Stephen Glover
Professor, Chemistry
Qualifications
MSc, PhD(Port Elizabeth), DIC(Imperial College), CChem, FRACI
Contact
| Email: | sglover@une.edu.au |
| Room: | Riggs Building 2.01 |
| Phone: | 02 6773 2361 (or +61 2 6773 2361 overseas) |
| Fax: | 02 6773 3268 |
| Homepage: | http://www-personal.une.edu.au/~sglover/ |
Steve Glover was born in the United Kingdom in 1950 and was educated at Grey High School and then the University of Port Elizabeth, South Africa where he obtained his B.Sc. (1971) majoring in Chemistry and Physics and B.Sc. Hons. (1972) and M.Sc. (1973) degrees in Organic Chemistry. He obtained his Ph.D. from the University of Port Elizabeth in 1976 for his research into reactions and properties of amidyl free radicals. He undertook postdoctoral studies in organotellurium chemistry with the late Professor Sir Derek Barton FRS at The Imperial College of Science and Technology, London for which he was awarded a D.I.C. in 1977, before taking up a lectureship at the University of Port Elizabeth. In 1985, he took up a position at the University of New England where he is currently Professor. His research interests span the areas of physical, biological, free radical and computational organic chemistry. He has a strong interest in modern approaches to teaching organic chemistry and, in 1997, was awarded The University of New England Vice-Chancellor's Award for Excellence in Teaching.
Research interests
he main thrust of our research is in the field of chemical mutagenesis and centred on elucidation of the mechanism of mutagenesis of a new class of nitrenium ion precursors, N-acyloxy-N-alkoxyamides, N-acyloxy-N-alkoxyamides (View X-ray structure*). These were first identified by this group in 1989 and all variants synthesised to date have been found to be mutagenic in the Ames test. The investigations are multi-faceted and involve chemical reactivity studies, biological testing in the form of Ames and yeast mutagenicity assays and DNA damage studies.
The overall aim is to try to evaluate the chemical interactions through which mutation processes are initiated. This work has been expanded to include an evaluation of these compounds for anticancer activity and the design of molecules with optimum and selective activity for use in chemotherapy. Research is continuing with these studies and with parallel investigations of analogues of the mutagens such as mutagens tethered to DNA affinic groups such as hydrophobic polycyclic aromatics and DNA intercalators. We are also using the direct-acting mutagenicity of these novel amides as a probe to investigate the non-reactive structural features that control binding to DNA. Recent QSAR analysis has shown, for the first time, a dependence of direct-mutagenicity upon LogP, the hydrophobicity and we are using this to detect the influence of reactivity, intercalation and steric effects upon drug-DNA interactions. A major review chapter on N-acyloxy-N-alkoxyamides was published recently in Advances in Physical Organic Chemistry (see publication [37] as well as publications [2], [3], [5], [6], [9], [16], [17], [22], [26], [28], [34]).
6-31G* lp surface showing sp3 hybridised amide nitrogen lp in N-dimethylamino-N-methoxyformamide.
Other areas of interest have evolved from the above studies. One of these involves the properties of amides that are geminally substituted at nitrogen with two heteroatoms, so-called "Anomeric Amides". This unusual class of compounds exhibits novel properties and reactions. They are pyramidal rather than planar at nitrogen with low E/Z isomerisation barriers and they can sustain anomeric interactions between the heteroatoms at nitrogen. Crystal structures of two of these amides show that they are the "most pyramidal" acyclic amides ever made [27] (View X-ray structure*). NNO systems also undergo a quite novel rearrangement to 1,1-diazenes and esters and which we have named HERON processes (Heteroatom Rearrangements On Nitrogen). The reaction is now in the Organic Named Reaction Index of the Merck Index (14 Ed. ONR-43) and has recently been reviewed (see publication [31]). These have been explored in depth by both chemical and theoretical means. In a fruitful collaboration with Professor Arvi Rauk at the University of Calgary, Alberta, numerous facets of the structure and reactions of anomeric amides have been explored by DF B3LYP/6-31G* computational methods. In addition, these reactions are relevant to the biological studies above in that such intermediates may form by the reaction of N-acyloxy-N-alkoxybenzamides with nucleotide components of DNA and may be a source of DNA damage. This work has culminated in the publication, in 1998, of a major Tetrahedron Report on the subject [17] and a book chapter is in press (see publication [40] as well as [10], [11], [13], [18], [19], [20], [21], [24], [25] and [31]).
