In the Finkelstein reaction

In 1976, Miller and Nunn observed remarkable rate accelerations in the Finkelstein reaction between tertiary alkyl chlorides and Nal in the presence of Fe- or Zn salts (Scheme 7.3) [1], Using CS2 as the solvent, the reaction took place within a few hours, giving rise to tertiary alkyl iodides in almost quantitative yield. 

Hayami, J., Koyanagi, T., Hihara, N., Kaji, A. Substrate-nucleophile association in the Finkelstein reaction system in a dipolar aprotic solvent. Formation of complex between substituted chloromethanes and halide ion in acetonitrile. Bull. Chem. Soc. Jpn. 1978, 51, 891-896. 

Hayami, J., Otani, S., Hashimoto, S. Solute-solvent interactions in the Finkelstein reaction system. Characterization of chloride and perchlorate anion. Stud. Org. Chem. (Amsterdam) 1987, 31, 561-566. 

To be of value the treatment must explain the enormous enhancement of rate in the Finkelstein reaction above, and it is clear that no single bulk-solvent property is adequate. If the transition state is in chemical equilibrium with reactants or, in collision theory parlance, if the stability of the encounter complex is directly reflected in the rate expression, then the change in rate with medium must reflect the free energy difference between the reactants and the transition state or encounter complex. This free energy difference must itself reflect the solvation free energies of the reactants and the transition state or encounter complex, as long as these latter two can be considered to retain their identity upon solvent change. 

These substances accelerate the reaction, and their effectiveness increases in the order given. This suggestion was questioned by Pocker, who found that the effects of such added substances were not directly proportional to their concentrations and could easily be explained by macro effects on the solvent character. He also found that common-ion effects were small in the reaction, the effect of added 1-methylpyridinium bromide was negligible, and that there was no evidence for surface catalysis on the walls of the vessel. There is an exact parallel between the relative rates of the Finkelstein reactions... 

Halide exchange, sometimes call the Finkelstein reaction, is an equilibrium process, but it is often possible to shift the equilibrium." The reaction is most often applied to the preparation of iodides and fluorides. Iodides can be prepared from chlorides or bromides by taking advantage of the fact that sodium iodide, but not the bromide or chloride, is soluble in acetone. When an alkyl chloride or bromide is treated with a solution of sodium iodide in acetone, the equilibrium is shifted by the precipitation of sodium chloride or bromide. Since the mechanism is Sn2, the reaction is much more successful for primary halides than for secondary or tertiary halides sodium iodide in acetone can be used as a test for primary bromides or chlorides. Tertiary chlorides can be converted to iodides by treatment with excess Nal in CS2, with ZnCl2 as catalyst. " Vinylic bromides give vinylic iodides with retention of configuration when treated with KI and a nickel bromide-zinc catalyst," or with KI and Cul in hot HMPA." ... 

The resulting homoallylic alcohol 24 is next transformed into a tosylate, which subsequently undergoes nucleophilic substitution with sodium iodide in a Finkelstein reaction to give compound 13. 

In their second approach (Scheme 3.51), the known 8-hydroxymethylpurine (282), available in two steps from (276) and glycolic acid [153], was treated with thionyl chloride. The resulting labile chloromethyl derivative (283) was used to alkylate />-aminobenzoyl L-glutamic acid after an in situ Finkelstein reaction furnishing (281a) directly. Use of (31) in this reaction sequence followed by saponification afforded no improvement in yield. Finally, reaction of (35) with (283) and ester hydrolysis yielded the purine MTX analogue (281b). 

As has already been pointed out, the Finkelstein reaction can be conducted in situ in the absence of solvents. For example, alkylations of purine and pyrimidine bases with alkyl halides and dimethyl sulfate have been carried out by solid/liquid phase-transfer catalysis in the absence of any additional solvent [48], as have cyanation of haloalkanes [49] and / -eliminations [50]. Noteworthy is the synthesis of glycosyl isothiocyanates by the reaction of potassium thiocyanate with molten glycosyl bromide at 190 °C [51]. 

In the presence of molar amounts of catalyst, the chloride/iodide exchange reaction is more effective as has been shown by Brandsrom178 for the conversion of chloroaceto-2,6-xylidide into the corresponding iodide. The Finkelstein reaction is also catalyzed by phos-phonium and arsonium salts1. 

Fig. 5-4. Schematic one-dimensional enthalpy diagram for the exothermic bimolecular Finkelstein reaction Cl -I- CFI3—Br Cl—CH3 -I- Br in the gas phase and in aqueous solution [469, 474, 476]. Ordinate standard molar enthalpies oi (a) the reactants, (b, d) loose ion-molecule clusters held together by ion-dipole and ion-induced dipole forces, (c) the activated complex, and (e) the products. Abscissa not defined, expresses only the sequence of (a). ..(e) as they occur in the chemical reaction.

Octa[(3-iodopropyl)-silsesquioxane] can be prepared by the Finkelstein-reaction treating octa-[(3-chloropropyl)-silsesquioxane] with sodium iodide in dry acetone under reflux. The structure of [I-(CH2)3]8(SiOi 5)g has been confirmed by X-ray crystallography [4, 5]. In the same way octa-[(3-thiocyanatopropyl)-silsesquioxane] was obtained. 

The precursors of the macrocycles 745, that is the bis(iodoallyl)-TTFs 744, were prepared in a few steps from bis-protected TTF 742 via the sequence of cyanoethyl deprotection, alkylation of the resulting thiolates, the Finkelstein reaction, and quaternization of the 4,4 -bipyridyl with the iodides obtained (Scheme 110). Other singly and doubly tethered D-A systems 746-748 were synthesized in a similar way <1997JOC679, 2002CEJ4461>. 

