Computational Chemistry as a Tool for Understanding Non-Covalent Interactions in Organic Reactions and Materials

Non-covalent interactions (NCIs) play vital roles in many areas of chemistry and materials science. Although there has been a great deal of progress understanding the nature of non-covalent interactions in recent years, many aspects of these phenomena are still unclear. Modern DFT methods have become a valuable tool for organic chemists in studies of systems in which dispersion-driven NCIs are vital. The role of non-covalent interactions in two organocatalyzed reactions and two novel organic materials were studied by means of these and other computational tools. The two organocatalyzed reactions presented are the allylation and propargylation reactions catalyzed by a bipyridine N,N‘-dioxide catalyst and a hetero-Diels – Alder reaction catalyzed by a cage-shaped borate catalyst. In the first case, the reaction was used as an example to benchmark DFT methods against high accuracy ab initio calculations. It was shown that B97-D/TZV(2d,2p) provides the best compromise of accuracy and computational efficiency. Additionally, it was demonstrated that the original transition state model used to explain the stereoselectivity of these reactions is flawed. We developed a simple model based on non-covalent electrostatic interactions that explains the stereoselectivity of these reactions as well as the fact that the propargylation reaction is less stereoselective than the allylation. For the second reaction, preliminary results provide some support that π-stacking interactions between the substrate and the catalyst are responsible for the selective reaction of aromatic over aliphatic aldehydes, as observed experimentally. In an effort to better control the properties of organic materials based on discotic systems, stacking interactions between contorted hexabenzocoronene (c-HBC) homodimers and complexes of c-HBC with C60 fullerene were studied using DFT methods. It was found that the preference to stack as homo or heterodimers can be tuned by controlling the curvature of the c-HBC. To achieve this, different substituents on the c-HBC were tested. However, only perfluorination imparts sufficient curvature to the c-HBC to lead to tip the balance towards heterodimer formation over homodimer formation. Finally, an additional explanation was provided for the rotational speed difference between the –OH and –OMe substituted pillar[5]arenes. It is shown that in addition to the hydrogen bond explanation for the –OH substituted case provided by Ogishi and coworkers (J. Phys.Chem. Lett.,2010, 817), non-covalent CH/π interactions contribute significantly to the TS stabilization of the –OMe substituted case, enhancing the rotational speed

The Structure and Reactivity of Hypervalent Organosilicon Compounds

The purpose of this thesis is to review the structure and reactivity of hypervaient silicon and to consider the underlying explanation for the observed enhanced reactivity of such compounds towards nucleophiles

Electronic properties of amino acid side chains: quantum mechanics calculation of substituent effects

BACKGROUND: Electronic properties of amino acid side chains such as inductive and field effects have not been characterized in any detail. Quantum mechanics (QM) calculations and fundamental equations that account for substituent effects may provide insight into these important properties. PM3 analysis of electron distribution and polarizability was used to derive quantitative scales that describe steric factors, inductive effects, resonance effects, and field effects of amino acid side chains. RESULTS: These studies revealed that: (1) different semiempirical QM methods yield similar results for the electronic effects of side chain groups, (2) polarizability, which reflects molecular deformability, represents steric factors in electronic terms, and (3) inductive effects contribute to the propensity of an amino acid for α-helices. CONCLUSION: The data provide initial characterization of the substituent effects of amino acid side chains and suggest that these properties affect electron density along the peptide backbone

Syntheses, Structures, and Characterizations of 2,2\u27,7,7\u27-Tetrasubstituted 1,1\u27-Ethynylenedinaphthalenes.

