ABSTRACT Predicting isotope effects using electronic structure calculations is widely done, but current software options can present a barrier for some chemists, depending upon their needs and software/programming proficiency. Building upon existing code bases, we have developed PyQuiverHS as a free web tool ( www.isotope‐effects.com ) to provide ready access to kinetic and equilibrium isotope effect (EIE) calculations employing the Bigeleisen–Mayer (B‐M) and enthalpy–entropy ( H‐S ) partition functions. A graphical user interface assists in setting up a configuration file, which contains scaling factor and isotope substitution information. After uploading the configuration file and Gaussian frequency jobs for the unlabeled system, users execute a kinetic isotope effect (KIE) or EIE calculation at a particular temperature or range of temperatures with a defined increment. Wigner and Bell tunneling corrections are provided for KIE calculations. Overall KIEs or EIEs and their contributing B‐M and H‐S terms are compiled in auto‐downloaded comma‐separated values (*.csv) and plain text files. Automating the process with PyQuiverHS is a significant gain in efficiency, as previous methods for these types of calculations have relied on spreadsheets, which require time‐intensive data manipulation. We demonstrate the utility of PyQuiverHS by calculating temperature‐dependent conformational KIEs in 9,10‐dihydro‐4,5‐dimethylphenanthrene ( 1 ), a doubly bridged biphenyl derivative ( 2 ), [2.2]‐metaparacyclophane ( 3 ), a secondary KIE for the S N 2 reaction of chloride with methyl bromide ( 4 ), and an EIE for the interconversion of chair conformations of 1,1,3,3‐tetramethylcyclohexane ( 6 ).

We have developed a set of multicolor 3D-printed molecular orbital models associated with topics taught in a second semester organic chemistry course at Pomona College. The set includes the following: (1) pi molecular orbitals (MOs) in benzene; (2) water sp- and p-type lone pair orbitals; (3) valence bond and pi-MO models of amide stability and reactivity; (4) formaldehyde (neutral, H+, and Li+ complexes) sp- and p-type lone pair and pi/pi* orbitals; (5) orbital interactions and the Burgi-Dunitz angle in a cyanohydrin transition state; (6) acetaldehyde enolate pi-MOs; (7) orbital interactions in an enolate alkylation transition state; (8) orbital interactions in a lithium enolate aldol transition state; (9) benzyne pi(HOMO) and pi*(LUMO) orbitals; (10) n-sigma* orbital interaction in the water dimer intermolecular hydrogen bond; (11) peptide alpha-helix structure and n-sigma* orbital interaction in an intramolecular i, i + 4 hydrogen bond; (12) anomeric effect (n(O)-sigma*(CO) orbital interaction) in a carbohydrate model compound. The models provide insights regarding aspects of pi molecular orbital theory, stability, reactivity, and mechanistic "arrow pushing". A hobby-grade five-color 3D fused deposition modeling (FDM) printer is used to make the models, which are sized to provide compact take-home class handouts and kits for each student. The models are fabricated with orbital bisections and text annotations to enhance information content. Student perceptions of this set of 3D-printed molecular models and their use in the classroom are generally favorable. 3D Manufacturing Format (3MF) model files are available in the Supporting Information for this article.

We have developed a set of multicolor 3D-printed structural and molecular orbital models for use in a first-semester organic chemistry course. These models provide visual and tactile insights regarding aspects of organic structure, reactivity, and mechanistic "arrow pushing". The set includes: 1. orbital models of sigma and pi bonding in methane and ethylene, 2. sigma CH-sigma*CH hyperconjugation in staggered and eclipsed ethane conformations, 3. LUMO accessibility in SN2 electrophiles and HOMO-LUMO orbital interactions in SN2 transition states, 4. E2 transition state structure and orbital interactions in beta-hydrogen removal and pi bond formation, 5. sigma CH-p C hyperconjugation in the ethyl cation, 6. transition state structure and sigma CH-p C orbital interactions in a carbocation 1,2-hydride shift, 7. late and early, respectively, Br center dot and Cl center dot H atom radical abstraction transition state structures and SOMO orbitals, 8. bromonium ion structure and LUMO orbital, 9. protonated epoxide ion and neutral epoxide structures and LUMO orbitals, 10. transition state structure and orbital interactions in a hydroboration reaction, 11. transition state structure and orbital interactions in the lithium aluminum hydride reduction of formaldehyde, and 12. pi molecular orbitals in 1,3-butadiene. The prints are made with hobby-grade 5-color 3D fused deposition modeling (FDM) printers and sized to provide compact take-home class handouts for each student or projected in-class with a document camera. Models are fabricated with orbital or electron density surface bisections and text annotations to enhance information content. Student perceptions of this set of 3D-printed molecular models are generally favorable and have improved their understanding of course materials.