The Finkelstein reactions of alkyl bromides with chloride ion show the same differences in rate (Fig. 5), no matter whether the solvent is acetone or DMF or whether the nucleophile is introduced as the weak electrolyte, lithium chloride in acetone, or the strong electrolyte, NEt4Cl in DMF. The calculated differences in activation energy in acetone (de la Mare et al., 1955) correlate well with observed activation energies in DMF, observed differences in acetone show less satisfactory correlation, but the behaviour of the activation energy is quite similar in... 

Halide exchange from the lower halides to iodine is often desirable due to the higher reactivity of iodides in nucleophilic substitutions, reductions, organometallic or radical reactions (Scheme 30). Conversion of chlorides and bromides to iodides with sodium iodide in acetone is called the Finkelstein reaction. This halide exchange is an equilibrium process, which is shifted to the iodinated products due to precipitation of the less soluble sodium bromide or chloride from acetone. Best results are obtained when the reaction mixture is free of water. 

During the endgame of the total synthesis of the stemona alkaloid (-)-stenine, Y. Morimoto and co-workers utilized the Finkelstein reaction to prepare a primary alkyl iodide from a primary alkyl mesylate. The mesylate was prepared from the corresponding primary alcohol with MsCI/EtsN. The resulting primary alkyl iodide was used in the subsequent intramolecular N-alkylation to construct the final perhydroazepine C-ring of the natural product. 

In the laboratory of J. Zhu, the synthesis of the fully functionalized 15-membered biaryl-containing macrocycle of RP 66453 was accomplished. One of the key steps in their approach was Corey s enantioselective alkylation of a glycine template with a structurally complex biaryl benzyl bromide. This benzyl bromide was prepared from the corresponding benzyl mesylate via the Finkelstein reaction using lithium bromide in acetone. 

Maartmann-Moe, K., Sanderud, K. A., Songstad, J. Reactions of benzylic compounds. Nucleophilicity, leaving group ability and carbon basicity of some ionic nucleophiles in acetonitrile. Comments on the utility of the Finkelstein reaction in synthesis. Acta Chem. Scand. 1982, 636,211-223. 

In 1967, Pedersen described the preparation and properties of crown ethers,3 which are macrocyclic polyethers capable of sequestering metal cations. These catalysts can enhance the solubility and reactivity of salts in nonpolar solvents. For example, 18-crown-6, i.e., yxo-anhydro-hexaethylene glycol, forms a host-guest complex with potassium cation (K+) (Equation (1)). This association enables ionic potassium fluoride (KF) to dissociate in nonpolar benzene. And since the nucleophilic F counterions are not complexed,4 the yield of the Finkelstein reaction,5 i.e., halide-halide exchange, is increased 6... 

An old but still useful alternative is the Finkelstein reaction,which involves treatment of an alkyl chloride, bromide, mesylate, or tosylate with sodium or potassium iodide to produce alkyl iodides via an Sn2 reaction. Refluxing chloride 159 with sodium iodide, in dry acetone, for example, gave a 95% yield of iodide 160 in Baldwin s synthesis of haliclamines A and Similarly, Shirai and co-workers converted a tosylate... 

The inadequacies of the present electrostatic models for solvent effects on reaction rates has been emphasised in the last ten years by the availability of a range of strongly dipolar aprotic solvents, typified by di-methylsulphoxide (DMSO), A,A-dimethylacetamide (DMA), N,N-dimethylformamide (DMF) and sulpholane (TMSOa). The magnitude of the effect that remains unaccounted for by the present electrostatic models can be demonstrated from measurements of the rate of the Finkelstein reaction ... 

This reaction was initially reported by Finkelstein in 1910. It is a preparation of alkyl iodide from alkyl bromide or chloride with potassium or sodium iodide in acetone. Therefore, this reaction is generally known as the Finkelstein reaction. Occasionally, it is also referred to as the Finkelstein halide exchange, Finkelstein displacement, or Conant-Finkelstein reaction. Mechanistically, this reaction is a simple nucleophilic substitution (often via Sn2), as iodide is a stronger nucleophile than bromide or chloride. The yield of this reaction is very high and can be quantitative if occurs in DMF. It was found that the trifluoromethyl group retards the displacement of bromide when it presents as an a- or /3-substituent but accelerates the reaction as a substituent in an allylic chloride. Under normal conditions, this type of halide displacement does not occur for aryl halides. For dihalides, unsaturated or cyclic compounds may form via carbocation intermediates, which form transient covalent iodides or are reduced directly by iodide to free radicals. However, the aromatic halide exchange reacts smoothly when 10% Cul is present in the reaction... 

Other references related to the Finkelstein reaction are cited in the literature. ... 

When the reagent is Nal in the solvent acetone (2-propanone see Chapter 16, Section 16.2), this transformation is known as the Finkelstein reaction, named after Hans Finkelstein (Germany 1885-1938). Because iodide is a better nucleophile than the bromide ion or the chloride ion, it is rmlikely that bromide or chloride will displace iodide ion from an alkyl iodide to give the alkyl bromide or the alkyl chloride. (This point was made in Chapter 7, Section 7.6.) In other words, iodide can displace bromide or chloride, but bromide or chloride will not displace iodide. In general, fluoride is a poor leaving group in the Sn2 reaction and it will not be used. 

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