i Stereo–Chemical Control of Organic Reactions in the Interlamellar Region of Cation–Exchanged Clay Minerals By Vinod Vishwapathi A thesis submitted in partial fulfilment for the requirements for the degree of Doctor of Philosophy at the University of Central Lancashire March 2015 STUDENT DECLARATION FORM Concurrent registration for two or more academic awards Either *I declare that while registered as a candidate for the research degree, I have not been a registered candidate or enrolled student for another award of the University or other academic or professional institution ___________________________________________________________________________________ Material submitted for another award Either *I declare that no material contained in the thesis has been used in any other submission for an academic award and is solely my own work ___________________________________________________________________________________ (state award and awarding body and list the material below): * delete as appropriate Collaboration Where a candidate’s research programme is part of a collaborative project, the thesis must indicate in addition clearly the candidate’s individual contribution and the extent of the collaboration. Please state below: Signature of Candidate ______________________________________________________ Type of Award ___________PhD (Doctor of Philosophy)___________ School School of Forensics and Investigative Sciences______ iii Abstract Carbene intermediates can be generated by thermal, photochemical and transition metal catalysed processes from diazoalkanes.1 The carbene intermediates are very reactive and can add across double bonds to give 3–membered rings (cyclopropanes),2 insert into –OH bonds to give esters3 or ethers4 and insert into neighbouring –C–H bonds to give 4 or 5–membered rings, such as β– and γ–lactams5,6 or γ–lactones.7 Copper salts and complexes were amongst the first catalysts to be used for carbene generation from diazoalkanes.8 However, current tendencies are to use very expensive, especially, platinum group salts and complexes to generate the carbene intermediates, as yields and specificity tend to be higher.2,9 We have found that Cu2+–exchanged clay minerals (e.g. Wyoming bentonite) and zeolites (zeolite A), have proven to be very competitive in yield with such transition metal catalysts and they have the added advantage that the restricted reaction space within the zeolite pore or clay interlayer favours the more planar/less bulky product. With the clay minerals, when the layer spacing is kept low by judicious choice of mineral or solvent, the selectivity is improved. Herein we report a wide range of carbene addition (cyclopropane formation) and –C–H insertion reactions (β–lactam, γ–lactam and–lactone formation) catalysed by the Cu2+– exchanged clay minerals and the stereo–chemical consequences of carrying out the reactions within the clay interlayer. Preliminary studies on the successful formation of aziridines from azides via nitrene intermediates with Cu2+–exchanged clay minerals are also reported. iv For my Loving Mom and Dad v Acknowledgments First and foremost I would like to thank my director of studies Dr Richard W McCabe for his constant support, and his continuous guidance and encouragement throughout my research work. I would also like to thank Prof Gary Bond for giving me funding for research and also valuable time to spend with him throughout the research and for giving me opportunity to present my work in various conferences. I am also very thankful to member of my supervisory team Dr Rob Smith for his guidance, valuable support and encouragement. I also thank to Dr Jennifer Elizabeth Readman for her guidance in XRD and XRF and Dr Stephen Johns for his support and guidance in the lab. I would like to thank the members of the technical department; Tamar Garcia, Sal Tracey, Jim Donnelly, Patrick Cookson, Steven Kirby and staff in the Forensic chemistry department for always being so helpful and friendly. I also thank to my lab mates Dr Adeyi Okoh, Hajira Faki, Dr Samridhi lal, Sandeep Kadam for making my time enjoyable and sharing knowledge in chemistry all the time. I would like to express my thanks to my friend Dr Vishnu Vardhan Reddy, Alessandro Sinopoli for providing modelling data, and house mates for constant encouragement. Finally, my appreciation goes to my family members: mother, dad, brother Vinay kumar, sister Sujatha, brother-in-law Kasoju Govardhan and my sweet sons-in-law Sumanth, Akhil and my loving wife Saritha and sweet son. vi Background 1 Aims of the research 1 Clay minerals as catalysts 2 Structures of clay minerals 3 Acid activation of clay minerals 5 Structures of zeolites 6 Clay minerals as catalysts in synthetic organic reactions 8 Ether formation 8 Synthesis