A memorial tribute detailing the life and scientific accomplishments of Frank A. L. Anet, a pioneer of nuclear magnetic resonance (NMR) spectroscopy who discovered bedrock principles in organic chemistry and magnetic resonance. He was the first to show that nuclear Overhauser effects could provide structural information, significantly impacting future NMR applications. In the 1960s and 1970s, he built entire multinuclear NMR spectrometers operating as high as 396 MHz for protons, detecting nuclei inaccessible to commercial instruments, and operating at very low temperatures for studying molecular structure and dynamics. A titan of physical organic chemistry, Frank made important contributions in the areas of conformational analysis, stereochemistry, isotope effects, NMR relaxation theory, and chemical origins of life.

This report outlines an approach for preparing 5-color 3D printed plastic models of molecular orbitals and electron density surfaces using a hobby-grade 3D printer. Instructions are provided for preparing 3D orbital and electron density surface (EDS) models using solid or mesh representations in ground state and transition state structures. We show that the information content of 3D orbital and surface models can be enhanced with text annotation, bisection, strut and dashed bond placement, and composite orbital-EDS model constructions. Example prints illustrate orbital concepts in organic and inorganic chemistry, such as the ethyl cation (a-p hyperconjugation), methane (hybridization and C-H bonding), ethane (a-a* hyperconjugation in the staggered and eclipsed conformations), 2-hydroxytetrahydropyran (the anomeric effect/n-a* hyperconjugation), the water dimer (hydrogen bonding/n-a* overlap), ethylene, 1,3-butadiene, and benzene (x molecular orbitals), Re2Cl82-, and U2(COT)2 (metal-metal quadruple bonds). Transition state models illustrate orbital interactions in the SN2 reaction of cyanide with methyl, ethyl, and isopropyl chloride and in a hydroboration reaction of BH3 with propene. Composite EDS models of methyl and isopropyl chloride (for exploring their relative reactivities as SN2 electrophiles) and methylcyclohexane (visualizing 1,3-diaxial interactions) are described. Student perceptions of a multicolor 3D orbital print used in an introductory organic chemistry laboratory course are reported.

Methanol titrations of partially deuterated 1,4- and 1,3-diols dissolved in nonpolar solvents such as CD2Cl2 and benzene-d6 have provided 1H NMR measurements of OH/OD isotope shifts, diagnostic for intact intramolecular hydrogen bonds, under conditions of increasing protic solvent concentration. 1,4- and 1,3-diols with conformationally favored intramolecular OH/OH hydrogen bonds can be titrated to constant isotope shift values, albeit with variable sign, in the presence of excess methanol equivalents, providing evidence for intact intramolecular hydrogen bonds under these conditions. Conversely, the isotope shift in a 1,3-diol with a conformationally labile intramolecular hydrogen bond titrated to zero when in the presence of excess equivalents methanol, consistent with intramolecular hydrogen bond rupture under these conditions. Additionally, the titration behavior of hydroxyl chemical shifts in diols and protected derivatives has revealed significant OH/OD isotope shifts in the absence of chemical shift differences (δOHin = δOHout) that are necessary for an equilibrium isotope effect, lending evidence for an intrinsic contribution to the isotope effect. OH/OD isotope shift titration thus provides a means for understanding the origins of these isotope effects and for probing the intact or nonintact nature of intramolecular OH/OH hydrogen bonds in response to intermolecular hydrogen bonds provided by a protic solvent.

