Glaser Group Research

Boldness has genius, power and magic in it. Johann Wolfgang von Goethe

Chemistry of Anisotropic Media.
Organic, Theoretical, and Materials Chemistry. Chemistry Education.
Descriptive Realism. Make, measure, and think with theory.

Projects 1. DNA Base Deamination and Cross-Link Formation.
2. Polar Order in Crystalline Organic Molecular Materials.
3. Electronic Structure Theory: Dative Bonding.
4. Structural Studies of Biopolymers: Deaminated DNA, ADA, and PMM/PGM.
5. Astrochemistry: Nucleobase Synthesis in Interstellar Space.
6. Nucleophilic Additions to Heterocumulenes.
7. Chemistry Is in the News: Collaboration, Communication, Community and Society.

We are studying topics in organic, organometallic, and bio-organic chemistry with modern theoretical methods in combination with laboratory experimentation. Due to the computer and the information access revolutions, access to and the generation and analysis of information and data has become one of the essential aspects of being a modern scientist. We use this new degree of freedom to the fullest in research and education. Several projects are pursued in collaboration with groups elsewhere in the US and in Europe creating opportunities for student exchanges. The interdisciplinary approach to pertinent problems exposes students to a broad spectrum of diverse techniques and provides a unique preparation for careers in modern research areas positioned at the interphases between the classical disciplines.

1. DNA Base Deamination and Cross-Link Formation

Methods: Chemical & Enzymatic Synthesis, Oligonucleotide Chemistry, Non-Natural DNA Bases, Labeling Techniques (18-O, 17-O), HPLC, LC/MS, NMR Studies (1-H, 13-C, 17-O, 18-O isotopic shifts on 13-C), Covalent and Dative Bonding, Ab Initio Theory, Molecular Dynamics

We have been interested in two types of deaminations and their relation to modifications of DNA bases: The deamination of amines and their role in the alkylation of DNA and the deamination of the DNA bases guanine, cytosine and adenine. These processes lead to genomic instability. Much of our work on oxidative DNA damage has been concerned with diazonium ions. We proposed a new bonding model and have established a variety of direct links between theory and experiment. Current studies of diazonium ions focus on the mechanisms of their SN chemistry.

The possibility of pyrimidine ring-opening during the dediazoniation of guaninediazonium ion has been one of the focal points of our research. We have succeeded in the demonstration that the theoretically postulated key intermediate can form all the known products of nitrosative guanosine deamination including the dG-to-dG cross-link. This research not only explains known chemistry, but instead it suggests that chemistry not previously considered may occur in vivo.

Details of the reaction mechanism of nitrosative deamination of guanosine were investingated with 18O-labeling techniques. The number of 18O-labels in the products was determined by MS spectrometry and the locations of the labels were determined by the 18O-isotopically induced shift of the 13C-NMR signals. The [6-18O]-guanosine was prepared by enzymatic synthesis. The results firmly establish the formation of oxanosine via 5-cyanoimino-4-oxomethylene-4,5-dihydroimidazole and 5-cyanoamino-4-imidazolecarboxylic acid intermediates.

2. Polar Order in Crystalline Organic Molecular Materials

Methods: Chemical Synthesis, Crystallization, X-Ray Crystallography, Differential Scanning Calorimetry (DSC), NMR (1-H, 11-B, 13-C, 15-N, 17-O, Solution, Solid State), Raman Spectroscopy, Optical Spectroscopy (Solution, Solid State), Halogen Bonding, Arene-Arene Bonding, van der Waals Bonding, Ab Initio and DFT Theory of Molecules, Clusters, and Crystals, Structure Analysis (as in "thinking about structure")

Polar order in the biosphere is limited to nanometer-sized domains, occurs with essentially complete cancellation, or is avoided on purpose. One thus wonders whether large-scale polar order is even possible and this question is the subject of the dipole alignment problem.

We have addressed this challenge with an interdisciplinary approach bringing together elements of mathematics, electronic structure theory and computational, physical-organic and synthetic chemistry, crystallization and crystallography, and, most importantly, patience and much thought about intermolecular bonding in molecular crystals.

Our approach involves the design of beloamphiphiles that form polar 2-d layers and also stack with polarity. A perfectly ordered parallel beloamphiphile monolayer (PBAM) is shown.

