Frontside nucleophilic attack

Figure 3.17 Molecular mechanisms giving rise to enhanced hydrolysis rates of glycosides with carboxylic acid groups. In the case of salicyl fi-glucoside, frontside nucleophilic attack is stereoelectronically prohibited and distinction between specific acid catalysis of the hydrolysis of the anion and intramolecular general acid catalysis was made on the basis of solvent isotope effects in related systems. ...

A stepwise mechanism with a rate-limiting leaving group expulsion from the intermediate was proposed for the reactions of Z-aryl dimethyl- (43a), methylphenyl-(43b), and diphenyl-phosphinates (43c) with substituted anilines in DMSO at 333 K, based on the positive cross-interaction constants, The steric effects of the two ligands (R, R ) play a role in determining the reactivity of the phosphinates, but are relatively small compared to other phosphinate systems. A dominant frontside nucleophilic attack involving a hydrogen-bonded four-centre-type transition state (44) was proposed... 

The results of frontside and backside attack of a nucleophile are illustrated with CH3CH(D)Br as substrate and the general nucleophile Nu . This substrate has the leaving group bonded to a ste-reogenic center, thus allowing us to see the structural difference that results when the nucleophile attacks from two different directions. 

A much better overlap is provided by the direct attack on the covalent bond, thus favoring frontside attack. Depending on the heterogeneity of the molecular orbital (HOMO), one may envision various possible cases, from a central attack on the covalent bond all the way to a backside attack. The latter rarely occurs in electrophilic reactions of saturated carbon atoms. In fact, a frontside attack as a possible interpretation of the formation of dicyclopropyl-bromonium ion under superacidic conditions (SbF5-SO2ClF, -78°C) was suggested. Other examples of frontside nucleophilic substitution are also known. ... 

The stereoelectronic basis for these trajectories is illustrated below. Trajectories of nucleophilic attack avoid the node in the antibonding orbitals because the unfavorable symmetry of orbital overlap involved in the attack at the node leads to the cancelation of bond-forming 2e-interactions. Attacks of electrophiles have no such restrictions because both o- and x-orbitals are bonding and, thus, do not have a node between the atoms. The lack of a symmetry restriction in electrophilic reactions opens stereoelectronic routes not available to nucleophiles. For o-bonds, this is the frontside attack with retention of configuration (Figure 2.38). For x-bonds, this is the acute (or perpendicular) attack leading to the so-called endo-cyclizations (vide infra). 

Backside attack may be favored for electrostatic reasons. Examine electrostatic potential maps fox bromide + methyl bromide frontside attack and bromide + methyl bromide backside attack, transition states involving frontside and backside attack of Br (the nucleophile) onto CHsBr, respectively. Which atoms in the transition states are most electron-rich Which trajectory better minimizes electrostatic repulsion ... 

Backside attack may be favored in order to facilitate transfer of nonbonding electrons from the nucleophile into the electrophile s lowest-unoccupied molecular orbital (LUMO). Efficient electron transfer requires maximal overlap of the LUMO and the donor orbital (usually a nonbonded electron pair on the nucleophile). Examine the LUMO of methyl bromide. How would a nucleophile have to approach in order to obtain the best overlap Is your answer more consistent with preferential backside or frontside attack ... 

By means of diastereomeric probes, it has been demonstrated that the vicinal nucleophilic displacement of a diethylphosphate group from a jS-(phosphatoxy)alkyl radical may occur through backside or frontside attack, depending on steric constraints. ... 

Contrary to the case of anionic reactions, the formation of a strong proton-bound dimer for alcohols suggests that nucleophilic displacement may actually involve a frontside attack. Recent experiments carried out at atmospheric pressure by Speranza and Angelini (1980) using radiolytic techniques with isolation and glc analysis of neutral products reveal some interesting stereochemistry. For example, the reaction of protonated epoxy-rra/is-but-2-ene with H20 results in 98% inversion of configuration, while a similar reaction with cis-1 -chloro-4-methylcyclohexane results in approximately 80% of tro/is-4-methylcyclohexanol. With the high pressures utilized and with the possible participation of cluster ions a likelihood in this case, the data are consistent with a Walden inversion for these cases. 

Further support for the idea that cationic nucleophilic displacement occurs with inversion of configuration has been advanced by Hall et al. (1981). The study of reaction (55) in an electron-bombardment flow reactor at reagent pressures below 10 3torr, followed by neutral product analysis (Marinelli and Morton, 1978), reveals that these reactions also occur via backside attack. This is in disagreement with the original suggestion of Beauchamp et al. (1974) who proposed a frontside displacement in the case of t-butyl alcohol. 

Figure 10.14 Frontside attack of a nucleophile, symbolized by N, on a C—X bond. Symmetry prevents HOMO-LUMO interaction the only interaction is between filled levels. The reaction will not take this path.

Another application is to bimolecular SN2 and S 2 substitutions. Recall from Chapter 4 (pp. 174 and 205) that the nucleophilic reaction prefers backside attack by nucleophile on substrate whereas the electrophilic reaction prefers frontside attack. Figure 10.14 shows the appropriate frontier orbitals for frontside attack by a nucleophile. The nucleophile, symbolized by N, is the donor, and the C—X bond is the acceptor. The symmetries of the nucleophile HOMO and the C—X LUMO do not match (13) therefore only the filled-filled HOMO-... 

Lee s group has published extensive results on aminolysis of sulfonates.278-281 Thus the reactions of anilines with 2-cyano-2-propyl and 1-cyanocyclooctylarenesulfonates in acetonitrile have been studied.278 A dissociative 5 2 mechanism with a loose TS is supported from the usual LFERs. An 5n2 mechanism is also found for the reaction in acetone of (Z)-benzyl (X)-benzenesulfonates with (Y)-pyridines.279 Nucleophilic substitutions with the cycloalkylmethylsulfonates (306) and anilines in MeOH were also studied.280 Finally the reaction of thiopheneethyl arenesulfonates (307) with anilines and /V, /V- d i m c th y I an i I i nc s in MeCN has been reported on.281 Frontside-attack in an 5n2 mechanism with a four-centre TS is supported. 

The classic S 2 mechanism invokes backside attack of the nucleophile, leading to inversion at the carbon center. The alternative attack from the frontside, the Sf F mechanism, has been examined by Glukhovtsev et al. and Bickelhaupt. ... 

Frontside attack The nucleophile approaches from the same side as the leaving group. 

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