NUCLEAR MAGNETIC RESONANCE

1. IB Chemistry - Option A :Modern Analytical Chemistry NUCLEAR MAGNETIC RESONANCE

2. Different Types of NMR • Electron Spin Resonance (ESR) • 1-10 GHz (frequency) used in analyzing free radicals (unpaired electrons) • Magnetic Resonance Imaging (MRI) • 50-300 MHz (frequency) for diagnostic imaging of soft tissues (water detection) • NMR Spectroscopy (MRS) • 300-900 MHz (frequency) primarily used for compound ID and characterization

3. NMR in Everyday Life Magnetic Resonance Imaging

4. NMR Spectroscopy

5. Explaining NMR UV/Vis spectroscopy Sample

6. Explaining NMR

7. Principles of NMR • Measures nuclear magnetism or changes in nuclear magnetism in a molecule • NMR spectroscopy measures the absorption of light (radio waves) due to changes in nuclear spin orientation • NMR only occurs when a sample is in a strong magnetic field • Different nuclei absorb at different energies (frequencies)

8. Bigger Magnets are Better Increasing magnetic field strength low frequency high frequency

9. Different Isotopes Absorb at Different Frequencies 2H 15N 13C 19F 1H 30 MHz 50 MHz 125 MHz 480 MHz 500 MHz low frequency high frequency

10. Which Elements or Molecules are NMR Active? • Any atom or element with an odd number of neutrons and/or an odd number of protons • Any molecule with NMR active atoms • 1H - 1 proton, no neutrons, AW = 1 • 13C - 6 protons, 7 neutrons, AW =13 • 15N - 7 protons, 8 neutrons, AW = 15 • 19F = 9 protons, 10 neutrons, AW = 19

11. NUCLEAR SPIN The nuclei of some atoms have a property called “SPIN”. These nuclei behave as if they were spinning. ….. we don’t know if they actually do spin! This is like the spin property of an electron, which can have two spins: +1/2 and -1/2 . Each spin-active nucleus has a number of spins defined by its spin quantum number, I. The spin quantum numbers of some common nuclei follow …..

12. Spin Quantum Numbers of Some Common Nuclei The most abundant isotopes of C and O do not have spin. Element1H 2H 12C 13C 14N 16O 17O 19F Nuclear Spin Quantum No1/2 1 0 1/2 1 0 5/21/2 ( I ) No. of Spin 2 3 0 2 3 0 6 2 States Elements with either odd mass or odd atomic number have the property of nuclear “spin”. The number of spin states is 2I + 1, whereI is the spin quantum number.

13. THE PROTON Although interest is increasing in other nuclei, particulary C-13, the hydrogen nucleus (proton) is studied most frequently, and we will devote our attention to it first.

14. NUCLEAR SPIN STATES - HYDROGEN NUCLEUS The spin of the positively charged nucleus generates a magnetic moment vector, m. m + + The two states are equivalent in energy in the absence of a magnetic or an electric field. m + 1/2 - 1/2 TWO SPIN STATES

15. THE “RESONANCE” PHENOMENON absorption of energy by the spinning nucleus

16. N w Nuclei precess at frequency w when placed in a strong magnetic field. RADIOFREQUENCY 40 - 600 MHz hn NUCLEAR MAGNETIC RESONANCE If n = w then energy will be absorbed and the spin will invert. NMR S

17. Absorbance Typical 1H NMR Spectrum

18. CLASSICAL INSTRUMENTATION

19. NMR Magnet

20. NMR Magnet Cross-Section Sample Bore Cryogens Magnet Coil Magnet Legs Probe

21. IN THE CLASSICAL NMR EXPERIMENT THE INSTRUMENT SCANS FROM “LOW FIELD” TO “HIGH FIELD” LOW FIELD HIGH FIELD NMR CHART increasing Bo DOWNFIELD UPFIELD scan

22. NMR Spectrum of Phenylacetone NOTICE THAT EACH DIFFERENT TYPE OF PROTON COMES AT A DIFFERENT PLACE - YOU CAN TELL HOW MANY DIFFERENT TYPES OF HYDROGEN THERE ARE

23. The Composite FID is Transformed into a classical NMR Spectrum :

24. INTEGRATION

25. NMR Spectrum of Phenylacetone Each different type of proton comes at a different place . You can tell how many different types of hydrogen there are in the molecule.