In order to study intramolecular enzyme catalysis, chemical models have been designed to quantify the proximity and orientation effects which occur in carboxylate catalyzed hydrolyses. As part of this broader study, various 2,2\sp\prime,7,7\sp\prime-tetrasubstituted 1,1\sp\prime-ethynylenedinaphthalenes are synthesized from 2,7-dihydroxynaphthalene. Two different strategies are used to obtain the title compounds. The first strategy involves palladium-mediated couplings between electron-poor aryl iodides and electron-rich arylethynes and allows synthesis of unsymmetrical binaphthylethynes. The second approach couples two 2,7-disubstituted naphthalenes with tetrachlorocyclopropene in the presence of aluminum chloride, but only symmetrical binaphthylethynes are obtained. During the course of this work, a number of 1,2,7-trisubstituted naphthalenes, some of them previously unknown, have been prepared. Several new or improved procedures have also been developed, most notably the monomethylation of 2,7-naphthalenediol in a two solvent system, a new three-step preparation of methyl 7-methoxy-2-naphthoate, and a new two-step synthetic method for the acyl $\to$ ethynyl conversion in electron-rich aromatic rings. Both strategies produce several new binaphthylethynes, two of which are unsymmetrical. These two compounds represent the first examples of this type of molecule. Through NMR spectroscopic techniques and X-ray diffraction, a large amount of spectral and structural data on naphthalenes has been assembled and discussed. In addition, a literature review of the previous syntheses of dinaphthylethynes is included

The biotransformation of benzene derivatives : the influence of active site and substrate characteristics on the metabolic fate

