An Investigation of (1R,2S)-(-)-Ephedrine Using Solid-State Density Functional Theory and Cryogenic Terahertz Spectroscopy

Accepted in ChemPhysChem. Two important points. First, as shown in the crystal cell figure below, the low-frequency study of the ephedrine molecular solid is one that is best considered in the context of two infinite chains (red and blue) that are strongly interacting along the chain and very weakly interacting between chains. The key point is the realization that the ephedrine molecular solid is not best considered as four molecules packed into a crystal cell. The original round of mode assignments, based only in crystal cell contents, was a very complicated list of relative motions and nearly irreconcilable collisions of in- and out-of-phase motions. Thinking outside-the-unit-cell and realizing that the mode motions could be described far more easily (and logically) as chains instead of packed molecules made the final assignment and analysis of the terahertz spectrum very straightforward. The lesson is to take a good look at your molecular solid before attempting to describe the motions and consider divide-and-conquer approaches if you see correlations.

The second reason I am specifically pleased with this paper is that it is the first real terahertz study using Crystal06 that employs multiple generalized gradient approximation density functionals (BP, PBE, PW91) and basis sets (6-31G(d,p) and 6-311G(d,p)) and shows that these multiple levels of theory provide very similar results. That has, generally, NOT been the case with the many previous DMol3 studies that required difference-dipole intensity calculations instead of the use of more rigorous Wannier function-based intensities possible within the Crystal06 code.

Patrick M. Hakey, Damian G. Allis, Matthew R. Hudson, Wayne Ouellette, and Timothy M. Korter

Department of Chemistry, 1-014 Center for Science and Technology, Syracuse University, Syracuse, NY 13244-4100, USA

Abstract: The terahertz (THz) spectrum of (1R,2S)-(-)-ephedrine from 8.0 to 100.0 cm-1 has been investigated at liquid-nitrogen (78.4 K) temperature. A complete structural analysis has been performed in conjunction with a vibrational assignment of the experimental spectrum using solid-state density functional theory (DFT). In order to obtain the crystallographic lattice constants at a temperature relevant for the DFT simulations, the compound has also been characterized by cryogenic single-crystal X-ray diffraction. Theoretical modeling (solid-state and isolated-molecule) of the compound includes the use of three generalized gradient approximation density functionals (BP, PBE, PW91) and two Gaussian-type basis sets (6-31G(d,p) and 6-311G(d,p)). Assignment of the THz spectrum is performed at a PW91/6-311G(d,p) level of theory, which provides the best solid-state simulation agreement with experiment. The solid-state analysis indicates that the seven experimental spectral features observed at liquid-nitrogen temperature are comprised of 13 IR-active vibrational modes. Of these modes, nine are external crystal vibrations and provide approximately 57% of the predicted spectral intensity.

www3.interscience.wiley.com/journal/72514732/home?CRETRY=1&SRETRY=0
en.wikipedia.org/wiki/Ephedrine
en.wikipedia.org/wiki/Terahertz
www.crystal.unito.it/
en.wikipedia.org/wiki/Density_functional_theory
en.wikipedia.org/wiki/Basis_set_(chemistry)
accelrys.com/products/materials-studio/modules/dmol3.html
en.wikipedia.org/wiki/Wannier_function
chemistry.syr.edu
www.syr.edu

The Inelastic Neutron Scattering Spectrum Of Nicotinic Acid And Its Assignment By Solid-State Density Functional Theory

Accepted in Chemical Physics Letters.  What began as a reasonably straightforward inelastic neutron scattering (INS) assignment was expanded upon reviewer request to include an analysis of the potential for in-cell nicotinic acid (or niacin, depending on who you ask.   Not to be confused with this Niacin, which would be another post altogether) prototropic tautomerization (technically, one might consider this just proton migration along the chain of the nicotinic acid molecules in the solid-state, which might just be more supported as, providing the punch line early, proton migration does not seem to occur in this system), a point that was mentioned in the paper as a possibility within the crystal cell but not originally examined as part of the spectral assignment.   In the crystal cell picture shown below, tautomerization would result in proton H5 migrating to N', yielding a chain (if it propagated down the entire one-dimensional chain of nicotinic acid molecules in the solid-state) of zwitterions (molecules with both positive and negative charges on the covalent framework).   Anyone with experience in the solid-state study of amino acids knows that zwitterions are not only stable species in the solid-state, but they can also the dominant species in the solid-state, as ionic interactions and the dipole alignment that results from the alignment of, in this case, zwitterions, can yield greater stability than the neutral species, where only hydrogen bonding and dispersions forces occur in the crystal packing arrangement.

