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ESSENTIAL NMR EXPERIMENTS FOR EVERY ORGANIC CHEMIST

ESSENTIAL NMR EXPERIMENTS FOR EVERY ORGANIC CHEMIST. A presentation by Dr. M. Sales in the Laboratories of Prof. A. B. Charette 10 January 2005. General Outline. 1. Introduction to information that can be obtained from NMR spectroscopy.

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ESSENTIAL NMR EXPERIMENTS FOR EVERY ORGANIC CHEMIST

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  1. ESSENTIAL NMR EXPERIMENTS FOR EVERY ORGANIC CHEMIST A presentation by Dr. M. Sales in the Laboratories of Prof. A. B. Charette 10 January 2005

  2. General Outline 1.Introduction to information that can be obtained from NMR spectroscopy 2. A Diels-Alder adduct is used as an example to illustrate The various NMR experiments that can be obtained 2.1-2.3 Examples of C,H (heteronuclear) correlation experiments 2.4, 2.5 and 2.10Examples of H,H (homonuclear) correlation experiments 2.6-2.9Examples of NOE and chemical exchange experiments 3.A brief application of experiments on a precursor substrate 4.Recommended resources for a detailed INTRODUCTION to NMR Theory and Application

  3. Problems, problems

  4. 1. What information can NMR spectroscopy provide

  5. 1.1 Functional group information from Chemical Shift

  6. 1.2 Connectivity information from scalar coupling

  7. 1.3 Spatial Relationships of atoms from scalar couplings The Karplusequation relates 3JHH with the dihedral angle. 3JHHvalues are obtained from routine H NMR spectra and homodecoupling experiments. C. Altona et al Magn. Res. Chem. 1994, 32, 670 Coupling constant analysis assigns the 4,4a-syn/anti relationship

  8. 1.4 Spatial Relationships of atoms from NOE Typical usage of NOE relationships in literature to assign relative stereochemistry Arakawa, Y. et al Chem. Pharm. Bull. 2003, 51, 1015-1020 1.5 Investigation of Dynamic processes by observation of Chemical Exchange Line-broadening and coalescence of signals are routine methods to investigate Dynamics in moleculer systems. However, 1D and 2D EXSY (EXchange SpectroscopY) methods can indicate chemical exchange before line broadening occurs Perrin, C. L. and Dwyer T. J. Chem. Rev. 1990, 90, 935-967 2D EXSY of N,N-dimethylformamide

  9. 2. DA derivative used in NMR study Examples of the following NMR experiments of the DA derivative will be presented : 13C NMR DEPT HMQC HMBC 1H NMR 2D COSY 2D TOCSY 2D NOESY 1D NOE 2D ROESY homodecoupling 1D selective COSY 1D EXSY

  10. 2.1 C-13 and DEPT 7 CO

  11. 4xAr d 2.1 C-13 and DEPT Ar = one aromatic carbon # = 2xAr d # # * = Ar d # # 4 d 3 d * 2 x Ar s Ar s * * 2 x Ar d

  12. 2.1 C-13 and DEPT 1’ 6 2 5 7 2’ 2” 1” 2 x CH2Ph

  13. 2.2 HMQC 4 3 2 5 1’ 2’ 1” 2”

  14. 2.2 HMQC 1” 2” o-Ar 1’ 5 3 2’ 4 2 6

  15. 2.3 HMBC D A C Regions A, B, C and D are expanded on next slide. B

  16. 2.3 HMBC o-Ar (Bn) Unambiguous assignment of ortho-Ar to the benzylic moeity attached to C-1”. 2 6 CO CH2Ph (1”) CH2Ph (2”) Region B Region A C-2’ CH2Ph (1”) C-1” 2” 2” C-5 C-2” CH2Ph (2”) C-1’ 1” 1” CH2Ph (1”) C-2 1” 1” CH2Ph (2”) C-6 2” 2” Region C Region D Unambiguous assignment of both CH2Ph is achieved from analysis of HMBC spectrum

  17. 2.4 COSY 7 5 6 2 3 4

  18. 2.4 COSY 2 6 5 1’ 1’ 5 6 2

  19. 2.4 COSY 2’ 1’ 1” 2” 2” 1”

  20. 2.4.1 Spin system deduced from COSY

  21. 2.5 Homodecoupling Reference (Irradiate 9 ppm) 2 (4.56 ppm) 2.6, 5.5 Hz 4 (6.37 ppm) decoupled (Irradiate 6.37 ppm) reference J 2-4 = 0.5 Hz J 2-3 = 5.5 Hz J 2-1’ = 2.6 Hz decoupled

  22. 2.5 Homodecoupling Reference (Irradiate 9 ppm) 3(6.28 ppm) 1.5, 7 Hz 2(4.56 ppm) 1’(2.56 pm) 4.7, 9.5, 10 Hz Decoupled (Irradiate 4.56 ppm) reference J 1’-2 = 2.6 Hz J 2-3 = 5.5 Hz J 1’-1” = 4.7 Hz J 1’-1” = 9.5 Hz J 1’-2’ = 10 Hz J 3-5 = 1.5 Hz J 3-4 = 7 Hz decoupled

  23. 2.5.1 Analysis of coupling constants 4 possible relative configurations where dihedral angle between HC-1’ and HC-2’ is = 0 º. (J 1’-2’= 10 Hz)

