Fine Refinement of Solid-State Molecular Structures of Leu- and Met-Enkephalins by NMR Crystallography

This paper presents a methodology that allows the fine refinement of the crystal and molecular structure for compounds for which the data deposited in the crystallographic bases are of poor quality. Such species belong to the group of samples with molecular disorder. In the Cambridge Crystallographic Data Center (CCDC), there are approximately 22 000 deposited structures with an <i>R</i>-factor over 10. The powerful methodology we present employs crystal data for Leu-enkephalin (two crystallographic forms) with <i>R</i>-factor values of 14.0 and 8.9 and for Met-enkephalin (one form) with an <i>R</i>-factor of 10.5. NMR crystallography was employed in testing the X-ray data and the quality of the structure refinement. The GIPAW (gauge invariant projector augmented wave) method was used to optimize the coordinates of the enkephalins and to compute NMR parameters. As we reveal, this complementary approach makes it possible to generate a reasonable set of new coordinates that better correlate to real samples. This methodology is general and can be employed in the study of each compound possessing magnetically active nuclei

NMR Crystallography Comparative Studies of Chiral (1<i>R</i>,2<i>S</i>,3<i>R</i>,5<i>R</i>)‑3-Amino-6,6-dimethylbicyclo[3.1.1]heptan-2-ol and Its <i>p</i>‑Toluenesulfonamide Derivative

The crystal structure of (1<i>R</i>,2<i>S</i>,3<i>R</i>,5<i>R</i>)-3-amino-6,6-dimethyl-2-hydroxybicyclo­[3.1.1]­heptane <b>1</b> was determined and it is presented in reference to the structure of (1<i>R</i>,2<i>S</i>,3<i>R</i>,5<i>R</i>)-3-(<i>p</i>-tosylamino)-6,6-dimethyl-2-hydroxybicyclo­[3.1.1]­heptane <b>2</b>. ¹H and ¹³C chemical shifts parameters for both structures and for whole unit cells were calculated by using the GIPAW (gauge including projector augmented waves) method. Theoretically calculated chemical shift tensor parameters were verified by ¹³C CP MAS, 2D PASS, and ¹³C–¹H FSLG HETCOR results to obtain a full structural assignment for ¹³C and ¹H resonances in the solid-state. PISEMA MAS experiment was performed to determine the molecular dynamics of aminoalcohol <b>1</b>. The comparison of two structures, obtained after all-atom positions optimization after the GIPAW calculations, revealed small conformational differences consistent with the single-crystal X-ray diffaction results

NMR Crystallography Comparative Studies of Chiral (1<i>R</i>,2<i>S</i>,3<i>R</i>,5<i>R</i>)‑3-Amino-6,6-dimethylbicyclo[3.1.1]heptan-2-ol and Its <i>p</i>‑Toluenesulfonamide Derivative

The crystal structure of (1<i>R</i>,2<i>S</i>,3<i>R</i>,5<i>R</i>)-3-amino-6,6-dimethyl-2-hydroxybicyclo­[3.1.1]­heptane <b>1</b> was determined and it is presented in reference to the structure of (1<i>R</i>,2<i>S</i>,3<i>R</i>,5<i>R</i>)-3-(<i>p</i>-tosylamino)-6,6-dimethyl-2-hydroxybicyclo­[3.1.1]­heptane <b>2</b>. ¹H and ¹³C chemical shifts parameters for both structures and for whole unit cells were calculated by using the GIPAW (gauge including projector augmented waves) method. Theoretically calculated chemical shift tensor parameters were verified by ¹³C CP MAS, 2D PASS, and ¹³C–¹H FSLG HETCOR results to obtain a full structural assignment for ¹³C and ¹H resonances in the solid-state. PISEMA MAS experiment was performed to determine the molecular dynamics of aminoalcohol <b>1</b>. The comparison of two structures, obtained after all-atom positions optimization after the GIPAW calculations, revealed small conformational differences consistent with the single-crystal X-ray diffaction results

NMR Crystallography Comparative Studies of Chiral (1<i>R</i>,2<i>S</i>,3<i>R</i>,5<i>R</i>)‑3-Amino-6,6-dimethylbicyclo[3.1.1]heptan-2-ol and Its <i>p</i>‑Toluenesulfonamide Derivative

The crystal structure of (1<i>R</i>,2<i>S</i>,3<i>R</i>,5<i>R</i>)-3-amino-6,6-dimethyl-2-hydroxybicyclo­[3.1.1]­heptane <b>1</b> was determined and it is presented in reference to the structure of (1<i>R</i>,2<i>S</i>,3<i>R</i>,5<i>R</i>)-3-(<i>p</i>-tosylamino)-6,6-dimethyl-2-hydroxybicyclo­[3.1.1]­heptane <b>2</b>. ¹H and ¹³C chemical shifts parameters for both structures and for whole unit cells were calculated by using the GIPAW (gauge including projector augmented waves) method. Theoretically calculated chemical shift tensor parameters were verified by ¹³C CP MAS, 2D PASS, and ¹³C–¹H FSLG HETCOR results to obtain a full structural assignment for ¹³C and ¹H resonances in the solid-state. PISEMA MAS experiment was performed to determine the molecular dynamics of aminoalcohol <b>1</b>. The comparison of two structures, obtained after all-atom positions optimization after the GIPAW calculations, revealed small conformational differences consistent with the single-crystal X-ray diffaction results

A Multi-Technique Experimental and Computational Approach To Study the Dehydration Processes in the Crystals of Endomorphin Opioid Peptide Derivative