The inelastic neutron scattering assignment by solid-state density functional theory (DFT) strongly supports that, at the 25 K temperature of the neutron experiment, the crystal cell is of the neutral, non-zwitterionic form (as shown below, which labels the possible arrangements of hydrogens in the Z=4 crystal cell).  Furthermore, despite the existence of several potentially stable proton arrangements in the crystal cell (the three additional forms shown below), the nicotinic acid crystal cell seems to prefer the neutral form even through room temperature.  Fortunately, previous studies using other spectroscopic methods seem to agree.  As has been the case for the vast majority of all of the previous INS studies, the solid-state DFT calculations were performed with DMol3 and the INS simulated spectra generated with Dr. A. J. Ramirez-Cuesta's most excellent aClimax program.

As is often the case when a competent reviewer serves you a critical analysis of your submitted work, the final result is all the better for it.

Matthew R. Hudson, Damian G. Allis, and Bruce S. Hudson

Department of Chemistry, 1-014 Center for Science and Technology, Syracuse University, Syracuse, NY 13244-4100, USA

Keywords: nicotinic acid, niacin, vitamin B3, inelastic neutron scattering spectroscopy, solid-state density functional theory

Abstract: The 25 K inelastic neutron scattering (INS) spectrum of nicotinic acid has been measured and assigned by solid-state density functional theory (DFT). Vibrational mode energies involving the carboxylic acid proton are found to be significantly altered due to intermolecular hydrogen-bonding. There is good overall agreement between experiment and simulation in all regions of the spectrum, with identified deviations considered in detail by spectral region: phonon (25 – 300 cm-1), molecular (300 – 1600 cm-1), and high-frequency (>2000 cm-1). The relative energies, geometries, and vibrational spectra associated with hypothesized tautomerization in the solid-state have also been investigated.

www.elsevier.com/locate/cplett
en.wikipedia.org/wiki/Inelastic_neutron_scattering
en.wikipedia.org/wiki/Nicotinic_acid
en.wikipedia.org/wiki/Niacin
www.niacinb3.com
en.wikipedia.org/wiki/Tautomerization
en.wikipedia.org/wiki/Zwitterion
en.wikipedia.org/wiki/Amino_acids
en.wikipedia.org/wiki/Density_functional_theory
chemistry.syr.edu
www.syr.edu
www.isis.rl.ac.uk/MolecularSpectroscopy/aclimax/
accelrys.com/products/materials-studio/modules/dmol3.html

The Cryogenic Terahertz Spectrum Of (+)-Methamphetamine Hydrochloride And Assignment Using Solid-State Density Functional Theory

In press in the Journal of Physical Chemistry.  This paper on the low-frequency vibrational properties of methamphetamine marks a transitional point in the simulation of terahertz (THz) spectra by density functional theory (DFT), as both Crystal06 and Abinit provide the means to calculating infrared intensities in the solid-state by a more rigorous method than the difference-dipole method that has been used in the many previous THz papers with DMol3 (performed externally from the DMol3 program proper).  The original manuscript came back with two important comments from Reviewer 3 (that crazy Reviewer 3.  Is there nothing they'll think of to critique?).

The best-fit spectral assignment by visual inspection (BOP/DNP level of theory) and by statistical analysis (BP/DNP level of theory) are shown below (the paper, of course, contains significantly more on this point).  With these two spectral simulations in mind, Reviewer 3 presented the following analysis that I think is certainly worth considering generally to anyone new to the computational chemistry game and even by general practitioners who might risk becoming complaisant in their favorite theoretical technique.  There's a reason we refer to the collection of computational quantum chemical tools as the "approximate methods."