We have achieved the fabrication of several classes of near-perfectly and perfectly aligned materials. Of the 15 prototypes (by 01/15/05), 8 are near-perfectly and 7 are perfectly parallel aligned! One near-perfectly and two perfectly polar crystals are shown. View the online database.

The new polar materials are ascendants of a new generation of highly anisotropic functional materials with perfect polar order. Among other classes of materials, push-push, pull-pull, and push-pull azines X-Ph-CR=N-N=CR-Ph-Y and dienes X-Ph-CR=CH-CH=CR-Ph-Y are being studied to understand and refine the design concepts. Entirely new structured, polar, and anisotropic materials are now conceivable and are being explored.

Polar order in (MeO,Br)-azine (left), (DecO,Br)-azine (center), and (PhO,Br)-azine (right). The three azines form perfectly parallel beloamphiphile monolayers and the PBAMs also stack with dipole alignment. In (MeO,Br)-azine, directed MeO...Br interlayer halogen bonding results in near-perfect dipole alignment in the stacking direction. Such RO...Br halogen bonding is impossible in the (DecO,Br)- and (PhO,Br)-azines and perfect dipole alignment results.

3. Electronic Structure Theory: Dative Bonding

Methods: Ab initio Theory, Perturbational Approaches (MP%, G1, G2, G3, G2MP2), Variational CI Methods (MCSCF, QCI, CC), Density Functional Theory (DFT), Population Analysis.

Our interest in fundamental bonding theory concerns aspects of dative bonding and analyses of energy distributions in molecules via fragment transfer energy analysis. We emphasize electron and spin density analysis in studies of bonding and analyze electronic structures in a variety of ways (multipole distributions with charges, dipole, and quadrupoles, polarizabilities, hyperpolarizabilities, ...).

Diazonium ions and diazonium ion chemistry has been at the focal point of our research on dative bonding. We developed a dative bonding model for diazonium ions and we have shown that this model is consistent with all experimental data. In particular, in 1995 we were able to explain why the rates of dediazoniation are hardly affected by the choice of the solvent. The extension of these studies lead to the conclusion that there is a non-zero solvent-independent solvent effect. This discovery had major consequences on the general theory of nucleophilic dediazoniation.

Most recently, we have been studying the mechanisms of nucleophilic substitution at heteroaromatic substrates. We have proposed that such reactions involve bimolecular processes with transition state structures of the type shown on the right for the reaction of water with benzenediazonium ion.

4. Structural Studies of Biopolymers: Deaminated DNA, ADA, and PMM/PGM.

Theoretical Methods: Molecular Mechanics, Molecular Dynamics, Force Fields, Conformational Theory, Docking.

Deaminated DNA: We are trying to understand how reactions in DNA and synthetic oligonucleotides are affected by their highly anisotropic environment. Specifically, we are interested in understanding just how the mechanism of oxanine formation in DNA differs from the reaction in homogeneous solution. Experimentally, we are determining oxanine isotropomer ratios obtained by deamination in (18O)water and by deamination of [6-18O]dG-containing synthetic oligonucleotides.

Click on the picture on the right to animate
the DNA decamer as AVI video (5.7 MB).

Adenine deaminase (ADA): We found that oxanosine is a substrate for ADA catalyzed ester hydrolysis. The reaction products derived from isotopomers of oxanosine have been identified. We are currently studying the mechanism of this enzymatic reaction.

Phosphomannomutase/Phosphoglucomutase (PMM/PGM): Pseudomonas aeruginosa, an opportunistic pathogen that amplifies cystic fibrosis, has been studied extensively, including its biosynthesis of mucus-like substances, e.g. alginate. The enzyme phosphomannomutase /phosphoglucomutase (PMM/PGM) is essential for this biosynthesis. PMM/PGM is a phosphoryl transfer enzyme that rearranges the phosphate from the 6-OH of mannose or glucose to the 1-OH. A primary research goal of the Tipton group has been the elucidation of the complete mechanism of PMM/PGM and the sequence of the mechanistic steps has been explained (Figure 1). It has been shown that the 1,6-bisphosphorylated intermediate is "flipped" within the active site without being released. This is a stunning act for an enzyme to accomplish and it is not all clear just what structural features of the enzyme provide this unique capability. We want to understand this process conceptually.
Scheme from Regni, Naught, Tipton, and Beamer J. Str. 2003, 12, 55-63.

