Natural Abundance 14N and 15N Solid-State NMR Studies of Organic, Biochemical, and

367 Pages·2017·16.61 MB·English

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Electronic Theses and Dissertations Theses, Dissertations, and Major Papers
2016
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Stanislav L. Veinberg
University of Windsor
Follow this and additional works at: https://scholar.uwindsor.ca/etd
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Veinberg, Stanislav L., "Natural Abundance 14N and 15N Solid-State NMR Studies of Organic,
Biochemical, and Pharmaceutical Systems" (2016). Electronic Theses and Dissertations. 5771.
https://scholar.uwindsor.ca/etd/5771
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Natural Abundance 14N and 15N Solid-State NMR Studies of
Organic, Biochemical, and Pharmaceutical Systems

by
Stanislav L. Veinberg

A Dissertation
Submitted to the Faculty of Graduate Studies
through the Department of Chemistry and Biochemistry
in Partial Fulfilment of the Requirements for
the Degree of Doctor of Philosophy at the
University of Windsor

Windsor, Ontario, Canada
2016
© 2016 Stanislav L. Veinberg
“Natural Abundance 14N and 15N Solid-State NMR Studies of Organic,
Biochemical, and Pharmaceutical Systems”
by
Stanislav L. Veinberg
APPROVED BY:
D. Bryce, External Examiner
University Of Ottawa
W. Kedzierski
Department of Physics
S. Johnson
Department of Chemistry & Biochemistry
S. Loeb
Department of Chemistry & Biochemistry
R. Schurko, Advisor
Department of Chemistry & Biochemistry
April 20, 2016
Declaration of Co-authorship / Previous Publications
This thesis is presented in manuscript format, as outlined in the guidelines set
forth by the Faculty of Graduate Studies. Chapter 3 of this dissertation was published in
a peer-reviewed journal where I was the primary author:
Chapter 3: Veinberg, S.L., Friedl, Z.W., Harris, K.J., O’Dell, L.A., and Schurko,
R.W. Ultra-wideline 14N Solid-State NMR as a Method of Differentiating
Polymorphs: Glycine as a Case Study. CrystEngComm. 2015, 17, 5225–
5236. DOI: 10.1039/C5CE00060B.

I am also the primary author on Chapters 2, 5, and 6, which are planned for
submission for publication.
Chapter 4 of this dissertation was a joint effort (vide infra) and was published in a
peer reviewed journal where I was the second author:
Chapter 4: Harris, K.J., Veinberg, S.L., Mireault, C.R., Lupulescu, A., Frydman, L.,
and Schurko, R.W. Rapid Acquisition of 14N Solid-State NMR Spectra
Using Broadband Cross Polarization. Chem. Eur. J. 2013, 19, 16469-
16475. DOI: 10.1002/chem.201301862.

