While in its traditional form the Finkelstein reaction involves the transformation of an alkyl chloride or bromide to the corresponding alkyl iodide via treatment with sodium iodide in acetone, the name also refers to the conversion of alkyl sulfonates to alkyl iodides. Alkyl sulfonates are readily prepared from alcohols.

Procedure:

A solution of 5-hexen-1-ol (5.0 g, 0.050 mol) and triethylamine (7.6 g, 0.076 mol) in 250 mL of dichloromethane is cooled under inert atmosphere in an ice salt bath to ca. -5 °C. Methanesulfonyl chloride (4.7 mL, 0.06 mol) is added dropwise with stirring. After stirring for an additional hour at ca. -5 °C, the reaction is washed with cold water, cold 10% aqueous hydrochloric acid, a cold saturated aqueous solution of sodium bicarbonate, and a cold solution of brine using approximately 75 mL for each wash. The organic fraction is dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the mesylate which is used in the next step without further purification.

To the flask containing the unpurified mesylate product are added 100 mL of dry acetone followed by anhydrous sodium iodide (9.3 g, 0.06 mol) with stirring under inert atmosphere. After stirring at reflux for 4 hours the reaction mixture is cooled to ambient temperature. The resulting solution is concentrated in vacuo and treated with 25 mL of pentane and 25 mL of 10 % aqueous sodium thiosulfate. The organic fraction is washed with 25 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude material is then passed through a plug of silica gel and eluted with pentane. The solution is then concentrated in vacuo to afford the title compound.

http://www.orgsyn.org/orgsyn/prep.asp?prep=v81p0121

The Williamson Ether synthesis continues to be an important reaction in organic synthesis. The procedure is simple and usually produces the desired compound in high overall yield. It is therefore frequently employed to introduce ether protective groups and ether functional groups in natural products.

The synthesis of 3-(2-methoxyethoxy)prop-1-ene from 2-methoxyethanol and allyl bromide is an excellent example of the procedure. In this case the electrophilic organobromide species is allyl bromide. Allyl bromide is much more reactive than a simple primary alkyl halide because the incipient positive charge that develops as the carbon undergoes nucleophilic attack can be delocalized by the π-orbital of the carbon-carbon double bond. Benzyl bromide also enjoys an increased reaction rate because the positive charge can be stabilized by the π-system of the aromatic ring. The Williamson Ether synthesis can proceed through either the S_N1 or S_N2 mechanism with these reagents, whereas simple primary alkyl halides such as ethyl bromide generally can only proceed through the S_N2 mechanism.

Procedure: 3-(2-methoxyethoxy)prop-1-ene

A solution of potassium hydroxide (25.5 g, 0.45 mol) in dry 2-methoxyethanol (32.5 mL, 31.15 g, 0.41 mol) is cooled to 0 °C. The reaction temperature is maintained below 10 °C as allyl bromide (36 mL, 25.0 g, 0.41 mol) is added dropwise with rapid stirring over several minutes. The reaction is then allowed to warm slowly to room temperature and is stirred for 10 hours at ambient temperature. The resulting mixture is then filtered and the solids are washed with 150 mL pentane in small portions. The combined organic fractions are dried over magnesium sulfate. Fractional distillation over calcium hydride provides the title compound in fractions collected between approximately 115-129 °C.

The Finkelstein reaction involves the reaction of an alkyl chloride or bromide with sodium iodide to produce the corresponding alkyl iodide. The reaction may proceed via either an S_N1 or S_N2 mechanism depending on the nature of the alkyl halide.

Mechanism:

Acetone is employed as solvent in the classical version of the reaction. Acetone is used in order to take advantage of the relatively higher solubility of sodium iodide compared to sodium bromide or chloride. The precipitation of the chloride or bromide salts removes the ions from solution and drives the reaction to completion. In the synthesis of ether compounds, the reaction can be used to prepare a suitable alkyl iodide for use in the Williamson Ether Synthesis.

The reaction can also be performed in other solvents and the reaction can be driven to completion by the addition of a large excess of iodide. The reaction can also be employed using a catalytic amount of iodide. The alkyl iodide product can be generated in situ where it reacts further, regenerating the iodide.

The relative rates of reactivity of various alkyl halides in the Finkelstein reaction resembles the rates of reactivity observed in other nucleophilic substitution reactions. The reaction rate increases as the number of carbons bonded to the carbon atom bearing the halogen decreases. The reaction rate is significantly higher when the carbon atom that undergoes attack is adjacent to a double bond or aromatic ring. Allyl bromide and benzyl bromide have a much higher rate of reaction than simple primary alkyl halides such as ethyl bromide. Electron donors on such double bonds or aromatic rings tend to increase the rate of reaction. Electron withdrawing groups tend to decrease the rate. This is consistent with a transition state that places a developing positive charge on the carbon atom undergoing attack.

One variant of the reaction involves converting an alcohol to an excellent leaving group such as a tosylate, and then converting the tosylate to the iodide. This sequence formally has the effect of converting an alcohol to an alkyl halide.

Experimental Procedure:

For an example of the laboratory procedure for the Finkelstein reaction, see the synthesis of ethyl 5-iodovalerate.

References:

H. Fickelstgein, Ber., 1910, 43, 1528.

C. K. Ingold, Structure and Mechanisms in Organic Chemistry (Cornell Univ. Press, London, 2nd ed., 1969) p. 435.

Streitwieser, A. Chem. Rev., 1956, 56, 571.

J. Hayami et al., Tetrahedron Letters, 1973, 385.

S. Samaan, F. Rolla, Phosphorus and Sulfur, 4, 145 (1978).

W. B. Smith, G. D. Branum, Tetrahedron Letters, 1981, 22, 2055.

F. G. Bordwell, W. T. Brannen, J. Am. Chem. Soc., 1964, 86, 4645.

D. W. Kim, C. E. Song, D. Y. Chi, J. Org. Chem., 2003, 68, 4281-4285.

T. W. Baughman, J. C. Sworen, K. B. Wagener, Tetrahedron, 2004, 60, 10943-10948.

Maloney, D. J. Hecht, S. M. Org. Lett., 2005, 7, 4297.

The Williamson ether synthesis is a nucleophilic substitution reaction that leads to the formation of an ether by reacting an alkyl halide with an alkoxide ion:

The reaction can also be used to prepare an ether from two alcohol starting materials by first converting the OH moiety on one of the alcohols to a better leaving group such as tosylate, nosylate, brosylate, trifluoromethanesulfonate, or other sulfonate.

The reaction works best with primary alkyl halides and alcohols. Tertiary alkyl halides will not undergo an S_N2 displacement. Depending on the alkoxide, either elimination products (by either an E1 or E2 mechanism) or S_N1 products generally will be observed.

Mechanism:

The reaction proceeds primarily through an S_N2 (second order nucleophilic substitution) mechanism, particularly when a primary alkyl halide is used. The reaction can also proceed through an S_N1 (first order nucleophilic substitution) mechanism. E1 and E2 elimination products can also be observed when secondary alkyl halides are used.

The reaction rate for alkyl chlorides and bromides can be improved by adding a catalytic amount of sodium iodide to the reaction in a variation known as the Finkelstein reaction. The highly nucleophilic iodide ion displaces chloride or bromide to form an alkyl iodide intermediate which then reacts with the alkoxide.

Experimental Procedure:

See 3-(2-methoxyethoxy)prop-1-ene for an example of the laboratory procedure.