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Reeve and coworkers performed mechanistic studies on the rearrangement of trichlorocarbinols to α-chloro acids.2, 10

Upon investigating the scope of the Jocic reaction1it was found that a variety of secondary trichlorocarbinols would react to form their corresponding α-chloro acid generally in good yields (Table 5).

R Yield % C(CH3)3 78 CH2CH3 23 C6H5 60 p-Cl-C6H5 63 p-Br-C6H5 93 o-allyl-C6H5 46

Table 5Jocic reaction with secondary trichlorocarbinols.

Throughout their studies Reeve and coworkers noticed that 1,1,1-trichloro-2- methylpropan-2-ol 71was unreactive at 0 ºC but would react slowly at 25 ºC, with the major product being acetone and carbon monoxide (Scheme 53).2

Furthermore, the reaction with 2,2,2-trichloro-1-phenylethan-1-ol23was found to be 83 % intramolecular, which was determined from adding radioactive chloride into the reaction mixture and measuring the incorporation in the α-chloro acid product 71.2 Additionally, rate studies demonstrated the reaction of 2,2,2-trichloro-1-phenylethan-1- ol 23 with aqueous potassium hydroxide to be first order in alcohol and zero order in base. These results indicate that the formation of the 2,2-dichloroepoxide intermediate is the rate determining step (Scheme 54).2

Scheme 54Proposed route for the synthesis of α-chloro acids.

Stereochemistry studies on (R)-23 (42 % e.e.) showed the α-chloro acid product to be 91 % racemised and 9 % inverted (Scheme 55).2 (R)-23 was obtained from the resolution of the quinine hydrogen succinate salt of 2,2,2-trichloro-1-phenylethan-1-ol23.10

Ph CCl3 OH 10 % KOH (aq) 8 h, 0oC Ph Cl OH O (S)-70 4 % e.e. (R)-23 42 % e.e.

Scheme 55Jocic reaction with (R)-23(42 % e.e.).

From these results it was postulated that racemisation could occur from the reversible formation of an α-lactone intermediate, from the unimolecular ring formation by the acetate anion (Scheme 56).10, 12

Since the experiments with radioactive chloride suggested that 17 % of the reaction is intermolecular it was expected that 17 % of the product should have inverted stereochemistry.2 It is thought that the much lower 9 % observed inverted stereochemistry comes from this 17 % of intermolecular formed product.2

With all of the experimental observations made by Reeve a greater understanding of the mechanism could be achieved.2 A suitable mechanism for this transformation should account for the following findings:

1. The requirement for a hydrogen on the α-carbon of the trichlorocarbinol. 2. The incorporation of 87 % unlabelled chlorine in the α-chloroacid product. 3. The requirement for aqueous, basic conditions.

4. Racemisation of the α-chloro acid product when enantiomeric enriched trichlorocarbinol is used.

5. No deuterium incorporation in the α-chloro acid product, when the reaction was carried out in deuterium oxide.

Reeve and coworkers postulated four different mechanisms that proceeded via a 2,2- dichloroepoxide intermediate:2

1. Carbonium ion mechanism.

This pathway suggests that a carbocation is formed by the unimolecular ring opening of the 2,2-dichloroepoxide ring followed by attack of a chloride (Scheme 57).

Scheme 57Proposed mechanism involving a carbonium ion.

This mechanism however fails to explain the observation that 2,2,2-trichloro-3,3- dimethylbutan-2-ol72 (Table 5, 78 % yield) goes through the reaction unrearranged to

give73(Scheme 58). Other faults include the failed explanation of why base is required in the reaction and also why tertiary trichlorocarbinols are unreactive.

Scheme 58a) Expected neopentyl rearrangement from 2,2-dichloroexpoide and b) observed reaction of72.

2. Carbene mechanism.

This mechanism suggests that the base in the reaction removes the hydrogen on the α- carbon atom, which subsequently opens the 2,2-dichloroepoxide and forms a carbene (Scheme 59). Following this the carbene abstracts one of the neighbouring chlorines to ultimately form the α-chloro acid.

Scheme 59Proposed mechanismviaa carbene intermediate.

This mechanism explains why tertiary trichlorocarbinols are unreactive. Nevertheless, carrying out the reaction in deuterium oxide should give some deuterium incorporated in the α-chloro acid product, which is not observed.

3. Enol hypochlorite mechanism.

In this mechanism one of the chlorines in the 2,2-dichloroepoxide migrates to the oxygen atom to form an enol hypochlorite intermediate. This species then transfers the chlorine to the α-carbon viaaquasifour-membered ring (Scheme 60).2

Scheme 60Proposed mechanism involving an enol hypochlorite intermediate. This mechanism fails to explain why the reaction with tertiary trichlorocarbinols is unsuccessful. Additionally, the suggested enol hypochlorite intermediate should be able to be trapped by a wide range of reducing agents, however attempted reactions with five different reducing agents were unsuccessful.2

4. Chlorooxirene mechanism.

Oxirenes have been proposed as reaction intermediates,13-15 but chlorooxirenes are unknown. They are thought to be highly strained unstable compounds.13 The chlorooxirene intermediate is proposed to be formed by loss of HCl from the 2,2- dichloroepoxide (Scheme 61).

Scheme 61Proposed mechanismviaa chlorooxirene intermediate.

If this was the reaction mechanism the α-hydrogen would be replaced by deuterium if the reaction was carried out in deuterium oxide and this does not occur.2

All of the four mechanisms described above, involving a carbonium ion, carbene, enol hypochlorite or chlorooxirene, fail to comply completely with the experimental observations. The most commonly proposed mechanism16involves thein situformation of a 2,2-dichloroepoxide intermediate and subsequent formation of an α-substituted acid chloride viaan SN2 reaction with a nucleophile (Scheme 62). The acid chloride is then

Scheme 62Most commonly proposed mechanism for Jocic-type reactions. In the case of the original Jocic reaction involving 2,2,2-trichloro-1-phenylethan-1-ol 23, the suggested 2,2-dichloroepoxide intermediate is not isolatable.17 In 1960, an intermediate of this nature was isolated, 2,2-dichloro-3-(trichloromethyl)oxirane 75 (Scheme 63).18This species was isolated from the reaction of 1,1,1,3,3,3-hexachloro-2- propanol 74 with aqueous sodium hydroxide. Further reaction of 75 with sulfuric acid afforded the α-hydroxy carboxylic acid 3,3,3-trichloro-2-hydroxypropanoic acid 76 (Scheme 63). This evidence suggests the existence of the 2,2-dichloroepoxide intermediate (Scheme 62).

Scheme 63Isolation and subsequent reaction of 2,2-dichloro-3- (trichloromethyl)oxirane.

Furthermore, Scaffidi and coworkers managed to isolate two different 2,2- dichloroepoxide intermediates.19 Both were isolated as a consequence of incomplete reactions, one of which being an attempted modified Corey-Link reaction as shown with the formation of78from77(Scheme 64).19

It was suggested that ‘the trajectory of approach for a successful displacement by the azide ion is blocked in this rigid tricyclic system’ and the structure was confirmed by a single-crystal X-ray structure investigation.19The isolation of these species explains the observed inversion of stereochemistry in the reaction and additionally the existence of the 2,2-dichloroepoxide intermediate (Scheme 62).

Since the discoveries of Jocic1 and Bargellini3 there have been several reports of this class of reaction using a wide variety of mono- and bis-nucleophiles.16These Jocic-type reactions will be discussed in detail, starting with oxygen nucleophiles (2.1.3).