Another unusual property of these amides is their ability to undergo SN2 reactions at nitrogen. Such reactions occur with anilines, thiols (glutathione) and azide and the last reaction provides a novel route to highly hindered esters. We have modelled these reactions computationally [23] and [24].
In addition to these studies, we have long-standing interests in the areas of reactive intermediates such as nitrenium ions and free radicals. This group has studied carbon and nitrogen radical additions to olefins and aromatic ring systems (publications [7], [8], [P1], [P5], [P6],and [P8] and more recently, we have embarked upon studies of the free radical decomposition of mutagenic N-acyloxy-N-alkoxyamides as well a the closely related, anomeric N,N-dialkoxyamides [10]. The properties and reactivity of N-alkoxynitrenium and N-arylnitrenium ions has been under study for a number of year. We are interested in factors affecting the stability and lifetimes of these reactive intermediates in solution with specific focus on their cyclisation reactions to give novel heterocycles, 2,1-benzoxazines and 2,1-benzoxazepines which were first synthesised by this group (publications [1], [4], [5], [P3] and [P7] and publications [14] and [15]. Current interests involve the dynamics of conformational change in strained 2,1-benzoxazepines and pericyclic rearrangement of N-acyl-2,1-benzoxazines to 3,1-benzoxazines [12].
In collaboration with Prof Mike Novak from Miami University , Ohio , we have recently carried out studies on another, unusual class of reactive intermediates, namely aryloxenium ions. Generation and reactivity studies have been underpinned by computational work which indicates these are highly delocalised ions [29], [30], [32], [36] and [39]. We have recently confirmed the observation of these ions by Resonance Raman Spectroscopy using density functional theory.
Our overall approach to research is an integrated one involving experimental, biological, physical and computational organic chemistry. We advocate the use of molecular orbital theoretical methods to predict and explain organic and bio-organic properties and reactivity as well as to confirm structure and conformation of organic molecules, an approach that has become the norm in modern organic chemistry.
*MDL's ChemScape CHIME plugin is required to view this structure. The download is available for free from http://www.mdlchime.com/chime
Speciality Area/s:
Biological Chemistry, Physical Organic Chemistry, Computational Chemistry, Reactive intermediates, Polymer chemistry, and Chemical EducationPUBLICATIONS
[40] S. A. Glover, N-Heteroatom-substituted hydroxamic esters. In The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids, ed.; Z. Rappoport and J. F. Liebman, Eds. Wiley: 2008; In press.
[39] Chemistry of 4-Alkylaryloxenium Ion "Precursors": Sound and Fury Signifying Something? M. Novak, A. M. Brinster, J. N. Dickhoff, J. M. Erb, M. P. Jones, S. H. Leopold, A. T. Vollman, Y. Wang and S. A. Glover, J. Org. Chem., 2007, 72, 9954-9962.
[38] S. A. Glover, Truly Australian—the HERON reaction. In Chemistry in Australia, 2007; Vol. 74, pp 6-10;
[37] S. A. Glover, N-Acyloxy-N-alkoxyamides —Structure, Properties, Reactivity and Biological Activity. In Adv. Phys. Org. Chem.; J. Richard, Ed. Elsevier: London, 2007; Vol. 42, pp 35-123.
[36] 4´-Substituted-4-biphenylyloxenium Ions: Reactivity and Selectivity In Aqueous Solution. M. Novak, M. J. Poturalski, W. L. Johnson, M. P. Jones, Y. Wang and S. A. Glover, J. Org. Chem., 2006, 71, 3778-3785.