I have difficulty with what appears to be a generalization of the applicability of using density functional for modeling THz spectra… It is disturbing that the different functionals will generate different numbers of modes within the spectral region, and it is hard to imagine how we should move forward with density functional for calculating spectra of this type.  In fact, it is true that one needs to include the "lattice" to get the spectra right in these regions, but it is not obvious that DFT will provide the level of rigor required to develop a predictive capability. Furthermore, given the "uncertainties regarding the number of modes", is it possible that the mode assignments are invalid?

In my opinion, the authors point out the need for solid-state DFT, but should point out that in its current incarnation, that DFT is currently inadequate for quantitative comparison with experiment, and that more work needs to be done with the theory to make it quantitative.

The response to the reviewer about these points goes as such:

We agree completely with the reviewer's criticism on these points of spectral reproduction, but we also believe that there should be a sharp separation between the capabilities of the DFT formalism and the capabilities of the many empirically-derived density functionals that currently make up the complement of "tools" within the DFT formalism.  Unlike the selection of basis set, which we often presume will improve agreement because of the improvement to the description of the electronic wavefunction that comes from additional functions, it is the case (specifically among the survey studies in THz simulations performed by the authors in this and previous publications) among the currently available GGA density functionals that the reproduction of the physical property under consideration is determined by the functional.  We also know that the reproduction of the lowest-energy solid-state vibrational features in molecular solids were NOT part of the initial complement of metrics used in gauging the accuracy of density functionals, so it is clear that we are performing survey calculations using available tools to determine which tools may be most reliably employed for performing THz assignments while not actively engaged in the development of new tools.  In the simulation of vibrational spectra, it is clear that we can never entirely trust the simulations until it is known unambiguously by experimentalists exactly what the motion associated with each vibrational mode is, which brings up the need for polarization experiments, Raman experiments to complement the mode assignments, etc.  Such rigorous detail for this region of the spectrum is very likely not known for a great many molecules of interest by the communities most interested in the benefits of THz spectroscopy.

In the meantime and in the absence of "complete datasets," we agree with all of the reviewers (to a point either addressed directly or indirectly through questions along the same vein) that the best that a theoretical survey like the one presented here can do is aid in the generation of a functional consensus view, which is something that requires mode-by-mode analyses as mentioned by the reviewer.

Patrick M. Hakey, Damian G. Allis, Wayne Ouellette, and Timothy M. Korter

Department of Chemistry, Syracuse University, Syracuse, NY 13244-4100

Abstract: The cryogenic terahertz spectrum of (+)-methamphetamine hydrochloride from 10.0 – 100.0 cm-1 is presented, as is the complete structural analysis and vibrational assignment of the compound using solid-state density functional theory. This cryogenic investigation reveals multiple spectral features not previously reported in room-temperature terahertz studies of the title compound. Modeling of the compound employed eight density functionals utilizing both solid-state and isolated-molecule methods. The results clearly indicate the necessity of solid-state simulations for the accurate assignment of solid-state THz spectra. Assignment of the observed spectral features to specific atomic motions is based upon the BP density functional, which provided the best-fit solid-state simulation of the experimental spectrum. The seven experimental spectral features are the result of thirteen infrared-active vibrational modes predicted at a BP/DNP level of theory, with more than 90% of the total spectral intensity associated with external crystal vibrations.

pubs.acs.org/journal/jpcafh
en.wikipedia.org/wiki/Methamphetamine
en.wikipedia.org/wiki/Time_domain_terahertz_spectroscopy
en.wikipedia.org/wiki/Density_functional_theory
www.physics.ohio-state.edu/~aulbur/dft.html
www.crystal.unito.it
www.abinit.org
www.somewhereville.com/?cat=8
accelrys.com/products/materials-studio/modules/dmol3.html
link.aip.org/link/?JCPSA6/110/10664/1
link.aps.org/doi/10.1103/PhysRevA.38.3098
en.wikipedia.org/wiki/Computational_chemistry
chemistry.syr.edu