When molecular crystals undergo partial dehydration, determining the crystal contents and precise localization of the remaining water in the crystal lattice becomes challenging, especially when the quality of crystals after dehydration is not suitable for X-ray diffraction studies. In this work, we describe a methodology that allows the determination and refinement of the structures of partially dehydrated crystals employing complementary experimental (advanced solid-state NMR techniques, differential scanning calorimetry, elemental analysis) and computational (gauge-including projector-augmented wave density functional theory) techniques. We present the power of the methodology using an opioid peptide derivative, endomorphin-2-OH (EM2-OH) heptahydrate. The advanced solid state NMR techniques 2D-PASS, inv-HETCOR, and cross polarization variable contact (CP-VC) carried out with very fast magic angle spinning were used as a source of the constraints showing differences and similarities in the structures and local molecular dynamics for crystallized and dehydrated samples. A crystal structure prediction employing the gauge-including projector-augmented wave (GIPAW) method was used for the determination and refinement of dehydrated EM2-OH. After dehydration, three out of the initial seven water molecules remain in the lattice of the EM2-OH crystals, with two water molecules located in the pockets made by the pseudocyclic conformations and one forming a bridge between two independent EM2-OH molecules

Computed and Experimental Chemical Shift Parameters for Rigid and Flexible YAF Peptides in the Solid State

DFT methods were employed to compute the ¹³C NMR chemical shift tensor (CST) parameters for crystals of YAF peptides (Tyr-Ala-Phe) with different stereochemistry for the Ala residue. Tyr-d-Ala-Phe <b>1</b> crystallizes in the <i>C</i>2 space group while Tyr- l-Ala-Phe crystallizes in either the <i>P</i>2₁2₁2 space group (<b>2a</b>) or the <i>P</i>6₅ space group (<b>2b</b>). PISEMA MAS measurements for samples with a natural abundance of ¹H and ¹³C nuclei and ²H QUADECHO experiments for samples with deuterium labeled aromatic rings were used to analyze the geometry and time scale of the molecular motion. At ambient temperature, the tyrosine ring of sample <b>1</b> is rigid and the phenylalanine ring undergoes a π-jump, both rings in sample <b>2a</b> are static, and both rings in sample <b>2b</b> undergo a fast regime exchange. The theoretical values of the CST were obtained for isolated molecules (IM) and clusters employing the ONIOM approach. The experimental ¹³C δ_ii parameters for all of the samples were measured via a 2D PASS sequence. Significant scatter of the computed versus the experimental ¹³C CST parameters was observed for <b>1</b> and <b>2b,</b> while the observed correlation was very good for <b>2a</b>. In this report, we show that the quality of the ¹³C σ_ii/¹³C δ_ii correlations, when properly interpreted, can be a source of important information about local molecular motions

Understanding the Electronic Factors Responsible for Ligand Spin–Orbit NMR Shielding in Transition-Metal Complexes

The significant role of relativistic effects in altering the NMR chemical shifts of light nuclei in heavy-element compounds has been recognized for a long time; however, full understanding of this phenomenon in relation to the electronic structure has not been achieved. In this study, the recently observed qualitative differences between the platinum and gold compounds in the magnitude and the sign of spin–orbit-induced (SO) nuclear magnetic shielding at the vicinal light atom (¹³C, ¹⁵N), σ^SO(LA), are explained by the contractions of 6s and 6p atomic orbitals in Au complexes, originating in the larger Au nuclear charge and stronger scalar relativistic effects in gold complexes. This leads to the chemical activation of metal 6s and 6p atomic orbitals in Au complexes and their larger participation in bonding with the ligand, which modulates the propagation of metal-induced SO effects on the NMR signal of the LA via the Spin–Orbit/Fermi Contact (SO/FC) mechanism. The magnitude of the σ^SO(LA) in these square-planar complexes can be understood on the basis of a balance between various metal-based 5d → 5d* and 6p → 6p* orbital magnetic couplings. The large and positive σ^SO(LA) in platinum complexes is dominated by the shielding platinum-based 5d → 5d* magnetic couplings, whereas small or negative σ^SO(LA) in gold complexes is related to the deshielding contribution of the gold-based 6p → 6p* magnetic couplings. Further, it is demonstrated that σ^SO(LA) correlates quantitatively with the extent of M–LA electron sharing that is the covalence of the M–LA bond (characterized by the QTAIM delocalization index, DI). The present findings will contribute to further understanding of the origin and propagation of the relativistic effects influencing the experimental NMR parameters in heavy-element systems

Synthesis, Structure, and Local Molecular Dynamics for Crystalline Rotors Based on Hecogenin/Botogenin Steroidal Frameworks

The synthesis and solid-state characterization of a series of cyclic/acyclic molecular rotors derived from naturally occurring steroidal 12-oxosapogenins are described. The bridged molecular rotors with rigid steroidal frameworks were obtained by employing ring-closing metathesis (RCM) as a key step. The X-ray diffraction technique was employed for determination and refinement of the crystal and molecular structure of selected models giving good quality single crystals. In the case of the bridged hecogenin molecular rotor <b>11</b><i><b>E</b></i> for which poor quality crystals were obtained, an NMR crystallography approach was used for fine refinement of the structure. Solid state NMR spectroscopic techniques were applied for the study of local molecular dynamics of the featured acyclic/cyclic molecular rotors. Analysis of ¹³C principal components of chemical shift tensors and chemical shift anisotropy (CSA) as well as heteronuclear ¹H–¹³C dipolar couplings (DC) unambiguously proved that aromatic rings located in the space within the rigid steroidal framework both for cyclic and acyclic rotors are under kHz exchange regime. Experimental results were confirmed by theoretical calculations of rotation barrier on the density functional theory level. Small distinctions in the values of CSA and DC for the rotors under investigation are explained on the basis of differences in their molecular structures