The amount of newly developed chemicals such as agrochemicals, drugs and food additives in our modem society is ever increasing. The industrial production, use and also the release in the environment of these chemicals expose organisms to these xenobiotics. Due to the often hydrophobic character of these xenobiotics they can be easily absorbed and accumulated in the body. However, organisms defend themselves against these agents by converting them enzymatically to more hydrophilic easily excretable products. Sometimes these biotransformation reactions can lead to reactive intermediates which cause cell damage, toxicity, malignancy and/or ultimately carcinogenicity. This indicates why a lot of toxicological screening and safety tests have to be performed during the development of these agents.However, modern society still requires new compounds with better properties. As it is unfeasible to test the biological activity and toxic effects of all newly developed chemicals in experimental animals, many in vitro systems have been developed in which these chemicals can be quickly tested for various biological and/or toxicological effects. To diminish the use of experimental test systems the QSAR concept has been developed, describing so-called Quantitative StructureActivity Relationships. This QSAR approach should make it possible to predict the biological effect, the biotransformation pattern and/or the toxicity of a chemical based on its physical and chemical characteristics. In this respect the application of MO (Molecular Orbital) computer calculations to describe at least some of these chemical characteristics appears to become more and more useful.The present thesis focuses on the use of these computer calculated MO parameters for the prediction of biotransformation characteristics of benzene derivatives. Benzene derivatives play an important role as precursors for the synthesis of many xenobiotics and industrially relevant chemicals. The cytochrome P450-catalysed biotransformation of various substituted benzenes was studied and the results were evaluated to determine whether (MO-based) computer calculated chemical parameters of benzenes could explain the results obtained. Where results could not be described well by the chemical reactivity of the substrate itself, additional experimental work was performed to investigate to which factors and/or interactions the observed deviations could be ascribed. This information can then be used to adopt and improve the predictive model.Biotransformation of xenobiotics by higher organisms is an enzymatic process in which cytochromes P450 play a major role. This system is able to handle an enormous amount of very structurally different chemicals. The cytochrome P450 enzymes differ in their substrate specificity, metabolic activity and their extent of contribution to the production of toxic metabolites. As outlined in the introduction of this thesis (Chapter 1 ), there are several factors which control the cytochrome P450-catalysed biotransformation. These factors include for example, electron donation to cytochrome P450, the accessibility of the active (FeO) 3+species in the active site of the enzyme, the interaction between the substrate and the active site and the chemical reactivity of the substrate itself. In cases where the latter factor controls the outcomes of the cytochrome P450-catalysed biotransformation, one could describe a QSARs for the reaction. Based on these QSARs the cytochrome P450-catalysed biotransformation of other chemicals might be predicted. Furthermore, these QSARs might give more insight in the mechanistic background of the biotransformation reaction for which it has been developed.An example of this approach is described in Chapter 2 of this thesis. In this chapter in vivo cytochrome P450-catalysed aromatic ring hydroxylation of various substituted benzene derivatives was determined using 19F NMR. Previous reported results on the regioselectivity of cytochrome P450-catalysed aromatic ring hydroxylation of a series (poly)fluorobenzenes demonstrated a clear QSAR (correlation 0.96) relating the site of hydroxylation of the site of the reactive HOMO π-electrons in the benzene substrate. Thus, in Chapter 2 the same parameter was tested for its ability to predict the regioselectivity of aromatic hydroxylation of a series C4-substituted fluorobenzenes. It turned out that the MO-QSAR approach could well predict the regioselectivity of the series of 4-X-substituted fluorobenzenes when X was a H, F, Cl, and CN group. However, this approach of predicting the regioselectivity of aromatic hydroxylation ran into problems when the para substituent was a bromine or iodine. The extent to which the hydroxylation adjacent to a bromine and iodine substituent was reduced, correlated qualitatively with the size of the substituents as given by their Van der Waals radius, i.e. the larger the substituent the greater the deviation between the predicted and observed hydroxylation at the adjacent aromatic carbon centre. Additional experiments showed that the observed deviations could not be ascribed to a stereoselective orientation of these substrates in the active sites of cytochromes P450. These results led to the hypothesis that bromine and iodine substituents sterically hamper the electrophilic attack of the cytochrome P450 high-valent iron-oxo species on the carbon atoms adjacent to the substituted carbon centres. This hypothesis was supported by calculating the steric effects of bromine and iodine substituents, thus defining a steric correction factor for prediction of the aromatic ring hydroxylation at sites ortho with respect to a bromine or iodine substituent. In a second series of regioselectivity experiments using a series of tri- substituted benzenes containing fluorine, chlorine, bromine, iodine and cyano substituents, these steric correction factors were validated. Without using the steric correction factors for bromine and iodine substituents no correlation between the predicted and observed regioselectivity was obtained. However, upon application of the correction factors a correlation factor of 0.91 was obtained for prediction and actually observed regioselectivity of cytochrome P450-catalysed aromatic hydroxylation of the series tri- substituted benzenes. These results show that the QSAR which was initially developed for a series of (poly)fluorobenzenes was still valid for other substituted benzenes taking into account the steric hindrance by relatively large substituents such as bromine and iodine. Furthermore, from a mechanistic point of view these MO-QSARs suggest that the cytochrome P450-catalysed aromatic ring hydroxylation of at least the benzene derivatives tested proceeds by an initial attack of the iron-oxo species on the ring carbon atom, without the formation of