[35] S. A. Glover, HERON Rearrangement. In Merck Index, Organic Name Reactions ONR-43, 14 ed.; M. J. O'Neil, Ed. Merck & Co., Inc.: Whitehouse Station, N.J., 2006; ONR-43.
[34] The Role of Steric Effects in the Direct Mutagenesis of N -Acyloxy-N-alkoxyamides.L. E. Andrews, A. M. Bonin, L. Fransson, A.-M. Gillson, E. and S. Glover, Mutat. Res. Gen. Tox. Environ. Mut., 2005, GEM-050905-1; date of acceptance, 01-02-2006.
[33] Molecular Orbital Properties as an Aid to Teaching Undergraduate Organic Chemistry. S. A. Glover, Chem. Educator, 2005, 11, 77-83.
[32] The Hydrolysis of 4-Acyloxy-4-substituted-2,5-cyclohexadineones: Limitations of Aryloxenium Ion Chemistry. M. Novak and S. A. Glover, J. Am. Chem. Soc., 2005, 127, 8090.
[31] The HERON reaction: Origin, Theoretical Background and Prevalence. S. A. Glover, A. Rauk, J. M. Buccigross, J. J. Campbell, G. A. Hammond, G. Mo, L. E. Andrews and A.-M. Gillson, E., Can. J. Chem., 2005, 83, 1492.
[30] A computational Study of the properties of phenyloxenium ions: a comparison with phenylnitrenium and phenylcarbenium ions. S. A. Glover and M. Novak, Can. J. Chem., 2005, 83, 1372.
[29] Generation and Trapping of the 4-Biphenylyloxenium Ion by Water and Azide: Comparisons with the 4-Biphenylylnitrenium Ion. M. Novak and S. A. Glover, J. Am. Chem. Soc., 2004, 126, 7748.
[28] Mutagenic N -acyloxy- N -alkoxyamides —Probes for Drug—DNA Interactions. L. E. Andrews, T. M. Banks, A. M. Bonin, S. F. Clay, A.-M. E. Gillson and S. A. Glover, Aust. J. Chem., 2004, 57, 377.
[27] Crystal structures and properties of mutagenic N-acyloxy-N-alkoxyamides- "most pyramidal" acyclic amides. Gillson, A.-M. E., Glover, S. A., Tucker, D. J., and Turner, P., Org. Biomol. Chem., 2003, 3430.
[26] Mutagenicity and DNA Damage Studies of N-acyloxy-N-alkoxyamides - the Role of Electrophilic Nitrogen. Banks, T. M., Bonin, A. M., Glover, S. A., and Prakash, A. S., Org. Biomol. Chem., 2003
[25] A computational Investigation of the Structure of the Novel Anomeric Amide N-Azido-N-methoxyformamide and its Concerted Decomposition to Methyl Formate and Nitrogen. S.A.Glover and A Rauk., J. Chem. Soc. Perkin Trans. 2, 2002, 1740.
[24] Hindered Ester Formation by SN2 Azidation of N-alkoxy- N-chloroamides - Novel Application of HERON Rearrangements. S.A.Glover and G.Mo., J. Chem. Soc. Perkin Trans. 2, 2002, 1728.
[23] SN2 reactions at amide nitrogen - Theoretical models for reaction of mutagenic N-acyloxy-N-alkoxyamides with bionucleophiles. S.A.Glover, Arkivok 2002 (xii). Issue in Honour of Profesor O.S.Tee, ms OT-308C (http://www.arkat-usa.org/ark/journal/Volume2/Part3/Tee/OT-308C/OT-3008.htm)
[22] Mutagenicity of electrophilic N-acyloxy-N-alkoxyamides. A.M.Bonin, T.M.Banks, J.J.Campbell, S.A.Glover, G.P.Hammond, A.S.Prakash, C.A.Rowbottom., Mutation Res. 494, 2001, 115.
