Competing nature of intramolecular [4 + 2] and [3 + 2] cycloaddition reactions: a theoretical study

Abstract

Comparative study of the intramolecular alkyne triple bond addition reaction to the conjugated CC-CH=X moiety (X = CH 2 ,O,S,NH) revealed that two different pathways are possible in the system, namely [4 2] and [3 2] cycloaddition reactions. The energetically preferred pathway for enynes (X = CH 2 ) involves [4 2] cycloaddition leading to benzene derivatives, whereas heteroatom-substituted substrates undergo [3 2] cycloaddition resulting in an five-membered aromatic ring in the final product. This paper reports a detailed mechanistic study based on full potential energy surface calculations at the MP2 and B3LYP theory levels, with MP4(SDTQ) energy evaluation. The effect of solvent was included within the PCM approach. epoc Scheme 2. Proposed mechanism of the cycloaddition reaction (hydrogen atoms of CH 2 groups are omitted)

Computational Study of a Model System of Enzyme-Mediated [4+2] Cycloaddition Reaction

“…d and e ) intramolecular linkages. This effect is well-known and reflects lowering of the reaction entropy [ 39 , 40 ]. In overall, the calculated energy parameters agree well with other [4+2] cycloaddition reactions involving 1,3-diene and alkene units as well as with an experimental study of reaction a [ 42 , 43 , 44 , 45 , 46 ].…”

“…Reaction ( a ) was investigated in several previous studies (see refs. [ 8 , 9 , 10 , 11 , 12 , 13 , 39 , 40 , 42 , 43 , 44 , 45 , 46 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ]) and the calculations here are provided for comparative purpose.…”

“…An important point of the model system is governed by intramolecular transformation of the cyclic substrate ( 1 ). Promoting the cyclization by reducing activation entropy and adopting a favorable mutual orientation of the reacting fragments may be feasible for an intermolecular reaction [ 29 , 30 , 39 , 40 ], whereas it may not be expected to play a significant role in the intramolecular transformation of chemically preorganized macrocyclic substrate 1 catalyzed by SpnF ( Fig. 1 ).…”

Novel [4 + 2] cycloaddition reactions of alkyne and enyne key-units: Direct access to bicyclic aromatic and heteroaromatic products. A theoretical mechanistic study

“…6 The mechanistic studies of both intermolecular (Scheme 1) and intramolecular (Scheme 2) reactions were carried out and have revealed preferable factors for the cycloaddition step involving an intramolecular pathway. 7,8 Smaller activation barriers due to lowered activation entropy and favorable intrinsic structural arrangements of reagent I afforded formation of cycloaddition products in good to high yields under simple experimental conditions (Scheme 2). 5,6 Inspired by Schreiner's recent concept on the description of reaction space of addition reactions 9 and in light of our previous studies 7,8 we have carried out a systematic theoretical investigation of the interconversions of alkyne and enyne key-units.…”

“…7,8 Smaller activation barriers due to lowered activation entropy and favorable intrinsic structural arrangements of reagent I afforded formation of cycloaddition products in good to high yields under simple experimental conditions (Scheme 2). 5,6 Inspired by Schreiner's recent concept on the description of reaction space of addition reactions 9 and in light of our previous studies 7,8 we have carried out a systematic theoretical investigation of the interconversions of alkyne and enyne key-units. Surprisingly, we have found six new intramolecular [4 + 2] cycloaddition reactions governed by an ene-yne link (Scheme 3).…”