A synthesis of N-monodeuteriomethyl-2-substituted piperidines is described. An efficient and readily scalable anodic methoxylation of N-formylpiperidine in an undivided microfluidic electrolysis cell delivers methoxylated piperidine 3, which is a precursor to a N-formyliminium ion and enables C-nucleophiles to be introduced at the 2-position. The isotopically labelled N-deuteriomethyl group is installed using the Eschweiler-Clarke reaction with formic acid-d2 and unlabelled formaldehyde. Monodeuterated N-methyl groups in these molecular systems possess small isotropic proton chemical shift differences important in the investigation of molecules that are able to support long-lived nuclear spin states in solution nuclear magnetic resonance.

While endeavoring to synthesize new chlorinated ligands for ruthenium-based metathesis catalysts, the title compound dimethyl 4,5-dichlorophthalate, C10H8Cl2O4, was prepared from commercially available 4,5-dichlorophthalic acid in ∼77% yield. The title molecule, which also finds utility as a precursor molecule for the synthesis of drugs used in the treatment of Alzheimer's disease, shows one carbonyl-containing methyl ester moiety lying nearly co-planar with the chlorine-derivatized aromatic ring while the second methyl ester shows a significant deviation of 101.05 (12)° from the least-squares plane of the aromatic ring. Within the crystal, structural integrity is maintained by the concerted effects of electrostatic interactions involving the electron-deficient carbonyl carbon atom and the electron-rich aromatic ring along the a-axis direction and C—H...O hydrogen bonds between neighboring molecules parallel to b.

Monodeuterated methyl groups have previously been demonstrated to provide access to long-lived nuclear spin states. This is possible when the CH2D rotamers have sufficiently different populations and the local environment is chiral, which foments a non-negligible isotropic chemical shift difference between the two CH2D protons. In this article, the focus is on the N-CH2D group of N-CH2D-2-methylpiperidine and other suitable CH2D-piperidine derivatives. We used a combined experimental and computational approach to investigate how rotameric symmetry breaking leads to a 1H CH2D chemical shift difference that can subsequently be tuned by a variety of factors such as temperature, acidity and 2-substituted molecular groups.

The measured changes in self-diffusion of small molecules during reactions have been attributed “boosted mobility”. We demonstrate the critical role of changing concentrations of paramagnetic ions on nuclear magnetic resonance (NMR) signal intensities, which lead to erroneous measurements of diffusion coefficients. We present simple methods to overcome this problem. The use of shuffled gradient amplitudes allows accurate diffusion NMR measurements, even with time-dependent relaxation rates caused by changing concentrations of paramagnetic ions. The addition of a paramagnetic relaxation agent allows accurate determination of both diffusion coefficients and reaction kinetics during a single experiment. We analyze a copper-catalyzed azide-alkyne cycloaddition ‘click’ reaction, for which boosted mobility has been claimed. With our methods, we accurately measure the diffusive behavior of solvent, starting materials and product, and find no global increase in diffusion coefficients during the reaction. We overcome NMR signal overlap using an alternative reducing agent to improve the accuracy of the diffusion measurements. The alkyne reactant diffuses slower as the reaction proceeds, due to binding to the copper catalyst during the catalytic cycle. The formation of this intermediate was confirmed by complementary NMR techniques and density functional theory calculations. Our work calls into question recent claims that molecules actively propel or swim during reactions, and establishes that time-resolved diffusion NMR measurements can provide valuable insight into reaction mechanisms.