26. INTEGRATION OF A PEAK Not only does each different type of hydrogen give a distinct peak in the NMR spectrum, but we can also tell the relative numbers of each type of hydrogen by a process called integration. Integration = determination of the area under a peak The area under a peak is proportional to the number of hydrogens that generate the peak.

27. Benzyl Acetate The integral line rises an amount proportional to the number of H in each peak METHOD 1 integral line integral line simplest ratio of the heights 55 : 22 : 33 = 5 : 2 : 3

28. Benzyl Acetate (FT-NMR) Actually : 5 2 3 21.215 / 11.3 = 1.90 33.929 / 11.3 = 3.00 58.117 / 11.3 = 5.14 METHOD 2 assume CH3 33.929 / 3 = 11.3 digital integration Integrals are good to about 10% accuracy. Modern instruments report the integral as a number.

29. CHEMICAL SHIFT

30. PEAKS ARE MEASURED RELATIVE TO TMS Rather than measure the exact resonance position of a peak, we measure how far downfield it is shifted from TMS. reference compound tetramethylsilane “TMS” Highly shielded protons appear way upfield. TMS Chemists originally thought no other compound would come at a higher field than TMS. shift in Hz downfield n 0

31. HIGHER FREQUENCIES GIVE LARGER SHIFTS The shift observed for a given proton in Hz also depends on the frequency of the instrument used. Higher frequencies = larger shifts in Hz. TMS shift in Hz downfield n 0

32. THE CHEMICAL SHIFT The shifts from TMS in Hz are bigger in higher field instruments (300 MHz, 500 MHz) than they are in the lower field instruments (60 MHz, 100 MHz). We can adjust the shift to a field-independent value, the “chemical shift” in the following way: parts per million shift in Hz chemical shift = d = = ppm spectrometer frequency in MHz This division gives a number independent of the instrument used. A particular proton in a given molecule will always come at the same chemical shift (constant value).

33. HERZ EQUIVALENCE OF 1 PPM What does a ppm represent? 1 part per million of n MHz is n Hz 1H Operating Frequency Hz Equivalent of 1 ppm 1 ( ) n MHz = n Hz 60 Mhz 60 Hz 106 100 MHz 100 Hz 300 MHz 300 Hz ppm 3 2 1 0 7 6 5 4 Each ppm unit represents either a 1 ppm change in Bo (magnetic field strength, Tesla) or a 1 ppm change in the precessional frequency (MHz).

34. NMR Correlation Chart -OH -NH DOWNFIELD UPFIELD DESHIELDED SHIELDED CHCl3 , TMS d (ppm) 12 11 10 9 8 7 6 5 4 3 2 1 0 H CH2Ar CH2NR2 CH2S C C-H C=C-CH2 CH2-C- CH2F CH2Cl CH2Br CH2I CH2O CH2NO2 C-CH-C RCOOH RCHO C=C C C-CH2-C C-CH3 O Ranges can be defined for different general types of protons. This chart is general, the next slide is more definite.