arene oxide intermediates as a major route.The question remains why going from a chlorine to a bromine substituent, steric hindrance is observed rather abrupt. A possible explanation might be found in the observation that when two molecules approach each other the potential energy goes through a minimum and thereafter increases rapidly with decreasing distance.Surprisingly, it was found that steric hindrance by the cyano group was not observed although this group is definitely larger than a bromine. However, with respect to steric hindrance of the electrophilic attack of the (FeO) 3+species, only the atom closest to the aromatic ring might have to be taken into account. Steric hindrance of this atom, a carbon, is not expected since a carbon, has a size similar to that of a chlorine.More complicated substituents than H, F, Cl, Br, I and CN were investigated in Chapter 3 where the regioselectivity of aromatic ring hydroxylation of 3-fluoro(methyl)anilines was investigated. Little is known about the cytochrome P450- catalysed biotransformation of such methylanilines. Results from the in vivo and in vitro cytochrome P450-catalysed regioselectivity of aromatic hydroxylation showed that the frontier orbital density distribution in the aromatic ring could only qualitatively predict the observed regioselectivity. Again, as for the bromine and iodine substituents the observed regioselectivity of aromatic ring hydroxylation for the various amino and methyl substituted substrates showed systematic deviations from the predicted regioselectivity, i.e. hydroxylation at the ring carbon C4 para with respect to the amino moiety was always higher than predicted while hydroxylation at the carbon atoms ortho with respect to the amino group (C2 and C6) was lower than expected. Further research was performed to investigate why for this series of amino and/or methyl substituted benzene derivatives the intrinsic chemical reactivity did not predict the observed regioselectivity of aromatic hydroxylation quantitatively. Three different experimental approaches were used to investigate possible reasons underlying the systematic deviations between predicted and observed regioselectivity for the cytochrome P450-catalysed aromatic hydroxylation of amino-containing benzenes. These results are discussed in some more detail hereafter.1. As a first approach, incubations of 3-fluoro-2-methylaniline with different microsomal preparations containing various cytochrome P450 enzyme patterns as well as with purified cytochrome P4502B1 were performed. The regioselectivity for aromatic hydroxylation of 3- fluoro-2-methylaniline observed in all these incubations were similar. This result indicates that cytochromes P450 with different active sites give similar regioselectivities and, thus, in case of 3-fluoro-2-methylaniline similar deviations for predicted values. This suggests that the observed discrepancy between predicted and observed aromatic hydroxylation patterns can not be ascribed to a stereoselective orientation of the 3-fluoro(methyl)anilines imposed by the active sites of the cytochromes P450 catalysing its conversion.2. Further support for this conclusion was obtained from 1H NMR T 1 relaxation studies on fluoromethylanilines. These studies are described in Chapter 4. It appears that the orientation of the tested fluoromethylanilines in the active sites of cytochromes P4501AI and 2B1 is similar. Based on the observation that all aromatic protons are at about the same average distance from the catalytic Fe 3+centre, these results are most compatible with a time-averaged orientation of the substrates with the Fe 3+above the aromatic ring and the π-orbitals of the aromatic ring and those of the porphyrin rings in a parallel position. This latter aspect would provide possibilities for energetically favourable π-πinteractions. Possibilities for a flip-flop rotation around an axis in the plane of the aromatic ring of the substrate can be included in this picture, as such rotations would still result in a similar average distance of all aromatic protons to the Fe 3+centre. Altogether, the data strongly suggest that, independent of the cytochrome P450 enzyme these substrates can rotate freely in the active site and are not hindered and/or specifically orientated by interactions with specific amino acid residues of the active site.3. Finally, the possible influence of the active site on the cytochrome P450-catalysed aromatic hydroxylation was tested by using microperoxidase-8 as a model system for cytochrome P450-catalysed aromatic ring hydroxylation. Microperoxidase-8 is a so-called mini-enzyme prepared by proteolytic digestion of horse-heart cytochrome c. MP-8 contains a heme covalently attached to a peptide chain of only eight amino acids and thus it lacks an active site. MP-8 is well known to perform peroxidase-like reactions. However, experimental evidence has been obtained described in Chapter 5 of this thesis that the MP-8-catalysed aromatic ring hydroxylation of aniline and phenol derivatives in a H 2 O 2 -driven system proceeds by a cytochrome P450-like oxygen-transfer mechanism. This could be concluded from the fact that 18O incorporation from H218O 2 into the 4-aminophenol formed from aniline was 100%. Thus, the H 2 O 2 -driven MP-8 system was used as a model to study regioselectivity of oxygen-transfer in a heme-based catalyst without an active site.The results of such experiments demonstrated that the MP-8-catalysed aromatic ring hydroxylation of 3-fluoro(methyl)anilines (Chapter 3) results in similar regioselectivities of aromatic ring hydroxylation as those observed for cytochrome P450- catalysis. As a specific substrate binding site in MP-8 can be excluded, these results, together with those obtained from different microsomal preparations (Chapter 3) and the 1H NMR T 1 relaxation measurements (Chapter 4), clearly eliminates the possibility that the regioselectivity of aromatic ring hydroxylation is predominantly dictated by a stereoselective orientation of the substrate in the active site of cytochromes P450. Thus for these relatively small and non-polar substrates specific interactions between molecular sides in the substrate and amino acid side chains present in the active site are not dictating a stereoselective orientation of these substrates.Since the MP-8-catalysed reactions showed similar deviations between predicted and observed regioselectivity of aromatic hydroxylation of 3-fluoro(methyl)anilines, it was concluded that the deviations must result from an orientating interaction between the substrate and the high-valent iron-oxo species (FeO) 3+itself, resulting in a stereoselective orientation of the substrate towards the catalytically active species. This interaction can be expected to be quite similar for different cytochromes P450 and might