Nucleophilic back-side* attack

Neopentyl (2,2-dimethylpropyl) systems are resistant to nucleo diilic substitution reactions. They are primary and do not form caibocation intermediates, but the /-butyl substituent efiTectively hinders back-side attack. The rate of reaction of neopent>i bromide with iodide ion is 470 times slower than that of n-butyl bromide. Usually, tiie ner rentyl system reacts with rearrangement to the /-pentyl system, aldiough use of good nucleophiles in polar aprotic solvents permits direct displacement to occur. Entry 2 shows that such a reaction with azide ion as the nucleophile proceeds with complete inversion of configuration. The primary beiuyl system in entry 3 exhibits high, but not complete, inversiotL This is attributed to racemization of the reactant by ionization and internal return. 

As shown in Fig. 1, the big lobes of these hybrids point toward each other. Therefore, if the nucleophile approaches the substrate from the front side, its HOMO overlaps in phase with the big lobe of 0c and out-of-phase with the big lobe of 0x-Numerical calculations show that the unfavourable (nucleophile-leaving group) interaction usually overrides the favourable (nucleophile - reaction center) interaction in this front-side approach, so that back-side attack is finally preferred, leading to inversion of configuration. 

Concerning the reactions occurring with inversion, the stereochemistry requires a back-side attack of the nucleophile opposite the leaving group. The skeleton of intermediate 14 corresponds to apical entry and departure. 

The fact that SN2 reactions always occur with inversion of configuration enables us to form a better picture of the transition state. The nucleophile must approach the carbon from the side opposite the leaving group (back-side attack). The structure of the transition state, with partial bonds to the entering hydroxide and the leaving chloride, is shown in the following structure. Figure 8.3 uses orbitals to show how this process occurs. 

Figure 6-6 shows the SN2 reaction of hydroxide ion with ethyl bromide (1°), isopropyl bromide (2°), and ferf-butyl bromide (3°). The nucleophile can easily approach the electrophilic carbon atom of ethyl bromide. In isopropyl bromide, the approach is hindered, but still possible. In contrast, SN2 approach to the tertiary carbon of ferf-butyl bromide is impossible because of the steric hindrance of the three methyl groups. Make models of ethyl bromide, isopropyl bromide, and ferf-butyl bromide, and compare the ease of bringing in an atom for a back-side attack. 

Back-side attack literally turns the tetrahedron of the carbon atom inside out, like an umbrella caught by the wind (Figure 6-7). In the product, the nucleophile assumes a stereochemical position opposite the position the leaving group originally occupied. We call this result an inversion of configuration at the carbon atom. 

Back-side attack in the SN2 reaction. The S 2 reaction takes place through nucleophilic attack on the back lobe of carbon s sp3 hybrid orbital. This back-side attack inverts the carbon atom s tetrahedron, like a strong wind inverts an umbrella. 

Vinyl and aryl halides generally do not undergo SN1 or Sn2 reactions. An SN1 reaction would require ionization to form a vinyl or aryl cation, either of which is less stable than most alkyl carbocations. An Sn2 reaction would require back-side attack by the nucleophile, which is made impossible by the repulsion of the electrons in the double bond or aromatic ring. 

Anti stereochemistry results from the bromonium ion mechanism. When a nucleophile attacks a halonium ion, it must do so from the back side, in a manner similar to the SN2 displacement. This back-side attack assures anti stereochemistry of addition. 

The crucial step is a back-side attack by the solvent on the protonated epoxide. Step 1 Protonation of the epoxide activates it toward nucleophilic attack. 

The alkoxide ion is a strong nucleophile as well as a powerful base. Unlike the alcohol itself, the alkoxide ion reacts with primary alkyl halides and tosylates to form ethers. This general reaction, called the Williamson ether synthesis, is an SN2 displacement. The alkyl halide (or tosylate) must be primary so that a back-side attack is not hindered. When the alkyl halide is not primary, elimination usually results. 

Figure 14.3. The SnI reaction racemization plus inversion. Nucleophilic reagent attacks both (a) back side and (b) front side of carbonium ion. Back-side attack predominates.

If the attack were purely random, we would expect equal amounts of the two isomers that is to say, we would expect only the racemic modification. But the product is not completely racemized, for the inverted product exce ds its enantiomer. How do we account for this The simplest explanation is that attack by the nucleophilic reagent occurs before the departing halide ion has completely left the neighborhood of the carbonium ion to a certain extent the departing ion thus shields the front side of the ion from attack. As a result, back-side attack is somewhat preferred. 

Water as nucleophile then displaces mercury by back-side attack at the more highly substituted carbon, breaking the C-Hg bond. 

It might help to think of E2 elimination reactions with periplanar geom-, etry as being similar to S 2 reactions with 180° geometry. In an Sm2 reaction, an electron pair from the incoming nucleophile pushes out the leav-, ing gi oup on the opposite side of the molecule (back-side attack). In an 21... 

Mechanisms of reactions of HCI with a tertiary and a primary alcohol. Both reactions involve initial protonation of the alcohol -OH group. A tertiary alcohol reacts by an mechanism because it can form a stable tertiary carbocation intermediate by loss of H O from the protonated reactant. A primary alcohol reacts by an m2 pathway because unhindered back-side attack of a nucleophile on the protonated reactant can occur ... 

Aryl halides don t undergo Sf,-2 reactions because the halo-substituted carbon atom is sterically shielded from back-side attack by the aromatic ring. For a nucleophile to attack an aryl halide, it would have to approach directly through the aromatic ring and invert the stereochemistry of the aromatic ring—a geometric impossibility. 

Acid-catalyzed epoxide cleavage takes place by back-side attack of] nucleophile on the protonated epoxide in a manner analogous to the fn step of alkene bromination, in which a cyclic bromonium ion is opened 1 nucleophilic attack (Section 7.2). When an epoxycycloalkane is opened 1 aqueous acid, a rans-1,2-diol results, just as a from cycloalkene bromination. 

Acid-induced ring opening of 1,2-epoxy-l-methykyclohexane with HBr. There is a high degree of SNi-like carbocation character in the transition state, which leads to back-side attack of the nucleophile at the tertiary center and to formation of the isomer of 2-bromo-2-methylcyclohexano1 that has -Br and OH groups trans. 

Perhaps the single most important reaction of enolate ions is their alkylation by treatment with an alkyl halide or tosylate. The alkylation reaction is useful because it forms a new C-C bond, thereby joining two smaller pieces into one larger molecule. Alkylation occurs when the nucleophilic enolate ion reacts with the electrophilic alkyl halide in an Sn2 reaction and displaces the leaving group by back-side attack. 

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