In the Newman-Kwart Rearrangement (NKR), intramolecular aryl migration of O-thiocarbamates at high temperatures leads to S-thiocarbamates. The NKR allows access to thiophenols from phenols, as O-thiocarbamates are readily prepared and hydrolysis of S-thiocarbamates can readily be achieved.
Mechanism of the Newman-Kwart Rearrangement
Relatively acidic phenols can be converted to with N,N-dialkylthiocarbamoyl chlorides in the presence of a strong tertiary amine base, whereas less-acidic phenols can be deprotonated prior to the thiocarbamoylation.
NKR reactions of N,N-dimethyl, N,N-diethyl, N-morpholino, N-methyl-N-phenyl thiocarbamates provide the desired product in comparable yields, but with mono-N-alkylated substrates phenol elimination yields the isocyanate upon warming.
As the Newman-Kwart Rearrangement requires elevated temperatures, several side reactions can occur, and these can be catalyzed by trace impurities. The use of N,N-dimethylthiocarbamates has a major advantage in that these compounds tend to crystallize more easily, and can therefore by purified more simply.
The accepted mechanism for the Newman-Kwart Rearrangement has been confirmed by kinetics experiments - the reaction exhibits the first order kinetics typical for intramolecular reactions together with a large and negative entropy of activation. The driving force is the thermodynamically favorable conversion of a C=S into a C=O bond (ΔH ~ 13 kcal mol-1).
The rearrangement can be viewed as an intramolecular aromatic nucleophilic substitution reaction:
Typically for aromatic nucleophilic substitution reactions, electron withdrawing groups in the para- and ortho-positions show a substantial activating effect, favoring nucleophilic attack by lowering the electron density on the aromatic ring and stabilizing the resultant negative charge.
Small substituents in the ortho-position have a beneficial effect: restriction of rotation around the Ar-O bond, leads to a decrease in entropy upon approach to the transition state for the rearrangement. The relative rates of reaction between O-(o-tolyl) and O-(p-tolyl) N,N-dimethylthiocarbamates was 1.9. However, the 2,6-dimethyl analog reacts slightly more slowly, and when the size of substituents is increased from methyl to tert-butyl the rate decreases substantially, as steric compression upon approach overwhelms the favorable entropic effect:
Some substrates require conditions so drastic that destruction of the substrate on prolonged contact with the hot reaction vessel walls leads to side products. For example, electron-rich aromatic compounds with higher activation barriers and substrates that bear either thermally sensitive groups or stereocenters (racemization) require specific conditions such as flash vacuum pyrolysis, in which the substrate in toluene is passed in a stream of nitrogen through a heated quartz tube (~ 400°C). Another solution is provided by the use of thermally stable polar solvents in a microwave-assisted procedure:
High temperature NKR reactions can be conducted more conveniently using pressure-proof microwave equipment, because the temperatures and slightly elevated pressures (10 bar) can be more easily accessed in a very short time, and better controlled. However, there is no specific microwave effect, so superheating alone is responsible for the acceleration of the reaction.
The reaction is unimolecular, but the zwitterionic intermediate can be stabilized to a certain extend by polar solvents or electrolytes. Reactions that lead to only 10% of product in xylene can produce up to 80% in formic acid. DMA, NMP and diphenyl ether are other solvents of choice that are polar and allow high reaction temperatures.
The formation of thiols from S-aryl thiocarbamates is readily achieved using 10% aqueous NaOH or methanolic potassium hydroxide. Alternatively, reduction with lithium aluminum hydride under non-hydrolytic conditions affords aryl thiols in good yields.
For a full review of the Newman-Kwart Rearrangement covering historic developments, mechanistic details, and applications please refer to a recent publication by Lloyd-Jones, Moseley and Renny (Synthesis 2008, 661. DOI).
The Newman-Kwart Rearrangement of O-Aryl Thiocarbamates: Substantial Reduction in Reaction Temperatures through Palladium Catalysis
J. N. Harvey, J. Jover, G. C. Lloyd-Jones, J. D. Moseley, P. Murray, J. S. Renny, Angew. Chem. Int. Ed., 2009, 48, 7612-7615.
A high temperature investigation using microwave synthesis for electronically and sterically disfavoured substrates of the Newman-Kwart rearrangement
J. D. Moseley, P. Lenden, Tetrahedron, 2007, 63, 4120-4125.