5. Astrochemistry: Chemistry in Interstellar Space

Methods: Ab Initio Theory, Ion-Molecule Chemistry, Mass Spectrometry, Statistics, Collision Kinetics, Astrobiology.
Interdisciplinary Opportunities: MU Space Science.

The universe is 13.7 billion years old, it is flat, 4 percent of its energy is condensed into matter as we know it ("normal" matter made out of "normal" energy), 23 percent of its energy is condensed into "dark matter" (particular matter we don't know yet which is made of "normal" energy), and 73 percent is dark energy (an energy form we don't know). After "The Big Bang" and subsequent inflation, the universal expansion was slowed by gravitation, and it is the dark energy that started, some 5 billion years ago, to again accelerate the universal expansion toward the "The Big Rip". All this is known, not merely hypothesized, because of measured data from the Wilkinson Microwave Anisotropy Probe (WMAP, unevenness in the 2K background radiation) and the Sloan Digital Sky Survey (SDSS, spacial distribution of 1 million galaxies).

Of the 4 percent of normal matter, we "see" only a rather small part: Light itself, the matter in stars, and the interstellar and intergalactic stuff that interacts with light in some way (reflect, absorb, emit, redirect). The locations of hydrogen clouds are being determined via Lyman a-forest analysis. It is already clear that there is a lot more invisible matter than there is visible matter and most chemistry in the cosmos occurs in the dark and unobserved in interstellar and intergalactic clouds.

It is our hypothesis that the DNA bases can be synthesized in the interstellar medium from the materials present in any galaxy. Hence, we think that life literally everywhere can be DNA based and, with the principle of parsimony, we believe that it is. We are studying conditions that occur, especially in our own Milky Way galaxy, to try to provide evidence for our belief.

6. Nucleophilic Additions to Heterocumulenes

Methods: Experimentation, Microsolvation & Catalysis, Hydrogen Bonding, van der Waals Bonding, Pseudopericyclic Reaction Theory, Ab Initio Theory, DFT Theory

Nucleophilic additions to heterocumulenes are central in many important areas and the hydrolysis of carbon dioxide is by far the most important reaction in this group (enzymatic reaction in metabolism, greenhouse gas capture). The hydrolysis of carbodiimides is important in synthesis and in industrial applications. Additions to ketenes and ketenimines fall into this category as well and their chemistry has been well explored.

We are interested in carbon dioxide, O=C=O, and its diimide, HN=C=NH, and we are motived by a desire to learn about the latter. The HN=C=N- group may play a role in nucleophilic additions to guanine derivatives. Cyanoamimes are likely to react by way of carbodiimides using pseudopericyclic reaction channels. Most recently, we explored the synergism of catalysis and reaction center rehybridization in nucleophilic additions to carbodiimide with one, two, and three water molecules. The placement of the third water makes all the difference for the catalysis of the hydrolysis of carbodiimide. Quantum-mechanical calculations show that micro-solvation by a spectator molecule is more important than increasing the size of the proton-transfer ring.

7. Chemistry Is in the News: Collaboration, Communication, Science Community and Society

Methods: Scientific Literacy, Media Literacy, Learning Theory, Constructivist Theory, Research on Peer Review, Assessment, Information Technology, Computer-Assisted Collaboration, Computer-Mediated Communication, Scientific Writing, Philosophy of Science. IRB Certified 2003-5 and 2005-7.

Bronowski pointed out the private (independence, originality) and public (truthfulness, dissent) components of science and the need for both in the scientific society. Ziman writes that Science is Public Knowledge and that science stands in the region where the intellectual, the psychological and the sociological coordinate axes intersect. Habermas talks about the systems sphere (science, technology, corporate capitalism, bureaucracy) and the cultural sphere (private and public life, morality, culture) and the need to harmonize progress in science and technology with the cultural sphere. Successful human evolution as a collective learning device requires effort to discuss and bring about consensus about the systems sphere in the cultural sphere to guarantee democracy.

University science education largely focuses on disciplinary skill training. Making the connections to the students (psychology) and to needs of the public (sociology) either is neglected or not attempted at all. Yet, it is the complexity that comes from these connections that brings the subject to life, makes students better learners, and provides them with the abilities to become life-long learners and free citizens in a democratic society.

The Chemistry is in the News project enables students to see the connections, to understand science and its role in society, and to use this knowledge in the evaluation and in making judgements about choices presented in everyday life.