I certify that I have obtained a written permission from the copyright owner(s) to
include the above published material(s) in my thesis. I certify that the above material
describes work completed during my registration as a graduate student at the University
of Windsor.
I acknowledge my supervisor, Professor Robert W. Schurko, as a co-author on
this work (the dissertation), who made key contributions to writing and editing of all
manuscripts. I hereby declare that this thesis incorporates material that is a result of joint
research, as follows:
Chapter 2, “14N Solid-State NMR of Amino Acids,” includes contributions from
Zachary W. Friedl, a former undergraduate student in our research group who assisted
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with sample preparation, acquisition of NMR spectra, and DFT calculations; Austin W.
Lindquist, an undergraduate student in our research group who assisted with
computational data analysis and the preparation of tensor figures, and Brianna M. Kispal,
a former undergraduate student in our research group who assisted in data organization.
Kris J. Harris, a former post-doctoral fellow in our group, and Luke A. O’Dell assisted
with the acquisition of high-field experiments.
Chapter 3, “Ultra-wideline 14N Solid-State NMR as a Method for Differentiating
Polymorphs: Glycine as a Case Study,” includes contributions from Zachary W. Friedl,
who assisted with the polymorph synthesis, sample preparation, acquisition of NMR
spectra, and DFT calculations.
Chapter 4, “Rapid Acquisition of 14N Solid-State NMR Spectra Using Broadband
Cross Polarization,” was a collaborative effort with Kristopher J. Harris. Christopher R.
Mireault acquired the direct-excitation spectrum of isoxsuprine HCl. I performed the
remainder of the data acquisition with occasional assistance from Kris J. Harris. I also
performed the majority of data processing and prepared all of the figures for publication.
I also made significant intellectual contributions during the writing and editing process.
Although my contributions to this manuscript were equal to those of Kris J. Harris,
assigning equal author contribution was not an available option during the submission
process. In regard to this, I have obtained the appropriate permissions from all involved
parties to use this publication in this dissertation.
Chapter 5, “Practical Considerations for the Acquisition of Ultra-Wideline 14N
NMR Spectra,” has contributions from Austin W. Lindquist, and Michael J. Jaroszewicz,
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a former M.Sc. student in our research group. Both assisted with the SIMPSON
simulations.
Chapter 6, “Natural Abundance 14N and 15N Solid-State NMR of Pharmaceuticals
and their Polymorphs,” was a collaborative effort with Karen E. Johnston, a former post-
doctoral fellow in our lab, and with Takeshi Kobayashi and Marek Pruski of the Ames
Lab at Iowa State University. Takeshi Kobayashi assisted with the acquisition of the
1H{15N}idHETCOR spectra and their processing, and acquired the 15N DNP spectra.
Karen E. Johnston acquired the 1H{15N}idHETCOR spectra and assisted with the
acquisition of the 14N SSNMR powder patterns. Karen E. Johnston also made invaluable
contributions to the writing of the manuscript. Christopher R. Mireault prepared the
bupivacaine HCl polymorphs, Brianna M. Kispal assisted with data organization, and
Michael J. Jaroszewicz provided intellectual contributions.
I am aware of the University of Windsor Senate Policy on Authorship and I affirm
that I have acknowledged the contribution of other individuals to my thesis, and I have
obtained permission from each of the co-authors to include the aforementioned material
in my thesis. I certify that the previously mentioned material describes work completed
during my registration as a graduate student at the University of Windsor.
I declare that, to the best of my knowledge, my thesis does not infringe upon
anyone’s copyright nor violate any proprietary rights and that any ideas, techniques,
quotations, or any other material from the work of other people included in my thesis,
published or otherwise, are fully acknowledged in accordance with the standard
referencing practices. Furthermore, to the extent that I have included copyrighted
material that surpasses the bounds of fair dealing within the meaning of the Canada
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Copyright Act, I certify that I have obtained a written permission from the copyright
owner(s) to include such material(s) in my thesis.
I declare that this is a true copy of my thesis, including any final revisions, as
approved by my thesis committee and the Graduate Studies office, and that this thesis has
not been submitted for a higher degree to any other University or Institution.
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Abstract
Nitrogen is an important element in all areas of chemistry, biology, and materials
science. However, it is challenging to probe directly with solid-state nuclear magnetic
resonance (SSNMR). The commonly studied isotope, 15N (nuclear spin, I, = ½), has a
low natural abundance (0.36%); therefore, 15N NMR experiments often require
isotopically enriched samples. 14N (I = 1) has a high natural abundance (99.64%) but is a
quadrupolar nucleus. 14N SSNMR spectra are generally very broad due to the moderate
quadrupole moment of 14N. Ultra-wideline (UW) 14N SSNMR spectra have very low
signal-to-noise, which complicates their acquisition; however, they are useful probes of
molecular-level structure and dynamics, and do not require isotopic enrichment for their
acquisition.
This dissertation focuses on developing and applying direct-detection techniques
for the acquisition of UW 14N SSNMR powder patterns. These techniques have been
studied from both empirical and theoretical points of view and are facile to implement on
modern NMR consoles.
First, we present a 14N SSNMR study of sp3-hybridized nitrogen moieties in
amino acids and related derivatives. 14N NMR powder patterns were acquired in
relatively short experimental times using moderate field strengths (e.g., 9.4 T), and from
these, the 14N quadrupolar parameters were determined. The 14N electric field gradient
(EFG) tensors are extremely sensitive to intermolecular hydrogen-bonding, and in
conjunction with plane-wave density functional theory calculations, correlations are
found between these tensors and nitrogen structural environments. Second, 14N SSNMR
was applied for the differentiation of polymorphs of glycine and its HCl salt. We also
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investigated the rotational dynamics of NH groups, finding that the 14N transverse
3
relaxation is dependent upon motional variation with temperature and can be exploited to
reduce the experimental times of CPMG-type 14N NMR experiments. Third, we describe
improvements in the efficiency of 14N UW SSNMR experiments by utilizing broadband
cross-polarization methods, improving the parameterization and execution of WURST
pulses, and strategically considering the appearances of 14N powder patterns. Finally, we
present a preliminary investigation of the tandem use of directly-detected 14N and
indirectly-detected 15N SSNMR for the characterization of active pharmaceutical
ingredients and their polymorphs, without isotopic enrichment.

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I would like to dedicate this work to my family and Maria for their continued support and
encouragement during my graduate studies.

In Loving Memory of Lidia Veinberg
(1954.04.23 – 2015.10.01)

несмотря на то что ты больше не с нами,
ты всегда будеш оставаться в моём сердце

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