of heterocyclic compounds 11 Formation of aziridine derivatives 13 Acid catalysed Pinacol-rearrangements 14 Aldol reactions 15 Cycloaddition reactions (Diels-Alder reaction) 16 Stereochemistry of Diels-Alder reaction, formation of endo-46 and exo-47 products 16 Stereo–control of Diels-Alder reactions in clay minerals 18 Carbenes 20 Generation and reactions of carbenes from diazoalkanes 21 The Bamford–Stevens reaction 23 Carbene generation via Ketenes 23 Generation of carbenes from ylides 24 Generation of carbenes from epoxides and cyclopropanes 26 Generation of carbenes from heterocyclic compounds 26 Generation of carbenes by α-elimination 27 Stereochemistry of catalytic carbene insertion reactions and examples 28 Stereochemistry of catalytic carbene addition reactions 33 Nitrenes 38 Generation of nitrenes 38 From azides ..........................................................................................................................38 Via isocyanate-type molecules .............................................................................................39 From ylides...........................................................................................................................40 Nitrene formation from various heterocycles 41 Nitrene formation by α-elimination 42 Stereochemistry of nitrene addition reactions 43 vii Project aims 45 Introduction to carbene and carbene catalysed reactions 47 Synthesis of diazo ester amides 48 Catalysed carbene reactions of diazo ester amides 52 Reactions of methyl N,N-diethylamidodiazomalonate (methyl 2-diazo-2-(diethylcarbamoyl)acetate) 183 52 Assignment of the structures of the β-lactam isomers from methyl N,N-diethylamidodiazomalonate 183. .......................................................................................53 Computational details for diastereomers ..............................................................................59 Relative stabilities and bulkiness of the -lactam diastereomers 193 and 194 .....................60 Chem 3D modelling .............................................................................................................62 Comparison of the carbene insertion reactions of methyl N,N-diethylamido-diazomalonate 183 ..............................................................................................................................................63 Effect of varying the layer charge of a clay mineral on the ratio of diastereomers 193 and 194 . ..............................................................................................................................................68 Modification of the interlayer region of a clay mineral ........................................................70 Conclusions for reactions of methyl N,N-diethylamidodiazomalonate 183 .........................72 Carbene reactions of benzyl N,N-diethylamidodiazomalonate (benzyl 2-diazo-2- (diethylcarbamoyl)acetate) 184 73 Assignment of the structures of the benzyloxy β-lactam isomers 202 and 203 ....................74 Relative stabilities and bulkiness of the -lactam diastereomers 202 and 203 .....................77 Results of carbene reactions of benzyl N,N-diethylamidodiazomalonate 184 .....................80 Effects of varying the solvent on the interlayer spacing of clay minerals ............................81 Effect of varying the layer charge of a clay mineral on the diastereomers 202 and 203 ......82 Conclusions for reactions of benzyl N,N-diethylamidodiazomalonate 184 ..........................83 Carbene reactions of methyl N-ethyl-N-phenylamidodiazomalonate (methyl 2-diazo- 2-[ethyl(phenyl)carbamoyl]acetate) 185 83 Structure assignment of the -lactams 205, 206 and indolidine product 207 .......................85 Relative stabilities and bulkiness of the -lactam diastereomers 205 and 206 .....................87 Results of carbene reactions of methyl N-ethyl-N-phenylamidodiazomalonate 185 ............88 Conclusions for reactions of methyl N-ethyl-N-phenylamidodiazomalonate 185 ................90 Carbene reactions of benzyl N–ethylphenylamidodiazomalonate (benzyl 2-diazo-2- [ethyl(phenyl)carbamoyl]acetate) 186 91 Structure assignment of the β-lactam isomers 214, 215 and indolidine 216 ........................92 viii Relative stabilities and bulkiness of the -lactam diastereomers 214 and 215. ....................95 Results of carbene reactions of benzyl N–ethyl-N-phenyldiazomalonate 186. ....................96 Effect of the substituent on the α-diazo carbonyl compounds N-benzyl-N-tert-butyl-2- diazoacetamide 206 and methyl 2-diazo-3-(methyl(phenyl)amino)-3-oxopropanoate 209. .97 Conclusions for reactions of benzyl N-ethyl-N-phenylamidodiazomalonate 186. ...............97 Carbene reactions of methyl N-piperidinodiazomalonate