Experimental and Computational Investigations into the Benzyl-Claisen Rearrangement

Burns, Jed (2016). Experimental and Computational Investigations into the Benzyl-Claisen Rearrangement PhD Thesis, School of Chemistry & Molecular Biosciences, The University of Queensland. doi:10.14264/uql.2016.456

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Author Burns, Jed
Thesis Title Experimental and Computational Investigations into the Benzyl-Claisen Rearrangement
School, Centre or Institute School of Chemistry & Molecular Biosciences
Institution The University of Queensland
DOI 10.14264/uql.2016.456
Publication date 2016-07-18
Thesis type PhD Thesis
Supervisor Ross McGeary
Elizabeth Krenske
Total pages 314
Total colour pages 19
Total black and white pages 295
Language eng
Subjects 0307 Theoretical and Computational Chemistry
0305 Organic Chemistry
Formatted abstract
Being a prime example of a [3,3]-sigmatropic process, the Claisen rearrangement is an essential reaction at the core of modern organic chemistry. Its undisputed value is derived not only from its reliable and predictable application to the synthesis of complex molecules but, also, in being a reaction of longstanding interest in the field of computational organic chemistry, contributing to our theoretical understanding of pericyclic reactions. A long-standing shortcoming of the Claisen rearrangement is that while allyl-vinyl and allyl-phenyl ethers are viable substrates for the reaction, applications to benzyl-vinyl ethers have rarely been reported. To date, a very limited number of benzylic substrates have been investigated, with the few successful reactions typically requiring harsh conditions.

Herein, we report the optimisation of a procedure for Claisen rearrangements of benzyl-vinyl ethers (referred to here as the “Benzyl-Claisen” rearrangement) based on a previous literature procedure and, for the first time, investigate the scope of such a process. Benzyl ketene acetals were generated in a short two-step procedure by bromoacetalisation of the requisite benzyl alcohol followed by elimination of HBr. Heating the ketene acetals in refluxing DMF smoothly converted the substrates to the product tolylacetates, which were saponified and isolated as their carboxylic acid derivatives. In the course of the reaction optimisation, a pronounced solvent effect was observed: DMF led to the [3,3]-rearranged product, whereas conducting the reaction in xylene led to a mixture of radical dissociation-recombination products. Electron-donating and electron-neutral substituents (–Me, –Ph, –Cl, –Br, –OMe and –SMe) gave the highest yields in the Benzyl-Claisen rearrangement (24–50%) whereas substrates derived from electron-poor aromatic systems (–NO2, –CN, –COOBn, –SO2Me or –CF3) tended to decompose under the reaction conditions. Claisen rearrangements conducted on meta-substituted systems were observed, unexpectedly, to preferentially generate products via rearrangement “towards” the meta substituent, leading to sterically crowded 1,2,3-trisubstituted tolylacetates.

By analogy to the aromatic Claisen rearrangement, it was expected that the Benzyl-Claisen rearrangement should proceed through a dearomatised isotoluene intermediate. A benzyl ketene acetal possessing a terminal alkene was observed to form a ring-closed product via a facile Alder-ene reaction when submitted to the standard reaction conditions. This supports the formation of a dearomatised isotoluene intermediate along the reaction pathway and therefore the operation of the [3,3]-sigmatropic rearrangement.

The mechanism of the Benzyl-Claisen rearrangement was investigated using computational methods. The activation free energy for rearrangement of benzyl vinyl ether calculated with the high-accuracy CBS-QB3 method was 40.1 kcal/mol, which is 10.2 kcal/mol higher than that of the aliphatic Claisen rearrangement of allyl vinyl ether at the same level of theory. The C-2 alkoxy substituent on the ketene acetal was shown to be essential in making the process both thermodynamically and kinetically favourable, lowering the barrier by 10.2 kcal/mol and stabilising the intermediate isotoluene by 18.0 kcal/mol. As a general rule, substitution of the aromatic systems with an electron-donor group was calculated to lower the barrier for the reaction whilst electron-withdrawing substituents were calculated to raise it. The para-OMe substituent was calculated to lower the activation free energy by 1.4 kcal/mol whereas the para-CN substituent raised the barrier by 0.9 kcal/mol. The regiochemical preference for rearrangement “towards” existing meta-substituents was confirmed in silico with 1,2,3-substituted product being favoured by 0.7 kcal/mol for the cyano substituent and 0.6 kcal/mol for the methoxy substituent. The results were rationalised as being due to the interaction of the frontier molecular orbitals of the system, with the preferred site on the aromatic ring possessing larger orbital coefficients. The computational results support the operation of a [3,3]-sigmatropic process and provide direction for the further development of the Benzyl-Claisen rearrangement.
Keyword Claisen rearrangement
ketene acetal
computational chemistry
density functional theory

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Created: Fri, 08 Jul 2016, 12:35:27 EST by Jed Burns on behalf of Learning and Research Services (UQ Library)