Structure of haloalkanes

Figure 12-1 The active site structure of haloalkane dehalogenase from Xanthobacter autotrophicus with a molecule of bound dichloroethane. See Pries et al.13 The arrows illustrate the initial nucleophilic displacement. The D260 - H289 pair is essential for the subsequent hydrolysis of the intermediate ester formed in the initial step.

Previous studies on other bacterial hydrolytic dehalogenases have revealed different mechanisms and structures. High resolution X-ray structures of haloalkane dehalogenase(iO), 4-chlorobenzoyl CoA dehalogenase 31) and L-2-haloacid dehalogenase (52) revealed that these enzymes use an active site aspartate in nucleophilic displacement of the chlorine substituent as chloride anion. The enzyme-substrate ester intermediate is subsequently hydrolyzed by... 

The reductive dehalogenation of haloalkanes has also been achieved in high yield using polymer supported hydridoiron tetracarbonyl anion (Table 11.15). In reactions where the structure of the alkyl group is such that anionic cleavage is not favoured, carbonylation of the intermediate alkyl(hydrido)iron complex produces an aldehyde (see Chapter 8) [3]. 

One important factor that helps us to decide is the structure of the haloalkane, i.e. whether it is primary, secondary or tertiary. 

Table 14.11 Critical structural features which can affect the carcinogenicity of haloalkanes and substituted haloalkanes.

Fortunately, there is now a comprehensive body of knowledge on the metabolic reactions that produce reactive (toxic) intermediates, so the drug designer can be aware of what might occur, and take steps to circumvent the possibility. Nelson (1982) has reviewed the classes and structures of drugs whose toxicities have been linked to metabolic activation. Problem classes include aromatic and some heteroaromatic nitro compounds (which may be reduced to a reactive toxin), and aromatic amines and their N-acylated derivatives (which may be oxidized, before or after hydrolysis, to a toxic hydroxylamine or iminoquinone). These are the most common classes, but others are hydrazines and acyl-hydrazines, haloalkanes, thiols and thioureas, quinones, many alkenes and alkynes, benzenoid aromatics, fused polycyclic aromatic compounds, and electron-rich heteroaromatics such as furans, thiophenes and pyrroles. 

Balaban, A. T., et al., Correlation Between Structure and Normal Boiling Points of Haloalkanes C1-C4 Using Neural Networks. J. Chem. Inf. Comput. Sci., 1994 34, 1118-1121. 

Structural formula of 1,2-dibromocyclohexane. This is a member of the homologous series of haloalkanes. 

Draw the structures of the functional groups alkene, alkyne, alcohol, haloalkane, carbonyl, ether, aldehyde, ketone, carboxylic acid, ester, amine, and amide. (Section 24.4)... 

What effect does the structure of the haloalkane have on the rate of reaction ... 

Predictions about the mechanism for a particular nucleophilic substitution reaction must be based on considerations of the structure of the haloalkane, the nucleophile, and the solvent. Following are analyses of three such reactions ... 

Reactions of secondary and tertiary haloalkanes in polar protic solvents give mixtures of substitution and elimination products. In both reactions, Step 1 is the formation of a car-bocation intermediate. This step is then followed by either (1) the loss of a hydrogen to give an alkene (El) or (2) reaction with solvent to give a substitution product (Sfjl). In polar protic solvents, the products formed depend only on the structure of the particular carbocation. For example, tgrt-butyl chloride and t rt-butyl iodide in 80% aqueous ethanol both react with solvent, giving the same mixture of substitution and elimination products ... 

The structure of the haloalkane. S g1 reactions are governed by electronic factors, namely, the relative stabilities of carbocation intermediates. 8 2 reactions are governed by steric factors, namely, the degree of crowding around the site of substitution. 

Dithiophosphate esters can be synthesized by adopting haloalkane and thiophosphates as raw materials [24]. The structure of disalkyl phosphate can be expressed as follows ... 

In this chapter, we begin with the structure and physical properties of haloalkanes. We then study radical halogenation of alkanes as a vehicle to introduce an important type of reaction mechanism, namely the mechanism of radical chain reactions. Reactions of oxygen with alkenes and a radical mechanism for HBr addition to alkenes complete the chapter. 

Predictions about the mechanism for a particular nucleophilic substitution reaction must be based on considerations of the structure of the haloalkane, the nucleophile, the leaving group, and the solvent. Following are five nucleophilic substitution reactions and an analysis of the factors that favor an S l or Sj 2 mechanism for each and the products that result from the mechanism used. Note that in the following examples, we ignore competing elimination because it has not been discussed yet. 

---