Brian H Northrop's research while affiliated with Wesleyan University and other places

Thermally promoted cycloaddition reactions of tropone-3,4-dimethylester and cyclopentadiene have been investigated using density functional theory calculations at the M06-2X level and the CBS-QB3 method. The reaction shares several characteristics with previously investigated cycloadditions involving unsubstituted tropone and cyclopentadiene, however substitution of the tropone component with methyl esters results in lower transition state free energy barriers, greater thermodynamic driving forces, and a significant increase in the number of possible pericyclic reaction pathways. Eighteen different [4 + 2], [6 + 4], or [8 + 2] cycloaddition products are possible and many of the initially formed cycloadducts can be interconverted through Cope or Claisen rearrangements. Of the many possible cycloaddition products only two are predicted to form: the exo-[6 + 4] product and one [4 + 2] product where the substituted tropone appears to be the diene. The two computationally predicted products are the same as the two that are observed experimentally, however computations indicate that both products result from ambimodal processes rather than single-step (monomodal) cycloaddition pathways.

The nucleophile‐initiated mechanism of thiol‐Michael reactions naturally leads to the formation of undesired nucleophile byproducts. Three aza‐Michael compounds representing nucleophile byproducts of thiol‐acrylate reactions initiated by 4‐dimethylaminopyridine (DMAP), 1‐methylimidazole (MIM), and 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) have been synthesized and their reactivity in the presence of thiolate has been investigated. Spectroscopic analysis shows that each nucleophile byproduct reacts with thiolate to produce a desired thiol‐acrylate product along with liberated aprotic amines DMAP, MIM, or DBU, thus demonstrating that these byproducts are reactive rather than persistent. Density functional theoretical computations support experimental observations and predict that a β‐elimination mechanism is favored for converting each nucleophile byproduct into a desired thiol‐acrylate product, though an SN2 process can be competitive (i. e. within <2.5 kcal/mol) in less polar solvents.

Three increasingly π-conjugated covalent organic polygons have been prepared by the dynamic covalent condensation of catechol-based oligo(phenylene ethynylene) derivatives with phenylenebis(boronic acid). The assemblies represent a series of boronate ester “ladders” wherein two electron rich oligo(phenylene ethynylene) “rungs” are bridged by electron deficient aryl boronate ester “rails,” resulting in quasi-two-dimensional oligomers of increasing size. Spectroscopic and computational investigations suggest that the ladders exhibit a greater effective conjugation length than comparable oligo(phenylene ethynylene) compounds not bridged by aryl boronate esters. Different conformations, substitutions, and constitutions of boronate ester ladders are also modeled to gain further insight into their influence on π-conjugation and HOMO-LUMO gaps of isolated one-dimensional versus bridged, quasi-two-dimensional conjugated organic materials.

Aryl Boronate Esters, such as 2-phenyl-1,3,2-benzodioxaborole (1), are important components in the formation of a variety of Covalent Organic Frameworks (COFs). The addition of substituents on the aromatic rings of aryl boronate esters has the potential to modify the structure, reactivity, and electronic properties of resulting materials and so it is useful to understand at a more fundamental level the properties of these important compounds. Experimental measurements and computational investigations are presented herein that provide insight regarding the structural and electronic properties of parent aryl boronate ester 1 as well as three substituted derivatives: 2-(o-tolyl)-1,3,2-benzodioxaborole (2), 2-(2,6-dimethylphenyl)-1,3,2-benzodioxaborole (3), and 2-(4-(tert-butyl)phenyl)-1,3,2-benzodioxaborole (4). Electronic spectroscopy combined with excited state calculations reveal two closely spaced electronic states, S1 and S2, which appear to have excitation primarily localized on the aromatic system of the phenyl substituent or the catecholborane moiety, respectively. Interestingly, the ortho-dimethyl derivative (3) shows a significantly red-shifted electronic origin with an extensive vibronic progression of a low frequency torsional motion about the C-B bond. Franck-Condon calculations on the ab initio determined ground and excited state potentials very accurately reproduce this spectrum confirming the non-planar ground state of this compound.

A set of dendrons and dendrimers is synthesized divergently using an orthogonal combination of kinetically-driven thiol-maleimide “click” chemistry and thermodynamically reversible furan-maleimide cycloaddition/retrocycloaddition reactions. Growth is controlled by taking advantage of the selective thiol-ene addition of thiols to the electron withdrawn alkene of maleimide in the presence of electron rich alkene of oxanorbornene. Subsequent activation of growing dendrons/dendrimers requires only heat to induce the dynamic covalent liberation of peripheral furan protecting groups. The methodology introduced provides a new route to multifunctional dendrimers that could, in principle, be synthesized by introducing different branched monomers at any stage of dendrimer growth, allowing dendrimer architectures and properties to be better tailored to their intended applications.

