Posts Tagged ‘Indole’

Exploring the electrophilic directing influence of heteroaromatic rings using crystal structure data mining.

Tuesday, June 21st, 2016
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This is a follow-up to the post on exploring the directing influence of (electron donating) substituents on benzene[1] with the focus on heteroaromatic rings such indoles, pyrroles and group 16 analogues (furans, thiophenes etc).

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References

  1. H.S. Rzepa, "Discovering More Chemical Concepts from 3D Chemical Information Searches of Crystal Structure Databases", Journal of Chemical Education, vol. 93, pp. 550-554, 2015. http://dx.doi.org/10.1021/acs.jchemed.5b00346

I’ve started so I’ll finish. Kinetic isotope effect models for a general acid as a catalyst in the protiodecarboxylation of indoles.

Sunday, January 10th, 2016
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Earlier I explored models for the heteroaromatic electrophilic protiodecarboxylation of an 3-substituted indole, focusing on the role of water as the proton transfer and delivery agent. Next, came models for both water and the general base catalysed ionization of indolinones. Here I explore general acid catalysis by evaluating the properties of two possible models for decarboxylation of 3-indole carboxylic acid, one involving proton transfer (PT) from neutral water in the presence of covalent un-ionized HCl (1) and one with PT from a protonated water resulting from ionised HCl (2).

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I’ve started so I’ll finish. The ionisation mechanism and kinetic isotope effects for 1,3-dimethylindolin-2 one

Thursday, January 7th, 2016
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This is the third and final study deriving from my Ph.D.[1]. The first two topics dealt with the mechanism of heteroaromatic electrophilic attack using either a diazonium cation or a proton as electrophile, followed by either proton abstraction or carbon dioxide loss from the resulting Wheland intermediate. This final study inverts this sequence by starting with the proton abstraction from an indolinone by a base to create/aromatize to a indole-2-enolate intermediate, which only then is followed by electrophilic attack (by iodine).  Here I explore what light quantum chemical modelling might cast on the mechanism.

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References

  1. B.C. Challis, and H.S. Rzepa, "Heteroaromatic hydrogen exchange reactions. Part VIII. The ionisation of 1,3-dimethylindolin-2-one", Journal of the Chemical Society, Perkin Transactions 2, pp. 1822, 1975. http://dx.doi.org/10.1039/P29750001822

I’ve started so I’ll finish. The mechanism of diazo coupling to indoles – forty (three) years on!

Thursday, December 24th, 2015
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The BBC TV quiz series Mastermind was first broadcast in the UK in 1972, the same time I was starting to investigate the mechanism of diazocoupling to substituted indoles as part of my Ph.D. researches. The BBC program became known for the catch phrase I've started so I'll finish; here I will try to follow this precept with the project I started then. Indole diazocoupling In 1972, one measured the rates of chemical reactions to gain insights into the transition state kinetic model. To obtain more data, we used isotopes such as 2H or 3H, together with substituents such as R-t-butyl to modify the potential energy surfaces of the reactions by inducing steric effects.[1],[2] We found that the kinetics for this reaction were actually complex (in part because of pH dependence) involving a Wheland intermediate (the formation of which is shown with red curly arrows above) followed by the collapse of this intermediate to the diazo-coupled product (blue arrows). Coupling to 2-methyl indole (R=X=H, R'=Me), 2-t-butyl indole (R=H, R'=t-butyl) and 4-methyl-2-t-butyl indole (R=Me, R'=t-butyl) revealed that the kinetic isotope effects induced by replacing H by D or T were "not apparent" (i.e. close to 1), the inference being that the rate constant k1 for those systems was slower than k2; the formation of the Wheland intermediate was rate determining (the rds) for the reaction. But with 2-methyl-4,6-di-t-butyl indole (R=t-butyl, R'=Me) this changed and a deuterium isotope effect of ~7 was observed. The rate determining proton removal from the Wheland intermediate k2 was now slower than k1. With 2,4,6-tri-t-butyl indole, we ended by noting that the reaction become almost too slow to observe and furthermore was accompanied by loss of a t-butyl cation as well as a proton. At this point we attempted to infer some transition state models consistent with these observations. Note that we had relatively little data with which to derive our 3D models (one needs to define a geometry using 3N-6 variables, along with its relative energy and force constants). The text and diagram of our attempt is shown below. TS1 The main points of this argument were;

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References

  1. B.C. Challis, and H.S. Rzepa, "The mechanism of diazo-coupling to indoles and the effect of steric hindrance on the rate-limiting step", Journal of the Chemical Society, Perkin Transactions 2, pp. 1209, 1975. http://dx.doi.org/10.1039/P29750001209
  2. Rzepa, Henry S.., "Hydrogen transfer reactions of Indoles", 1974. http://dx.doi.org/10.5281/zenodo.18777