[21] Structure, Conformation, Anomeric Effects and Rotational Barriers in the HERON Amides, N,N'-Diacyl-N,N'-dialkoxyhydrazines. Glover, S. A., Mo, G., Rauk, A., Tucker, D., and Turner, P., J. Chem Soc. Perkin. Trans. 2 1999, 2053.
[20] HERON rearrangement of N,N'-diacyl-N,N'-dialkoxyhydrazines - a theoretical and experimental study. S. A. Glover, G. Mo and A. Rauk, Tetrahedron, 1999, 55, 3413.
[19] Conformational Stereochemistry of the HERON Amide, N-methoxy-N-dimethylaminoformamide: a Theoretical Study. S. Glover and A. Rauk, J. Org. Chem. 1999, 64, 2340.
[18] Bimolecular reactions of Mutagenic N-(Acyloxy)-N-alkoxybenzamides with Aromatic Amines. J. J. Campbell and S. A. Glover, J. Chem. Res., 1999, 8, 474.
[17] Anomeric Amides-Structure, Properties and Reactivity. S. A. Glover, Tetrahedron, 1998, 54, 7229. Tetrahedron Report 455.
[16] A Comparison of the Reactivity and Mutagenicity of N-Benzoyloxy-N-benzyloxybenzamides. A. M. Bonin, S. A. Glover and G. P. Hammond, J. Org. Chem., 1998, 63, 9684.
[15] Mechanism of Nitrenium Ion Cyclisations in Formation of N-acyl-3,4-dihydro-1H-2,1-benzoxazines and N-acyl-1,3,4,5-tetrahydro-2,1-benzoxazepines. S. A. Glover, A. P. Scott and G. J. Tarrant, Electronic Conference on Heterocyclic Chemistry (ECHET 96), 1996, H. Rzepa, Royal Society of Chemistry. Paper 102.ISBN 0 85404 894 4.
[14] A Dynamic NMR Investigation of the Conformational Isomerism in Novel 1,3,4,5-Tetrahydro-2,1-benzoxazepines. T. M. Banks, G. C. Cowin, S. A. Glover, G. J. Tarrant, C. A. Rowbottom, D. J. Tucker and Y. Zengjia, Electronic Conference on Heterocyclic Chemistry (ECHET 96), 1996, Royal Society of Chemistry.| Paper 107. ISBN 0 85404 894 4.
[13] A Computational Investigation of the Stereoisomerism in Heteroatom-substituted Amides. S. A. Glover and A. Rauk, J.Org.Chem., 1996, 61, 2337.
[12] Rearrangement of N-acyl-3,4-dihydro-1H-2,1-benzoxazines 2-substituted-4H-3,1-benzoxazines through a retro-Diels-Alder extrusion of formaldehyde. S. A. Glover, K. M. Jones, I. R. McNee and C. A. Rowbottom, J. Chem. Soc. Perkin Trans. 2, 1996, 1367.
[11] Molecular orbital studies of N to C migrations in N,N-bisheteroatom-substituted amides - HERON rearrangements. J. M. Buccigross and S. A. Glover, J. Chem. Soc. Perkin Trans. 2, 1995, 595.
[10] Decomposition of N,N-diacyl-N,N-dialkoxyhydrazines revisited. J. M. Buccigross, S. A. Glover and G. P. Hammond, Aust. J. Chem., 1995, 48., 353.
[9] Reactive intermediates from the solvolysis of mutagenic O-alkyl N-acetoxybenzohydroxamates. A. M. Bonin, S. A. Glover and G. P. Hammond, J. Chem. Soc. Perkin Trans. 2, 1994, 1173.
[8] Aryl Radical Cyclizations onto Enamine Double Bonds. S. A. Glover and J. Warkentin, J. Org. Chem., 1993, 58, 2115.
[7] Cyclisation of Alkoxyiminyl Radicals onto Olefins: Formation of 2-alkoxy-D1-pyrrolines, 4,5-dihydrooxazoles and 5,6-dihydro-4H-1,3-oxazines. S. A. Glover, G. P. Hammond, D. G. Harman, J. G. Mills and C. A. Rowbottom, Aust. J. Chem., 1993, 46, 1213.
