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Investigation of the substitution reaction pathways of antidiabetic chromium(III) supplements

Uddin, K.M. (2017) Investigation of the substitution reaction pathways of antidiabetic chromium(III) supplements. PhD thesis, Murdoch University.

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Chromium(III) complexes are regularly included in nutritional supplements and are reported to lower blood glucose levels in type 2 diabetics. However, questions have been raised about potential toxicity. Understanding the reactivity of these complexes is key to understanding their behaviour in physiological environments. Therefore, the central aim of this work is to explore the speciation of these complexes under different conditions using both computational and experimental methods.

The computational studies involved a detailed mechanistic investigation of the substitution reaction pathways of several chromium(III) nutritional supplements (e.g. chromium(III) chloride, glycinato-chromium(III) [Cr(gly)x(H2O)6-2x](3-x)+ where x = 1 ‒3) and their conjugate bases and chromium(III) picolinate (Cr(pic)3) using state-of-the art computational chemistry techniques.

A number of mechanistic aquation pathways were investigated including associative interchange (Ia), dissociative interchange (Id), associative (A) and dissociative (D), to predict the overall activation enthalpies of these processes. Our initial computational investigations have focussed on the mechanistic pathways for aquation of chromium(III) chloride under acidic (stomach) and mild (duodenum and blood) conditions. DFT calculations reveal that aquation of CrCl3 is slow in an acidic environment and this limits speciation of the complex. However, at mild pH, conjugate base complexes easily form, leading to a significant number of species that may be involved in halide-water exchange pathways.

The activation enthalpies for aquation of tris-glycinatochromium(III) and its conjugate base at mild and physiological pHs via the dissociative (D) mechanism are in consistent agreement with the experimental results. Aquation of [Cr(pic)3]0 initially proceeds via a dissociative ring-opening step to form the [Cr(pic)2(H2O)(picH2)]+intermediate in acidic media. The reaction may then proceed via two possible pathways involving either stepwise (two-step) or concerted (one-step) mechanisms. Throughout these studies solvent calculations were performed using the polarizable continuum model (PCM). However, the inclusion of explicit solvation was also found to be important for many processes.

The experimental component of the study involved the synthesis of chromium(III) nutritional supplements and characterization (elemental analysis, atomic absorption spectroscopy, NMR, HPLC, ATR-FTIR, Raman, and ESI−MS spectroscopy). Investigation of solvent and pH effects using UV−Vis monitoring (pH ~3.0 to ~8.5) and electron paramagnetic resonance (in both solid and frozen state) complemented the theoretical studies of the speciation and interaction of Cr(III) metal with amino acid ligands. The electrochemical properties of [Cr(gly)3]0 were also investigated for the first time using cyclic voltammetry (CV) and it was found that this complex can undergo reversible electron transfer, which may play a role in its biological activity.

Item Type: Thesis (PhD)
Murdoch Affiliation(s): School of Engineering and Information Technology
Supervisor(s): Henry, David, Ralph, David and Hughes, Leonie
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