Halohydrins, displacement reactions

This intermediate, it will be observed, is the same one that was postulated to explain the abnormal course of the displacement reactions of the halohydrins (pp. 96, 99). 

Oxirane formation by intramolecular displacement reactions of halohydrins (2-halo-1-ols) is a general and useful reaction, as discussed in Chapter 1.03.4.2. A unique example of an intramolecular substitution is observed during f-butyllithium addition to (156) the reaction involves 1,2-attack of the resulting alkoxide ion in (157) with concomitant 1,2-alkyl shift to give the protoadamantane derivative (158), reminiscent of a fragmentation reaction (Scheme 29) <91JOC1700>. 

In its simplest form, the study of neighboring group effects notes that a heteroatom with a pair of nonbonding electrons can act as a nucleophile in an intramolecular displacement reaction, just as external nucleophiles can participate in intermolecu-lar S]v2 reactions. In an example we have seen (p. 317), oxiranes can be formed from halohydrins in base (Fig. 21.2). 

Base-promoted cyclization of vicinal halohydrins (Section 16.10) This reaction is an intramolecular version of the Williamson ether synthesis. The alcohol function of a vicinal halohydrin is converted to its conjugate base, which then displaces halide from the adjacent carbon to give an epoxide. 

The chlorohydrin reaction with sodium hydroxide is assumed to be a two-step process in which a rate-determining intramolecular displacement of chloride ion by negatively charged oxygen follows a prior equilibrium between the hydroxide ion and the hydroxyl group of the halohydrin (5). 

Reaction of the epoxy alcohol with LiBr forms the halohydrin salt that equilibrates to the equatorial-Br conformer, which then undergoes ring contraction via an /-parallel displacement of Br (Step A). Proton transfer (Step B), although proceeding at a slower rate, leads to another anti-parallel Br displacement (Step C), forming the minor product FI. 

They can also be obtained from alkenes in a two-step process (Fig. A). The first step involves electrophilic addition of a halogen in aqueous solution to form a halohydrin. Treatment of the halohydrin with base then ionises the alcohol group, that can then act as a nucleophile. The oxygen uses a lone pair of electrons to form a bond to the neighbouring electrophilic carbon, thus displacing the halogen by an intramolecular SN2 reaction. 

The study of gas-phase acid-induced nucleophilic displacement on 2,3-dihalobutanes has provided stereochemical evidence for the occurrence of cyclic chloronium and bromo-nium ions (X = Cl, Br), but not fluoronium ions17. Protonation or methylation of the neutral 2,3-dihalobutane by a suitable acid GA+ produces a halonium intermediate 2, which in the presence of water ultimately leads to the corresponding halohydrin neutral product (Scheme 4). Analysis of these neutral products indicated that the reaction proceeds with retention of configuration when X = Cl, Br and with inversion of configuration when X = F. The results were rationalized by the mechanisms sketched in Scheme 4, namely direct bimolecular nucleophilic displacement by H20 on 2 when X= F and intramolecular nucleophilic displacement to convert 2 into the cyclic halonium ion 3 (with inversion of configuation) followed by bimolecular nucleophilic displacement on 3 (with inversion of configuration) when X = Cl and Br. 

Of course, aziridines can also be synthesized by the ring-closing reactions of appropriately substituted amines. For example, halohydrins of type 142 are converted to iV-hydroxy-aziridines 144 by treatment with hydroxylamine derivatives, followed by base-catalyzed intramolecular Sn2 reaction of the intermediate p-haloaminoesters 143 under phase-transfer conditions <03TL3259>. A -Bromoethylimines 146, formed from the reaction of benzaldehyde derivatives (e.g., 145) and 2-bromo-2-methylpropylamine hydrobromide, undergo nucleophilic attack by methoxide, followed by intramolecular displacement of bromide to form A -(a-methoxybenzyl)aziridines 147 <03TL1137>. 

The reaction of cyclohexene oxide with MeMgX was reexamined in 1969, in work which clearly established the importance of the halide. Standard conditions (1 h at 80 C) were employed with 1.4 equiv. of the organometallic, to give the yields listed under equation (83). Only minor amounts of the normal displacement product (200) are formed from the chloride and bromide, and none from the iodide. The iodide and bromide give extensive rearrangement, with the bromide being more selective in the sense that product (198) is expected on the basis of stereoelectronic considerations (backside displacement of halide) from the rra/is-halohydrin. The unusual product from this perspective is (199). It must arise either from the c/s-halohydrin or a process which is not subject to the same stereoelectronic controls, e.g. via a carbenium ion. 

Figure 11 Three possible mechanisms for the dehalogenation of frans-3-chloroacrylate. (a) Addition of water to the double bond, followed by enzyme-catalyzed or chemical decomposition of a short-lived halohydrin intermediate to afford malonate semialdehyde, (b) Conjugate addition reaction where the chlorine atom is displaced by a water-derived hydroxyl group, followed by tautomerization of the enol intermediate, (c) Conjugate addition reaction where the chlorine atom is displaced by an active site carboxylate group, followed by hydrolysis of the covalent ester intermediate, and tautomerization of the enol intermediate.

This section will begin with a simple method for producing epoxides that uses the reaction of alkenes and hypohalous acids (generated by the reactions CI2 + H2O HOCl or Br2 + H2O HOBr) to give the trans-(or anti-) halohydrin as the major product. An example is the conversion of cyclohexene to bromohydrin 149 (sec. 2.10.C). Subsequent treatment with a base such as sodium hydride generates the alkoxide (150), which is anti- to the adjacent bromine, which anti- orientation leads to displacement of halide... 

We Studied the reaction of alkenes with chlorine or bromine in water to form halohydrins in Section 6.3E and saw that it is both regioselective and stereoselective (for an alkene that shows cis-trans isomerism, it is also stereospecific). Conversion of a halohydrin to an epoxide with base is stereoselective as well and can be viewed as an internal Sj. 2 reaction. Hydroxide ion or another base abstracts a proton from the halohydrin hydroxyl group to form an alkoxide ion, a good nucleophile, which then displaces halogen on the adjacent carbon. As with all S 2 reactions, attack of the nucleophile is from the backside of the C—X bond and causes inversion of configuration at the site of substitution. 

Conversion of an alkene to a halohydrin and internal displacement of a halide ion by an alkoxide ion are both stereoselective. Use this information to demonstrate that the configuration of the alkene is preserved in the epoxide. As an illustration, show that reaction of ds-2-butene by this two-step sequence gives ds-2,3-dimethyloxirane (ds-2-butene oxide). 

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