  24. 2.6 2D NOESY 3 4 1’ 2’ 7 5 6 1’ 2’ Integration of NOE crosspeaks : Reference = Diagonal of protons 1’ and 2’ Integrate for 2.00 4 3 6 5 7 -1% NOE -4% NOE -3% NOE

  25. 2.6.1 Assignment of benzylic protons with the aid of NOE crosspeaks CH2Ph CH2Ph Note: No scalar couplings between 1” or 2” to any of the benzylic were observed in the COSY or homodecoupling experiments. Therefore NOE/dipolar interactions are used to assign benzylic protons 2” 1” 1” 2” 5 1’ 2’ 2 6 1’/2’-2 -4% 1’/2’-6 -7% 1”-CH2Ph -3% 1”-CH2Ph -2% 5-6 -5% CH2Ph (1”) CH2Ph (2”) 2”-CH2Ph -3% 2”-CH2Ph -3% 1”-2 -2% Note: The combined NOE between 1’,2’-6 of -7% offers further support for assigned relative configuration

  26. 2.6.2 Chemical exchange crosspeaks observed in 2-D NOESY E/Z isomerism of 3o amide

  27. 2.6.2 Chemical exchange crosspeaks observed in 2-D NOESY 2 (Z) 2 (E) These expansions of the 2-D NOESY spectrum clearly indicate that the crosspeaks correlate the proton resonances of the major conformer (E) to those of the minor conformer (Z). This establsihes the identity of the minor species in the H NMR spectrum as a conformer of the major compound and not a contaminant. 2 (E) 2 (Z) 7 (E) 7 (Z) 6 (E) 6 (Z) 2” (Z) 2” (E) 7 (Z) 2” (E) 2” (Z) 6 (Z) 7 (E) 6 (E)

  28. 2.6.3 Further support for the assigment of o-Ar (Bn) via analysis of NOE crosspeaks CH2Ph (1”) 2 o-Ar (PhCON) -0.5% -1% -1.5% region expanded

  29. 2.7 1D NOE 7 4 1.5% 3 0.5% 6 4% 5 3% 7 (Z) 4 5 8% 2 3% 3 40% Irradiation Frequency = 3 4 34% 2 9% 5 5%

  30. 2.8 2D ROESY n0 = Larmor frequency of precessing proton nucleus tc = correlation time which is dependant on solvent viscosity and moleculer weight Imax/Io represents relative maximum crosspeak signal intensity 2D NOESY c→ maximum 20%, the case for small molecules c→ 0 maximum 50%, the case for proteins o x c = 0 the crosspeak intensitiy = 0 2D ROESY c → 0 maximum 20% c →  maximum 34% Useful for molecules of intermediate molecule weight

  31. 2.8 2D ROESY Chemical exchange crosspeaks observed in 2D ROESY ROE crosspeaks detected between methyl proton 7 to protons 4 and 3 support assigned relative configuration 4 3 7 E 7 Z 7 Z 7 0.15 % ROE 7 E 0.3 % ROE Integration of NOE crosspeaks : Reference = Diagonal of protons 1’ and 2’ Integrate for 2.00

  32. 2.9 TOCSY 1” 2” 2” 5 1” 1’ 2’ B A regions A and B are expanded on next slide

  33. 2.9 TOCSY 3 1” 2” 2” 1” 4 1’ 2’ 5 7 1’ 2’ 1’ 2’ 5 1” 1” 5 2” 2” 1” 2” 1” 2” 2 Region A Region B

  34. 2.10 1D EXSY experiment 1D EXSY (EXchange SpectroscopY) uses the same pulse sequence as the 1D NOESY except that the mixing time has been optimised to observe chemical exchange. Reference (1H NMR) Expt 1 (1D EXSY) 2 (Z) 2 (E) Irradiation Frequency = Expt 2 (1D EXSY) 7 (E) 7 (Z)

  35. 3.1 Chemical exchange 7 (E) 4 (E), 4 (Z) 2 (E) 7 (Z) 3 (Z) 3 (E) 2 (Z)

  36. 3.2 1D selective COSY used for assignment of proton resonances 7 (E) 4 (E), 4 (Z) 2 (E) 7 (Z) 3 (Z) 3 (E) 2 (Z) 3 (Z) 2 (Z) Irradiation Frequency = 2 (E) 3 (E)

  37. 3.3 1D EXSY experiment These 1D EXSY experiments provide evidence that the two species observed in the H NMR spectrum are conformers. 3 (Z) 3 (E) 3 (Z) 3 (E) Irradiation Frequency = 2 (Z) 2 (E) 7 (E) 7 (Z)

  38. 4. Recommended resources for a detailed INTRODUCTION to NMR Theory and Application H. Friebolin Basic One- and Two-Dimensional NMR Sectroscopy 3rd Edition 1998 Wiley-VCH Croasmun W. R., Carlson R. M. K. Two-Dimensional NMR Spectroscopy – Applications for Chemists and Biochemists 2nd Edition 1994 VCH Publishers Sanders J. K. M. and Hunter B. K. Modern NMR spectroscopy – A Guide for Chemists 2nd Edition 1993 Oxford University Press Derome A. E. Modern NMR techniques for chemistry research 1st Edition 1987 Pergamon press Braun S., Kalinowski H.-O., Berger S. 150 and More Basc NMR Experiments – A Practical Course 2nd Edition 1998 Wiley VCH Publishers

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