also be comparable in the active MP-8 system. This implies that, in contrast to what was observed by 1H NMR for substrates bound to the Fe 3+resting state of the enzyme, the (FeO) 3+form of the protein would impose a preferential orientation of the amino-containing substrate in such a way that on the average C4 ( para to the amino) is closer to whereas C2/6 (ortho to the amino) are further away from the (FeO) 3+species. Support for a different substrate orientation in the Fe 3+resting state and the (FeO) 3+activated form respectively can be found in a study of Paulsen and Ornstein. They showed that the orientation of camphor in the presence and absence of the high-valent iron-oxo species (FeO) 3+was different and that orientation in the presence of the catalytically active form of the enzyme (FeO) 3+was in accordance with the observed regioselectivity of oxidation.Altogether, results from all studies on the regioselectivity of aromatic hydroxylation of the various benzene derivatives show that the regioselectivity of the H, F, Cl, Br, I, CN, CH 3 and NH 2 substituted benzene derivatives investigated is predominantly determined by their chemical reactivity. However, especially for amino-containing benzene derivatives interactions between the substrate and the high-valent iron-oxo species, resulting in a stereoselective orientation of the substrate, might also play a role. This means that the QSAR for aromatic ring hydroxylation in the case of amino-containing benzenes predicts only qualitatively the regioselectivity of aromatic ring hydroxylation for these series of substrates.An additional result obtained in all regioselectivity studies was the absence of formation of NIH shifted phenolic metabolites. The formation of such NIH shifted phenolic metabolites has been well documented especially for the biotransformation of chlorinated and brominated benzene derivatives. As the benzenes in our studies were mainly fluorinated, we decided to investigate whether there was a (chemical) reason for this discrepancy.In Chapter 6 the possibility of a cytochrome P450-catalysed fluorine NIH shift in a series of polyfluorobenzenes was investigated and compared with the literature data of the chlorinated analogues. The in vivo biotransformation of a series polyfluorobenzenes showed that formation of NIH shifted metabolites was not a significant biotransformation route. As outlined above, this is in contrast to the results reported in the literature for the chlorinated analogues. However, in contrast to the in vivo data, in in vitro microsomal studies with 1,4-difluorobenzene formation of a significant amount of fluorine NIH shifted phenolic metabolite was observed. Unfortunately, the in vitro microsomal conversion of the other used polyfluorobenzenes could not be detected, possibly due to the fact that the HOMO energy of these substrates was too low for an efficient conversion by cytochromes P450 [5]. It is generally accepted that formation of NIH shifted metabolites proceeds via arene oxide intermediates and that these arene oxides, especially in vivo, but not in vitro in a microsomal system, might react in competing conjugation pathways such as GSH conjugation. Additional in vivo and in vitro experiments showed that indeed GSH conjugation was a competing pathway for the arene oxide intermediates, its presence or absence resulting in an influence on the amount of NIH shifted phenolic metabolites observed.Nevertheless, the results thus obtained also clearly illustrated and confirmed the reduced capacity for formation of NIH shifted phenolic metabolites for fluoro- as compared to chlorobenzenes. This differences between the NIH shift for fluorine and chlorine containing benzenes was further investigated and could be explained by MO computer calculations on the proposed reaction intermediates in the two biotransformation pathways. Epoxide ring opening, supposed to be the rate-limiting step in the formation of NIH shifted metabolites, appeared easier for chlorinated benzenes compared to their fluorinated analogues. Furthermore, these MO calculations in combination with a MO-QSAR for the rate of GS-conjugation of electrophilic model compounds were indicative for higher rates of GSH conjugation for the fluorinated benzene arene oxides than the chlorinated analogues. The detoxifying pathway of GSH conjugation is very important for assessing the risks of these kind of substrates as arene oxides are known to react with protein and DNA provoking toxic and/or mutagenic /carcinogenic responses.Altogether, the results from this study show that MO calculations can not only explain and thus predict the regiospecificity of biotransformation in a molecule but also explain the relative rates, i.e. chances, on different biotransformation routes.Finally, in addition to all studies on model benzene derivatives, the last chapter of this thesis (Chapter 7) describes studies on the biotransformation of a halogenated benzene derived compound that is used as an insecticide, i.e. teflubenzuron. This may provide some insight in the possibilities to use outcomes from studies on model compounds to obtain insights also in the biotransformation of other compounds. Teflubenzuron, which is used for the protection of fruit and vegetables against larves, contains two aromatic benzene-derived rings connected via an urea bridge. These aromatic rings are differently substituted and are a suitable starting point to evaluate the influence of various substituents on the metabolic fate of the chemical. Basically, they are an aniline and a benzoate derived moiety. Results of this study on the biotransformation of teflubenzuron demonstrate that upon an oral dose of the insecticide to male Wistar rats the metabolic fate of the two aromatic rings is significantly different. Though about 90% of the dose was excreted unchanged in the faeces, the remainder of the dose was absorbed from the gastrointestinal tract and -in part- excreted in the urine mainly after hydrolysis of the urea bridge. Interestingly, the urinary recovery of the benzoate moiety was about 8 times higher than that of the aniline moiety of teflubenzuron. Dose-recovery studies on the scission products of teflubenzuron confirmed these results as the urinary recovery of the metabolites from the benzoate moiety were nearly 100% while the recovery of the aniline derivatives was only about 50%. The benzoate moiety is excreted unchanged or after a Phase IIreaction, while the aniline moiety has to undergo both a Phase I and II reaction before it can be excreted.The significant difference between the recovery of the benzoate and aniline moiety can be best explained by the formation of a cytochrome P450-catalysed reactive benzoquinoneimine from the C4 halogenated aniline derivatives. Swift binding of these reactive benzoquinoneimine