The commonly accepted mechanism of nucleophile-initiated thiol-acrylate reactions requires the formation of undesired nucleophile byproducts. A systematic evaluation of the formation of such nucleophile byproducts has been carried out to understand the relationships between byproduct formation and nucleophile structure, stoichiometry, solvent, and reaction type. Three common nucleophiles for thiol-Michael reactions were investigated: dimethylphenylphosphine (DMPP), diethylamine (DEA), and hexylamine (HA). The formation of phosphonium ester and aza-Michael byproducts upon initiating a representative thiol-acrylate reaction between 1-hexanethiol and methyl acrylate at a range of initiator loading (0.01–10.0 equivs) and in different solvents (neat, DMSO, THF, and CHCl3) was determined by 1H NMR spectroscopy. The influence of reaction type was investigated by expanding from small molecule reactions to end group thiol-acrylate functionalization of PEG-diacrylate polymers and and through investigations of polymer-polymer coupling reactions. Results indicate that the propensity of forming nucleophile byproducts varies with nucleophile type, solvent, and reaction type. Interestingly, for all but polymer-polymer ligation reactions, nucleophile byproduct formation is largely unobserved for nitrogen-centered nucleophiles DEA and HA, and essentially nonexistent for the phorphorous-centered nucleophile DMPP. A rationale for the differences in nucleophile byproduct formation for DMPP, DEA, and HA is proposed and supported by experimental and computational analysis.

Thiol-Michael ‘click’ reactions are essential synthetic tools in the preparation of various materials including polymers, dendrimers, and other macromolecules. In spite of increasing efforts to apply thiol-Michael chemistry in a controlled fashion, the selectivity of base- or nucleophile-promoted thiol-Michael reactions in complex mixtures of multiple thiols and/or acceptors remains largely unknown. Herein, we report a thorough fundamental study of the selectivity of the thiol-Michael reactions through a series of 270 ternary reactions, using 1H NMR spectroscopy to quantify product selectivity. The varying influences of different catalysts/initiators are explored using ternary reactions between two Michael acceptors and a single thiol, or between a single Michael acceptor and two thiols, using three different catalysts/initiators (TEA, DBU, and DMPP) in chloroform. The results from the ternary reactions provide a platform from which sequential quaternary, one-pot quaternary, and sequential senary thiol-Michael reactions were designed and their selectivity quantified. These results provide insights into the design of selective thiol-Michael reactions that can be used for the synthesis and functionalization of multicomponent polymers, and further informs how catalyst/initiator choice influences the reactivity between a given thiol and Michael acceptor.

The limited processability of two-dimensional covalent organic frameworks (2D COFs), which are typically isolated as insoluble microcrystalline powders, detracts from their utility. Here we apply similar design criteria to access hexagonal boronate ester-linked macrocycles that represent discrete analogues of 2D COFs. The macrocycles readily pack into hexagonal, layered solid-state structures whose spacing is determined by the size of the macrocycle and its side chains. In contrast to 2D COFs, the assembled macrocycles undergo reversible swelling upon exposure to solvents that interact favorably with the side chains. Incorporating hexa(ethylene glycol) monomethyl ether groups leads to dispersible macrocycles that cofacially assemble both in solution and the solid state. This approach expands the directional bonding approach to processable, boronate ester-linked macrocycles with designed size, shape, and functional group organization.

The solution phase self-assembly of boronate esters, diazaboroles, oxathiaboroles, and dithiaboroles from the condensation of arylboronic acids with aromatic diol, diamine, hydroxythiol, and dithiol compounds in chloroform has been investigated by 1H NMR spectroscopy and computational methods. Six arylboronic acids were included in the investigations with each boronic acid varying in the substituent at its 4-position. Both computational and experimental results show that the para-substituent of the arylboronic acid does not significantly influence the favorability of forming a condensation product with a given organic donor. The type of donor, however, greatly influences the favorability of self-assembly. 1H NMR spectroscopy indicates that condensation reactions between arylboronic acids and catechol to give boronate esters are the most favored thermodynamically, followed by diazaborole formation. Computational investigations support this conclusion. Neither oxathiaboroles nor dithiaboroles form spontaneously at equilibrium in chloroform at room temperature. Computational results suggest that the effect of borylation on the frontier orbitals of each donor helps to explain differences in the favorability of their condensation reactions with arylboronic acids. The results can inform the use of boronic acids as they are increasingly utilized in the dynamic self-assembly of organic materials and as components in dynamic combinatorial libraries.

The mechanism and kinetics of thiol-maleimide “click” reactions carried out under a variety of conditions have been investigated computationally and using experimental competition reactions. The influence of three different solvents (chloroform, ethane thiol, and N,N-dimethylformamide), five different initiators (ethylamine, diethylamine, triethylamine, diazabicyclo[2.2.2]octane, and dimethylphenyl-phosphine), and seven different thiols (methyl mercaptan, β-mercaptoethanol, thioacetic acid, methyl thioglycolate, methyl 3-mercaptopropionate, cysteine methyl ester, and thiophenol) on the energetics and kinetics of thiol-maleimide reactions have been examined using density functional methods. Computational and kinetic modeling indicate that the choice of solvent, initiator, and thiol directly influences whether product formation follows a base-, nucleophile-, or ion pair-initiated mechanism (or some combination thereof). The type of mechanism followed determines the overall thiol-maleimide reaction kinetics. Insights from computational studies are then used to understand the selectivity of ternary thiol-maleimide reactions between N-methyl maleimide, thiophenol, and 1-hexanethiol in different combinations of solvents and initiators. The results provide considerable insight into the interplay between reaction conditions, kinetics, and selectivity in thiol-maleimide reactions in particular and thiol-Michael reactions in general, with implications ranging from small molecule synthesis to bioconjugation chemistry and multifunctional materials.