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Nuclear Magnetic Resonance 2

Nuclear Magnetic Resonance 2. Lecture Date: February 13 th , 2008. Selected Applications of NMR. Structural analysis Stereochemical and conformational analysis Quantitative analysis Solid-state analysis. NMR Experiments. NMR experiments fall into some basic categories:

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Nuclear Magnetic Resonance 2

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  1. Nuclear Magnetic Resonance 2 Lecture Date: February 13th, 2008

  2. Selected Applications of NMR • Structural analysis • Stereochemical and conformational analysis • Quantitative analysis • Solid-state analysis

  3. NMR Experiments • NMR experiments fall into some basic categories: • Basic pulse methods • Single pulse • Selective pulse or selective decoupling • Solvent suppression • 2D and multi-dimensional experiments • unravel complex spectra by separation of overlapping signals, control of “mixing” between signals (to obtain more data) • Multiple resonance (heteronuclear techniques) • Are often 2D or nD sequences • Diffusion, dynamics and relaxation experiments

  4. Common Solution-state NMR Experiments for Organic Structural Analysis

  5. Pulse Sequences • Modern NMR involves flexible spectrometers that can implement pulse sequences, which are designed to extract and simplify relevant information for the spectroscopist • Designed to harness a property or properties of the nuclear spin Hamiltonians • J-coupling • Chemical shift • Quadrupolar coupling • Dipolar coupling • Or, are designed to measure a bulk effect • Relaxation • Diffusion • Chemical exchange or dynamics

  6. An Example of 1D NMR Top – 1H spectrum Middle – Selective pulse Bottom – homonuclear decoupling

  7. Structural Analysis – 13C NMR and Editing 13C spectra of cholesteryl acetate: (a) continuous 1H decopling (b) 1H during acquisition (no NOE) (c) GASPE (APT) (d) DEPT-135

  8. Preparation Multi-dimensional NMR Can include NOE or J-coupling mixing • The general scheme of 2D and multi-dimensional NMR: Evolution (t1) Mixing (tm) Detection (t2) Experiment Time • 2D NMR data has two frequency dimensions: FT(t1) FT(t2)

  9. A Simple 2D NMR Spectrum 1 Cross peak (“correlation”) 2 F1 (ppm) 3 4 Diagonal Peak 5 5 4 3 2 1 F2 (ppm)

  10. An Example of 2D NMR – the COSY Experiment Correlations are observed between J-coupled protons! (Example is a sample of sucrose in D2O)

  11. Structural Analysis: 1H –13C Correlation The 1H-13C HSQC analysis of clarithromycin:

  12. Structural Analysis: Long-range 1H –13C Correlation The 1H-13C HMBC analysis of carvedilol:

  13. Structural Analysis: 1H –15N Correlation The 1H-15N long-range HMQC analysis of telithromycin:

  14. Determination of Relative Stereochemistry NOE difference spectroscopy

  15. Determination of Absolute Stereochemistry Remember the ring current effect? shielding (opposes field) deshielding (aligned with field) J. A. Dale and H. S. Mosher, J. Am. Chem. Soc., 95, 512-519 (1973). C. E. Johnson and F. A. Bovey, J. Chem. Phys., 29, 1012 (1958).

  16. Determination of Absolute Stereochemistry by Mosher-Dale Method • Procedure: Derivatize a chiral alcohol with MPTA, -methoxy-- (trifluoromethyl)phenyl acetic acid • Because a phenyl group’s deshielding effects drop off more rapidly with distance than its shielding effects, protons close to a phenyl should be more shielded! • Example: 5-nitro-2-pentanol J. A. Dale and H. S. Mosher, J. Am. Chem. Soc., 95, 512-519 (1973). A. Guarna, E. O. Occhiato, L. M. Spinetti, M. E. Vallecchi, and D. Scarpi, Tetrahedron, 51, 1775-1788 (1995).

  17. 19F Quantitative Analysis: TFA Salt Stoichiometry

  18. Solid-state Nuclear Magnetic Resonance Field = B0 No field • NMR in solids, like solution-state, relies on the behavior of nuclear spin energy levels in a magnetic field. However, the interactions that affect NMR spectra act differently. • In liquids, molecules reorient and diffuse quickly, leading to narrow isotropic resonances. • In solids, the fixed orientation of individual crystallites leads to a range of resonance frequencies for anisotropic interactions. m=-1/2 E E=(h/2)B0 m=+1/2

  19. Solid-state NMR: Magic-Angle Spinning • The following anisotropic interactions are dependent on their orientation with respect to the large magnetic field (B0): • dipolar (homo- and heteronuclear) coupling • 1st-order quadrupolar coupling • anisotropic chemical shift • These can be averaged away over time by spinning at a root of the scaling factor: • The result of magicangle spinning (often combined with dipolar decoupling): E. R. Andrew, A. Bradbury, and R. G. Eades, Nature, 183, 1802 (1959). I. J. Lowe. Phys. Rev. Lett. 2, 285 (1959).

  20. 90 CW Decoupling CP 1H CP 13C Cross-Polarization • Cross-polarization is an example of a double resonance experiment • Two resonances, typically two different nuclei, are excited in a single experiment. • Cross-Polarization combined with MAS (CP-MAS): • Enhancement of signal from “sparse” spins via transfer of polarization from “abundant” spins • The “Hartmann-Hahn condition” allows for efficient energy transfer between the two spins, usually via dipolar interactions • The basic CP pulse sequence for 1H to 13C experiments: E. O. Stejskal and J. D. Memory. “High Resolution NMR in the Solid State,” Oxford University Press, New York (1994). A. Pines, M. G. Gibby and J. S. Waugh. J. Chem. Phys., 59, 569 (1973).

  21. An Example: Polymorphism in Carvedilol • 13C CP-TOSS spectra of the polymorphs of SKF105517 free base • Amorphous forms generally give broadened spectra

  22. An Example: Polymorphism in Carvedilol • 15N SSNMR spectroscopy also shows similar effects. • Advantages: simple and easy-to-interpret spectra, valuable information about the nitrogen chemical environment • Disadvantage: much lower sensitivity

  23. LC-SPE-NMR for Impurity Analysis LC separation and solid-phase extraction (SPE) concentration

  24. Magnetic Resonance Imaging • The basic idea: a linear magnetic field gradient imposes a linear spread of Larmor frequencies on a sample. Gradient Figure from S. W. Homans, A Dictionary of Concepts in NMR, Oxford, 1989. For more details, see P. G. Morris, NMR Imaging in Medicine and Biology, Oxford University Press, 1986.

  25. Magnetic Resonance Force Microscopy • A “combination” of AFM and EPR/NMR • Uses a nano-scale cantilever to detect spin motion induced by RF via in an magnetic field Rugar, D.; et al. Nature 2004, 430, 329–332. R. Mukhopadhyay, Anal. Chem. 2005, 449A-452A.

  26. Nuclear Spin Optical Rotation (NSOR) • Measures NMR signals by detecting phase shifts induced in a laser beam as a the beam passes through a liquid • Gives excellent spatial resolution • Currently lacks sensitivity • Developed by Romalis group at Princeton Nature 2006, 442, 1021

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