[6] Bimolecular Reactions of Mutagenic N-Acetoxy-N-alkoxybenzamides and N-methylaniline. J. J. Campbell and S. A. Glover, J. Chem. Soc. Perkin Trans. 2, 1992, 1661.
[5] Evidence for the Formation of Nitrenium ions in the Acid-catalysed Solvolysis of Mutagenic N-acetoxy-N-Alkoxybenzamides. J. J. Campbell, S. A. Glover, G. P. Hammond and C. A. Rowbottom, J. Chem. Soc. Perkin Trans. 2, 1991, 2067.
[4] Alkoxynitrenium Ion Cyclisations: Evidence for Difference Mechanisms in the Formation of Benzoxazines and Benzoxazepines. S. A. Glover, C. A. Rowbottom, A. P. Scott and J. L. Schoonraad, Tetrahedron, 1990, 46, 7247.
[3] Solvolysis and Mutagenesis of N-Acetoxy-N-Alkoxybenzamides - Evidence for Nitrenium Ion Formation. J. J. Campbell, S. A. Glover and C. A. Rowbottom, Tetrahedron Let., 1990, 31, 5377.
[2] N-Acetoxy-N-alkoxyamides - a new class of nitrenium ion precursors which are mutagenic. R. G. Gerdes, S. A. Glover, J. F. Ten Have and C. A. Rowbottom, Tetrahedron Lett., 1989, 30, 2649.
[1] MNDO properties of heteroatom and phenyl substituted nitrenium ions. S. A. Glover and A. P. Scott, Tetrahedron, 1989, 45, 1763.
SELECTED PUBLICATIONS BEFORE 1989
[P8] An E.S.R. Investigation of Ethoxy and Trimethylsilyloxy Iminyl Radicals. S. A. Glover and A. L. J. Beckwith, Australian Journal of Chemistry, 1987, 40, 701.
[P7] N-Alkoxy-N-Acylnitrenium Ions in Intramolecular Aromatic Addition Reactions. S. A. Glover, A. Goosen, C. W. McCleland and J. L. Schoonraad, Tetrahedron, 1987, 43, 2577.
[P6] Determination of the Rates of Ring Closure of Oxygen-Containing Analogues of Hex-5-enyl Radical by Kinetic E.S.R. Spectroscopy. A. L. J. Beckwith and S. A. Glover, Australian Journal of Chemistry, 1987, 40, 157.
[P5] Factors affecting the Electronic States of Amidyls: Evidence for P-S Mixing in Simple Amidyls. S. A. Glover, A. Goosen, C. W. McCleland and J. L. Schoonraad, Journal of the Chemical Society, Perkin Transactions II, 1986, 645.
[P4] Phosphoric-Carboxylic Imides. Part 4. MNDO Molecular Orbital Calculations on N-Formylphosphinamide, H2P(O)NHCHO, and Related Systems. S. A. Glover, V. Mizrahi and T. A. Modro, Journal of the Chemical Society, Perkin Transactions II, 1984, 325.
[P3] N-Alkoxy-N-acylnitrenium Ions as Possible Intermediates in Intramolecular Aromatic Substitution: Novel Formation of N-Acyl-3,4-dihydro-1H-2,1-benzoxazines and N-Acyl-4,5-dihydro-1H-2,1-benzoxazepine. S. A. Glover, A. Goosen, C. W. McCleland and J. L. Schoonraad, J. Chem. Soc. Perkin Trans. 2, 1984, 2255.
[P2] Mechanism of the Thermal Decomposition of Tetra-aryltellurium Species. D. H. R. Barton, S. A. Glover and S. V. Ley, Journal of the Chemical Society, Chemical Communications, 1977, 266.
[P1] N-Iodo-amides: Mechanism of Intramolecular Reactions with Aromatic Rings of Amido-radicals in S- and P-Electronic States. S. A. Glover and A. Goosen, Journal of the Chemical Society, Perkin Transactions I, 1977, 1348.