35. O O O O O O O APPROXIMATE CHEMICAL SHIFT RANGES (ppm) FOR SELECTED TYPES OF PROTONS R-CH3 0.7 - 1.3 R-N-C-H 2.2 - 2.9 R-C=C-H R-CH2-R 1.2 - 1.4 4.5 - 6.5 R-S-C-H 2.0 - 3.0 R3CH 1.4 - 1.7 I-C-H 2.0 - 4.0 H R-C=C-C-H 1.6 - 2.6 Br-C-H 2.7 - 4.1 6.5 - 8.0 Cl-C-H 3.1 - 4.1 R-C-C-H 2.1 - 2.4 R-C-N-H RO-C-H 3.2 - 3.8 5.0 - 9.0 RO-C-C-H 2.1 - 2.5 HO-C-H 3.2 - 3.8 R-C-H HO-C-C-H 2.1 - 2.5 9.0 - 10.0 R-C-O-C-H 3.5 - 4.8 N C-C-H 2.1 - 3.0 O2N-C-H 4.1 - 4.3 R-C-O-H R-C C-C-H 2.1 - 3.0 11.0 - 12.0 F-C-H 4.2 - 4.8 C-H 2.3 - 2.7 R-N-H 0.5 - 4.0 Ar-N-H 3.0 - 5.0 R-S-H R-O-H 0.5 - 5.0 Ar-O-H 4.0 - 7.0 1.0 - 4.0 R-C C-H 1.7 - 2.7

36. Characteristic Chemical Shifts

37. YOU DO NOT NEED TO MEMORIZE THE PREVIOUS CHART! IT IS USUALLY SUFFICIENT TO KNOW WHAT TYPES OF HYDROGENS COME IN SELECTED AREAS OF THE NMR CHART C-H where C is attached to an electronega-tive atom CH on C next to pi bonds aliphatic C-H acid COOH aldehyde CHO benzene CH alkene =C-H X=C-C-H X-C-H 12 10 9 7 6 4 3 2 0 MOST SPECTRA CAN BE INTERPRETED WITH A KNOWLEDGE OF WHAT IS SHOWN HERE

38. Chemical Shifts • Key to the utility of NMR in chemistry • Different 1H in different molecules exhibit different absorption frequencies • Arise from the electron cloud effects of nearby atoms or bonds, which act as little magnets to shift absorption n up or down • Mostly affected by electronegativity of neighbouring atoms or groups

39. Spin-Spin Coupling • Many 1H NMR spectra exhibit peak splitting (doublets, triplets, quartets) • This splitting arises from adjacent hydrogens (protons) which cause the absorption frequencies of the observed 1H to jump to different levels • These energy jumps are quantized and the number of levels or splittings = n + 1 where “n” is the number of nearby 1H’s

40. 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 1H NMR Spectra Exhibit... • Chemical Shifts (peaks at different frequencies or ppm values) • Splitting Patterns (from spin coupling) • Different Peak Intensities (# 1H)

41. X X X X Z Z Z Z Spin-Spin Coupling H | H | H | H | C - Y C - CH C - CH2 C - CH3 J singlet doublet triplet quartet

42. Spin Coupling Intensities 1 1 1 1 2 1 1 3 3 1 1 4 6 4 1 1 5 10 10 5 1 3 3 2 1 1 11 11 Pascal’s Triangle

43. X X X Z Z Z NMR Peak Intensities Y | Y | Y | C - CH C - CH2 C - CH3 AUC = 1 AUC = 2 AUC = 3

44. DESHIELDING BY ELECTRONEGATIVE ELEMENTS

45. Substitution Effects on Chemical Shift most deshielded The effect increases with greater numbers of electronegative atoms. CHCl3 CH2Cl2 CH3Cl 7.27 5.30 3.05 ppm most deshielded -CH2-Br -CH2-CH2Br -CH2-CH2CH2Br 3.30 1.69 1.25 ppm The effect decreases with incresing distance.

46. ANISOTROPIC FIELDS DUE TO THE PRESENCE OF PI BONDS The presence of a nearby pi bond or pi system greatly affects the chemical shift. Benzene rings have the greatest effect.

47. Applications • Determination of exact structure of drugs and drug metabolites - MOST POWERFUL METHOD KNOWN • Detection/quantitation of impurities • Detection of enantiomers (shift reagents) • High throughput drug screening • Analysis/deconvolution of liquid mixtures • Water content measurement

48. NMR vs. IR • NMR has narrower peaks relative to IR • NMR yields far more information than IR • NMR allows you to collect data on solids & liquids but NOT gases • NMR is more quantitative than IR or UV • NMR samples are easier to prepare • NMR is much less sensitive than IR or UV • NMR spectrometers are very expensive

49. IR vs. NMR Absorbance