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I recently came across a Friedel-Crafts reaction happening between benzoyl chloride and mesitylene with $\ce{AlCl3}$ as a catalyst. Apparently this reaction doesn't occur due to steric effects even though the mesitylene ring is highly activated by the three methyl groups. This got me wondering whether the reaction between benzoyl chloride with two methyl groups at ortho positions and benzene with $\ce{AlCl3}$ catalyst would occur or not. Most importantly, my question is: where all do steric effects become the major factor in the reaction, and how do we identify that? Why is it so?

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    $\begingroup$ "Highly activated due to steric effects" This statement is a bit weird. Steric effects at the site of reactivity reduce reactivity because the reactive species have a harder time with productive collisions. The general question is a bit broad because it depends on the nature of the reaction and the scale of the steric bulk. $\endgroup$ – Zhe Jul 7 at 14:47
  • $\begingroup$ Ah no I meant something else, I'll edit it at once. $\endgroup$ – Atharva Jul 7 at 15:30
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Based on literature, I'd say the unsuccessful Friedel-Crafts reaction between benzoyl chloride and mesitylene is not due to steric reasoning. My argument is based on at least one report of Friedel-Crafts acylation on following polymethylated aromatic compounds (Ref.1):

Poly methylated aromatic compounds

The mono- and di-acylation have been taken place between 1,3-substitutions in each occasion as indicated in the abstract:

Diacylation of mesitylene, durene and isodurene by the Friedel–Crafts method, using the acylating agent in excess (as both solvent and reagent), gives derivatives which are of potential use as monomers. The bis(p-fluorobenzoyl) derivatives, for example, can function as the electrophilic components in poly(ether ether ketone)(PEEK)-type Polymerisations, and the bisnitrobenzoyl compounds are potential sources of novel diamines. Tribenzoylation [although not tris(p-fluorobenzoylation)] of mesitylene has been observed, but dibenzoylation of m-xylene is a much less efficient process than previously reported.

The reasoning for the resistance to dibenzoylation on m-xylene must be rationalized due to the deactivation of in-plane carbonyl $\pi$-electrons of benzoyl group on aromatic ring after first benzoylation (highly possible 1-benzoyl-2,4-dimethylbenzene). All other instances (2-benzoyl-1,3-dimethyl substitutions), the benzoyl carbonyl group is in out of plane with the corresponding aromatic nucleus (Ref.2), probably due to steric hindrance:

$$ \begin{array}{c|ccc} \text{Compound} & \nu_\ce{C=O} \ (\ce{CH3C=O}) & \nu_\ce{C=O} \ (\ce{C6H5C=O}) & \text{ECA} \ (c.a.) \\ \hline \text{Acetophenone} & \pu{1688 cm-1} & - & -\\ \text{Benzophenone} & - & \pu{1664 cm-1} & 42^\circ\\ \text{2,4,6-trimethylacetylbenzene} & \pu{1703 cm-1} & - & 73^\circ\\ \text{2,4,6-trimethylbenzylbenzene} & -& \pu{1672 cm-1} & 90^\circ, 40^\circ\\ \text{2,4,6-trimethyl-1,3-diacetylbenzene} & \pu{1705 cm-1} & - & -\\ \hline \end{array} $$ $^a$ ECA: Effective Conformational Angle (whenever two angles are given, first refer to the angle with mesitylene ring).

A comprehensive study of mono- and di-acylation of mesitylene have been done and in all cases, at least mono-acylation was achieved in $\gt 90\%$ whenever anticipated Ref:2). The abstract states:

The Friedel–Crafts acylation of mesitylene has been studied in detail. In the acetylation, propionylation or benzoylation reactions mono- or di-ketones may be formed. Mesitoylation leads only to the monoketone. A two-stage acylation procedure is described for the synthesis of acetylbenzoylmesitylene and acetylpropionylmesitylene. Reversibility has been shown to be a factor in these acylations, especially where an aliphatic acyl group is involved. The relationship between the stereochemistry of mesityl ketones and their u.v., i.r., and $\ce{^1H}$ n.m.r. spectra is discussed.

Overall, these results suggest that Friedel-Crafts acylation reaction would not effected by steric hindrence, at least created by 1,3-dimethyl substitutions. For example, 2,4,6-trimethylacetylbenzene (acetylmesitylene) was achieved in 92% yield; 2,4,6-trimethylbenzoylbenzene (benzoylmesitylene) in 83% yield; 2,4,6-trimethyl-1,3-diacetylylbenzene (diacetylmesitylene) in 95% yield; and 2,4,6-trimethyl-1,3-dibenzoylbenzene (dibenzoylmesitylene) in 89% yield (Ref.2).

It is also noteworthy that the nitration of mesitylene is not effected by steric effects as well. You can find more details on this aspect in here.


References:

  1. Brian N. Hendy, Kevin H. Patterson, David M. Smith, Susan E. Gardner, Neil J. Nicolson, “Polyalkylated aromatic monomers and polymers. Part 1.—Friedel–Crafts diacylation of polymethylbenzenes as a means of monomer synthesis,” J. Mater. Chem. 1995, 5(2), 199-204 (https://doi.org/10.1039/JM9950500199).
  2. P. H. Gore, J. A. Hoskins, “Friedel–Crafts acylations of aromatic hydrocarbons. Part VIII. Mono- and di-acylation of mesitylene,” J. Chem. Soc. C 1970, (4), 517-522 (https://doi.org/10.1039/J39700000517).
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  • $\begingroup$ So it seems that the reaction does occur at least once. So can it be said that in general Friedel-Crafts reactions aren't affected too much by steric hindrance? Will steric hindrance on the electrophile affect the reaction feasibility ( I know reaction rate will slow down)? $\endgroup$ – Atharva Jul 8 at 2:16
  • $\begingroup$ This conclution is based on 1,3-dimethyl substituents. If they are a larger group such as iso-propyl, the story would be different. I know for sury, if we use tert-Bu group, the substitution on ortho-position is nearly impossible. This is a good example the facts for Zhe's comments (vide supra). $\endgroup$ – Mathew Mahindaratne Jul 8 at 3:35

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