Mirroring Enzymes: The Role of H-Bonding In HQuin-BAM Catalyzed Asymmetric Aza-Henry Reactions: A DFT Study into the Reactivity, Mechanism, and Origins of Selectivity

The exact mechanistic understanding of various organocatalytic systems in asymmetric reactions such as Henry and aza-Henry transformations is important for developing and designing new synthetic organocatalysts. The focus of this dissertation will be on the use of density functional theory (DFT) for studying the asymmetric aza-Henry reaction. The first part of the thesis is a detailed mechanistic investigation of a poorly understood chiral bis(amidine) (BAM) Brønsted acid catalyzed aza-Henry reaction between nitromethane and N-Boc phenylaldimine. The catalyst, in addition to acting as a Brønsted base, serves to simultaneously activate both the electrophile and the nucleophile through dual H-bonding during C-C bond formation and is thus essential for both reaction rate and selectivity. Analysis of the H-bonding interactions revealed that there was a strong preference for the formation of a homonuclear positive charge-assisted H-bond, which in turn governed the relative orientation of substrate binding. Attracted by this well-defined mechanistic investigation, the other important aspect of my PhD research addressed a detailed theoretical analysis accounting for the observed selectivity in diastereoselective versions of this reaction. A detailed inspection of the stereodetermining C-C bond forming transition states for monoalkylated nitronate addition to a range of electronically different aldimines, revealed that the origins of stereoselectivity were controlled by a delicate balance of different factors such as steric, orbital interactions, and the extent of distortion in the catalyst and substrates. The structural analysis of different substituted transition states established an interesting dependency on matching the shape and size of the catalyst (host molecule) and substrates (guest molecules) upon binding, both being key factors governing selectivity, in essence, offering an analogy to positive cooperative binding effect of catalytic enzymes and substrates in Nature. In addition, both intra-molecular (intra-host) and inter-molecular (host-guest, guest-guest) stabilizing interactions play a key role to the high π-facial selectivity. The application of dispersion-corrected functionals (i.e., ωB97X-D and B3LYP-D3) was essential for accurately modeling these stabilizing interactions, indicating the importance of dispersion effects in enantioselectivity. As a brief prelude to more extensive future studies, the influence of a triflate counterion on both reactivity and selectivity in this reaction was also addressed.

Letter to S.D. Woodruff from Dexter Deverardo

Letter to S.D. Woodruff from Dexter Deverardo in which he says that he fears that a mistake has been made in A. Mains’ pay. He may have overpaid a considerable sum, April 25, 1857.

Notice from Dexter Deverardo regarding minutes of the meeting of the Municipal Council of the County of Welland

Notice from Dexter Deverardo regarding minutes of the meeting of the Municipal Council of the County of Welland that was held May 21, 1857. It was moved that the warden and clerk be requested to procure a plan of the marsh lands tract, May, 1857.

Letter to S.D. Woodruff from Dexter Deverardo

Letter to S.D. Woodruff from Dexter Deverardo stating that he has enclosed a cheque for the engineers’ pay, June 9, 1857.

Letter to S.D. Woodruff from Dexter Deverardo

Letter to S.D. Woodruff from Dexter Deverardo in which he says he has enclosed a copy of the resolution of the council, June 20, 1857.

Letter to S.D. Woodruff from Dexter Deverardo

Letter to S.D. Woodruff from Dexter Deverardo stating that he has enclosed a cheque for the engineers’ pay for July and August, Sept. 5, 1857.

Letter to S.D. Woodruff from Dexter Deverardo

Letter to S.D. Woodruff from Dexter Deverardo regarding ditching on both sides of the canal near Marshville (2 ½ pages, handwritten), Sept. 11, 1857.

Letter to S.D. Woodruff from Dexter Deverardo

Letter to S.D. Woodruff from Dexter Deverardo regarding ditching near Marshville, Sept. 15 (3 pages, handwritten), 1857.

Letter to S.D. Woodruff from Dexter Deverardo

Letter to S.D. Woodruff from Dexter Deverardo stating that a cheque is enclosed for the services of the engineers and a resolution is also provided to continue the services of the engineer, Jan. 20, 1858.

Letter to S.D. Woodruff from Dexter Deverardo

Letter to S.D. Woodruff from Dexter Deverardo regarding the completion of the drain (2 pages, handwritten), May 19, 1858.

Letter to S.D. Woodruff from Dexter Deverardo

Letter to S.D. Woodruff from Dexter Deverardo to get matters settled as early as possible and while the house is still in session (2 pages, handwritten), May 24, 1858.

Letter to S.D. Woodruff from Dexter Deverardo

Letter to S.D. Woodruff from Dexter Deverardo stating that there appears to be a difference of opinion between Mr. Woodruff and Mr. Holmes (2 pages, handwritten), Aug. 5, 1858.

Letter to S.D. Woodruff from Dexter Deverardo

Letter to S.D. Woodruff from Dexter Deverardo enquiring about the location of Alexander McDonell’s farm lots, Aug. 18, 1858.

Estimates for marsh drainage sent to Dexter Deverardo from S.D. Woodruff for Alexander Cook and Andrew Mains

Estimates for marsh drainage sent to Dexter Deverardo from S.D. Woodruff for Alexander Cook and Andrew Mains, Nov. 30, 1855.

Time on marsh lands for the months of January, February, March and April for Fred Holmes, Joseph Simpson, Duncan Davidson, Rose Osborne, Henry Wilson and William Baird

Time on marsh lands for the months of January, February, March and April for Fred Holmes, Joseph Simpson, Duncan Davidson, Rose Osborne, Henry Wilson and William Baird. This is signed by Fred Holmes, April 28, 1857.