Halogenation hetero-atom

Goldfarb, J.L., Suuberg, E.M., 2008a. The effect of halogen hetero-atoms on the vapor pressures and thermodynamics of polycyclic aromatic compounds measured via the Knudsen effusion technique. J Chem Thermodyn 40,460-466. 

When a heteroatom, such as N, O, or a halogen, is present in a molecule containing an aromatic ring or a double bond, lithiation is usually quite regio-selective. The lithium usually bonds with the sp carbon closest to the hetero atom, probably because the attacking species coordinates with the hetero atom. Such reactions with compounds such as anisole are often called directed metala-tions. In the case of aromatic rings, this means attack at the ortho position.Two examples are... 

Another structural feature that increases carbocation stability is the presence, adjacent to the cationic center, of a hetero atom bearing an unshared pair,39 e.g., oxygen,40 nitrogen,41 or halogen.42 Such ions are stabilized by resonance ... 

Alkylation at a Position a to a Hetero Atom. Alkylation of 1,3-Dithianes 2-(2-Alkyl-1,3-dithianyl)-de-halogenation... 

Note that these group rate constants and substituent group factors should be used only for homologs of the compounds from which these factors were derived (Kwok and Atkinson, 1995 Koch et al., 1996). For example, the group rate constants k, N, k>NH and k N,l2 and the substituent factors F(-NH2), F(>NH) and F(>N-) are appropriate only for alkyl-substituted amines and not for amines containing halogen or other hetero-atoms (in particular, see Koch et al., 1996). For the phosphorothioamidates (with ->P(=S)N< structures) and... 

A posteriori, the addition of halogen to heterocycles can ensue in at least three distinct fashions, exemplified by the following adduct types (a) covalent bonding of halogen to carbon with the partial or complete saturation of the ring (1) (b) n-complexation of the halogen at the hetero atom 2) and (e) Tr-eomplexation of the molecular halogen (3). Whereas n and ir types of adduction occur... 

The majority of the metallated hetero-aromatic compounds are obtained by direct metallation [1, 2, 5]. The hetero-atom effect (inductive, coordinative and polarizability influence) in most cases directs the metallation to the position a- to the hetero atom and gives rise to an easier deprotonation compared with that of benzene [1]. In some cases, bromine-lithium exchange offers the possibility of introducing the metal in a position that is not accessible by direct deprotonation. In incidental cases, Grignard compounds have been prepared from halogenated hetero aromates and magnesium. 

The first definition is that of sulphonic acids and their derivatives , a term that has already appeared several times. For the purpose of this chapter, we take it to mean any compound of the generic type RS02X, where R is some group bound by carbon to the sulphur and X is a group that is bound to the sulphur by some hetero atom (N, O, S, halogen). Secondly, the phrase thermochemical data is customarily taken to mean heat of formation. AH heat capacity, Cp and entropy, S, all considered for both gaseous and condensed (liquid and/or solid) phases. However, we are personally interested almost exclusively in the heats of formation. Thus our only reference to heat capacity and entropy data is the compilation of data of these quantities2. (See Table 1.)... 

Covalent bond energies are close to 100 kcal/mol in single bonds, 150 kcal/mol in double bonds, and 200 kcal/mol in triple bonds in natural compounds (Table 1.2.2). Hetero atom-hetero atom single bonds (e.g., in hydrazine, peroxides, disulfides, and elementary halogen molecules) have bond energies of less than 50 kcal/mol. They tend to homolyze spontaneously, giving two radical moieties with an unpaired electron each. 

As with the azoles, oxa- and thiadiazoles are very weak bases due to the inductive effects of the extra hetero atoms, although A-quaternisation reactions can be carried out. For similar reasons, electrophilic substitutions on carbon are practically unknown, apart from a few halogenations and mercurations - it is an intriguing paradox that mercurations, with what is generally thought of as a weak electrophile, are often successful in electron-poor heterocycles. Another important difference from the azoles is of course the absence of A-hydrogen, so that A-anion-mediated reactions are not possible. 

Similar rate enhancements are expected for aliphatic hydrocarbons containing nitrogen and sulfur hetero-atoms bonded directly to the halogen-bearing carbon. It is readily apparent that chemicals containing structural features that allow for the delocalization of carbonium ion intermediates will not be persistent in aquatic environments. 

Benzo[fe]thiophenes and -furans, and V-blocked indoles lithiate on the heterocyclic ring, a to the hetero atom. Lithiation at the other hetero-ring position can be achieved via halogen exchange, but low temperatures must be maintained to prevent equilibration to the more stable 2-lithiated heterocycle. ... 

Such substitutions follow the same mechanistic route as the displacement of halide from 2- and 4-halo-nitro-benzenes, i.e. the nucleophile first adds and then the halide departs. By analogy with the benzenoid situation, the addition is facilitated by (i) the electron-deficiency at a- and y-carbons, increased by a halogen substituent, and (ii) the ability of the hetero atom to accommodate negative charge in the intermediate thus produced. Once again, a comparison of the three possible intermediates makes it immediately plain that this latter is not available for attack at a P-position, and thus P nucleophilic displacements are very much slower. 

Lithiobenzothiophenes can be generated, and reacted with electrophiles, if the temperature is kept low. Direct deprotonation of benzothiophenes follows the usual pattern for five-membered heterocycles and takes place adjacent to the hetero atom, and in concord with this pattern, metal-halogen exchange processes favour a 2- over a 3-halogen. 2-Trialkylstannylbenzofurans are useful for palladium-catalysed coupling with aromatic halides. ... 

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