Self-Assembly of Azulenic Monolayer Films on Metallic Gold Surfaces

Derivatives of azulene, an unusual nonbenzenoid aromatic hydrocarbon featuring fused five- and seven-membered sp2 carbon rings, are of substantial current interest in the design of advanced functional materials such as organic electronics. The overarching theme of this dissertation is the chemistry of new hybrid metal/azulene platforms featuring azulenic monolayer films anchored to the atomically flat metallic gold via isocyanide or thiolate junctions. One of the key aspects of this work addresses the influence of the junction group's nature on the formation, stability, reactivity, and physicochemical characteristics of azulenic self-assembled monolayer (SAM) films on the Au(111) surface. Both isocyanide and thiolate "alligator clips" in these SAMs were shown to induce approximately upright orientation of the azulenic framework with respect to the gold surface. The films' properties were evaluated by various means including surface-enhanced infrared spectroscopy and optical ellipsometry. Of particular significance are the initial examples of molecular films involving all three possible linear biazulenic scaffolds. These SAMs feature isocyanide junction groups and exhibit good stability toward ambient lighting and, in some cases, air atmosphere. Characterization of certain isocyano- and mercaptoazulenic molecular films reported herein was greatly facilitated by incorporation of ancillary nitrile infrared spectroscopic reporters into the azulenic scaffold. Such an approach constitutes a novel strategy in the surface chemistry of organic thiols, to the best of the author's knowledge. In addition, the thesis describes, among other isocyanide/thiol competitive binding investigations, the first monolayer film displacement studies involving the RSH and RNC species with identical substituents R that underscore the higher affinity of the thiolate versus isocyanide junctions for metallic gold. Accessibility of the new monolayer films reported in this dissertation paves the way for future experimental validation of the theoretically predicted low resistivity of the linear 2,6-azulenic framework

Org. semin. abstr.

Issued by: University of Illinois, Department of Chemistry and Chemical Engineering, 1962-1963/semester I-; University of Illinois at Urbana-Champaign, Department of Chemistry, <1982-83-