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. 2014 Nov 5;136(44):15798-805.
doi: 10.1021/ja5099935. Epub 2014 Oct 23.

The role of aryne distortions, steric effects, and charges in regioselectivities of aryne reactions

Jose M Medina  1 , Joel L Mackey, Neil K Garg, K N Houk
Affiliations

The role of aryne distortions, steric effects, and charges in regioselectivities of aryne reactions

Jose M Medina et al. J Am Chem Soc. .

Abstract

The distortion/interaction model has been used to explain and predict reactivity in a variety of reactions where more common explanations, such as steric and electronic factors, do not suffice. This model has also provided new fundamental insight into regioselectivity trends in reactions of unsymmetrical arynes, which in turn has fueled advances in aryne methodology and natural product synthesis. This article describes a systematic experimental and computational study of one particularly important class of arynes, 3-halobenzynes. 3-Halobenzynes are useful synthetic building blocks whose regioselectivities have been explained by several different models over the past few decades. Our efforts show that aryne distortion, rather than steric factors or charge distribution, are responsible for the regioselectivities observed in 3-haloaryne trapping experiments. We also demonstrate the synthetic utility of 3-halobenzynes for the efficient synthesis of functionalized heterocycles, using a tandem aryne-trapping/cross-coupling sequence involving 3-chlorobenzyne.

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Figures

Figure 1
Figure 1
Charge-controlled, steric, and aryne distortion models.
Figure 2
Figure 2
Geometry-optimized structures of 1a–1e (B3LYP) and regioselectivity predictions for nucleophilic attack based on the aryne distortion model.
Figure 3
Figure 3
Geometry-optimized structures and NBO charges for o-benzyne (7) (B3LYP).
Figure 4
Figure 4
Geometry-optimized structure and NBO charges for 3-fluorobenzyne (1b) (B3LYP) and point charge analysis.
Figure 5
Figure 5
NBO charges for 1b separated based on distortion or inductive effects. Electrostatic potentials of benzyne (7) and 3-fluorobenzyne (1b). Also shown are electrostatic potentials for benzyne with 3-fluorobenzyne geometry and 3-fluorobenzyne with benzyne geometry (red indicates the lowest electrostatic potential energy, whereas blue indicates the highest).
Figure 6
Figure 6
Geometry-optimized structure and NBO charges for 3-trimethylsilylbenzyne (8), in addition to charge distribution due to distortion or inductive effects.
Figure 7
Figure 7
Benzyne internal angles and transition state for methyl azide/benzyne cycloaddition.
Figure 8
Figure 8
Competing transition states for the addition of N-methylaniline and methyl azide to 3-fluorobenzyne (1b) and 3-chlorobenzyne (1c). Transition states were located using B3LYP/6-311+G(d).
Figure 9
Figure 9
Tandem aryne trapping/cross-coupling sequence.
Figure 10
Figure 10
Nickel-catalyzed C–C and C–N bond-forming reactions for the synthesis of functionalized benzotriazoles 11 and 12.
See this image and copyright information in PMC

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