Secreted amyloid precursor protein-alpha (sAPPα), generated by enzymatic processing of the APP, possesses a range of neurotrophic and neuroprotective properties and plays a critical role in the molecular mechanisms of memory and learning. One of the key active regions of sAPPα is the central APP domain (E2) that contains within it the tripeptide sequence, RER. This sequence is exposed on the surface of a coiled coil substructure of E2. RER has by itself displayed memory-enhancing properties, and can protect newly formed engrams from interference in a manner similar to that displayed by sAPPα itself. In order to determine whether RER mimics other properties of sAPPα, we investigated the electrophysiological effects of the N-terminal protected acetylated RER (Ac-RER) and an isoform containing a chiral switch in the first amino acid from an l- to a d-orientation (Ac-rER), on synaptic plasticity. We found that, like sAPPα, exogenous perfusion with nanomolar concentrations of Ac-RER or Ac-rER enhanced the induction and stability of long-term potentiation (LTP) in area CA1 of rat and mouse hippocampal slices, in a protein synthesis- and trafficking-dependent manner. This effect did not occur with a control Ac-AAA or Ac-IFR tripeptide, nor with a full-length sAPPα protein where RER was substituted with AAA. Ac-rER also protected LTP against amyloid-beta (Aβ25 - 35)-induced LTP impairment. Our findings provide further evidence that the RER-containing region of sAPPα is functionally significant and by itself can produce effects similar to those displayed by full length sAPPα, suggesting that this tripeptide, like sAPPα, may have therapeutic potential.

The singlet state of nuclear spin-1/2 pairs is protected against many common relaxation mechanisms. Singlet order, which is defined as the population difference between the nuclear singlet and triplet states, usually decays more slowly than the nuclear magnetization. Nevertheless, some decay mechanisms for nuclear singlet order persist. One such mechanism is called scalar relaxation of the second kind (SR2K) and involves the relaxation of additional nuclei ("third spins") which have scalar couplings to the spin-1/2 pair. This mechanism requires a difference between the couplings of at least one third spin with the two members of the spin-1/2 pair, and depends on the longitudinal relaxation time of the third spin. The SR2K mechanism of nuclear singlet relaxation has previously been examined in the case where the relaxation rate of the additional spins is on the time scale of the nuclear Larmor frequency. In this paper, we consider a different regime, in which the longitudinal relaxation of the third spins is on a similar time scale to the J-coupling between the members of the spin pair. This regime is often encountered when the spin-1/2 pair has scalar couplings to nearby deuterium nuclei. We show that the SR2K mechanism may be suppressed in this regime by applying a radiofrequency field which is resonant either with the members of the spin pair, or with the third spins. These phenomena are analyzed theoretically and by numerical simulations, and demonstrated experimentally on a diester of [13C2, 2H2]-labeled fumarate in solution.

ABSTRACT A range of nuclear magnetic resonance spectroscopy and imaging applications are limited by the short lifetimes of magnetisation in solution. Long-lived states, which are slowly relaxing configurations of nuclear spins, have been shown to alleviate this limitation. Long-lived states have decay lifetimes significantly exceeding the longitudinal relaxation time , in some cases by an order of magnitude. Here we present an experimental case of a long-lived state for a 15N labelled molecular system in solution. We observe a strongly biexponential decay for the long-lived state, with the lifetime of the slowly relaxing component exceeding 40 minutes, ∼21 times longer than the spin-lattice relaxation time . The lifetime of the long-lived state was revealed by using a dedicated two-field NMR spectrometer capable of fast sample shuttling between high and low magnetic fields, and the application of a resonant radiofrequency field at low magnetic field. The relaxation characteristics of the long-lived state are examined. GRAPHICAL ABSTRACT

The origin of equilibrium isotope effects in 2,4- and 2,6-dihydroxybenzaldehyde is discussed.

An enthalpy-entropy approach to analyzing a rate-slowing conformational kinetic isotope effect (CKIE) in a deuterated doubly-bridged biaryl system is described. The computed isotope effect (k(H)/k(D) = 1.075, 368 K) agrees well with the measured value (k(H)/k(D) = 1.06, 368 K). The rate-slowing (normal isotope effect) nature of the computed CKIE is shown to originate from a vibrational entropy contribution defined by the twenty lowest frequency normal modes in the ground state and transition state structures. This normal entropy contribution is offset by an inverse vibrational enthalpy contribution, which also arises from the twenty lowest frequency normal modes. Zero point vibrational energy contributions are found to be relatively small when all normal modes are considered. Analysis of the H-ZPE, H-vib, and S-vib energy terms arising from the low frequency vibrational modes reveals their signs and magnitudes are determined by larger vibrational energy differences in the labeled and unlabeled ground state structures. (C) 2018 Elsevier Ltd. All rights reserved.

