halide in water (i.e., I- > Br > Cl-). The order of reactivity is also consistent with the order of the softness of the nucleophiles. The reaction is first order in propiolic acid and the halide anion. It was proposed that the addition involves two mechanistic pathways a major /ra/z.v-addition via a transient carbanion formed with specific geometry and a minor cO-addition process (Scheme 10.2). 

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