(−)‐Sparteine (1) and (−)‐(α)‐isosparteine (2) are members of the lupine alkaloid family. Sparteine has found extensive use in asymmetric organic transformations, including lithiations and Pd‐catalyzed oxidations. (α)‐Isosparteine, which can be made from sparteine, has been utilized as a chiral ligand for a limited number of stereoselective reactions. The two compounds differ in that 1 displays an exo–endo arrangement of the bridgehead hydrogens at C‐11 and C‐6, respectively, while 2 retains an exo–exo arrangement of these atoms (Figure 1). This study is focused on assigning H chemical shifts and coupling constants and C chemical shifts for N‐Methyl derivatives of sparteine and isosparteine, both of which have been fully characterized by X‐ray crystallography. X‐ray analysis of (N‐Methyl)‐(−)‐sparteinium iodide (3) revealed a chair‐chair‐boat‐chair conformation (Figure 1), and its H and C NMR chemical shift assignments were reported by Duddeck and coworkers in 1995. An X‐ray analysis of (N‐Methyl)‐(α)‐ isosparteinium iodide (4) showed an all‐chair conformation in which the N‐CH3 group is positioned in close proximity to the transannular nitrogen lone pair, resulting in a NCH•••N hydrogen bond. Our group has harnessed the bridging geometry in 4 with an equilibrium isotope effect to investigate H and H chemical shift differences in (N‐CH2D) and (N‐CHDT) isotopologs. Simeonov, Duddeck, and coworkers have previously reported H and C NMR chemical shift assignments for 4 dissolved in DMSO‐d6. [16] We noticed discrepancies between our H and C assignments for 3 and 4 and values reported in the earlier studies. This was especially true for the H data for 4, where 16 out of 27 assignments differ from the previously reported values. Spectral assignments for 3 and 4 are also compared with quantum‐mechanically computed C and H NMR chemical shifts to further validate the assignments reported here.

Applied Theoretical Organic Chemistry, pp. 403-450 (2018) No AccessChapter 14: Spreadsheet-Based Computational Predictions of Isotope EffectsO. Maduka Ogba, John D. Thoburn, and Daniel J. O'LearyO. Maduka OgbaDepartment of Chemistry, Pomona College, USA, John D. ThoburnDepartment of Chemistry, Randolph-Macon College, Ashland, VA, 23005, USA, and Daniel J. O'LearyDepartment of Chemistry, Pomona College, USAhttps://doi.org/10.1142/9781786344090_0014Cited by:0 PreviousNext AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsRecommend to Library ShareShare onFacebookTwitterLinked InRedditEmail Abstract: The following sections are included: Historical perspective and motivation General steps for calculating isotope effects Secondary KIEs in the C–N rotation in formamide: A detailed case study Applications of isotope effects in the literature Practical advice References FiguresReferencesRelatedDetails Applied Theoretical Organic ChemistryMetrics History PDF download

We have recently shown that the small proton chemical shift difference in 2-methyl-1-(methyl-d)piperidine supports a long-lived nuclear spin state. To identify additional candidate molecules with CH2D groups exhibiting accessible long-lived states, and to investigate the factors governing the magnitude of the shift differences, we report a computational and experimental investigation of methyl rotational equilibria and proton chemical shifts in a variety of 2-substituted 1-(methyl-d)piperidines. The polarity and size of the 2-substituent affect the 1,2-stereoisomeric relationship, and consequently, the strength of the rotational asymmetry within the CH2D group. Nonpolar and large 2-substituents prefer the equatorial position, and relatively large shift differences (i.e., > 13 ppb) are observed. Polar and small substituents, however, increasingly prefer the axial position, and medium to small shift differences (i.e., 0 to 9 ppb) are observed. In addition, the diastereotopic CH2D proton chemical shift difference for tricarbonyl(1-chloro-2-deuteriomethylbenzene) chromium(0) was computed, showing that reasonable predictions of these small shift differences can be extended to more complex, organometallic species.