1. Advanced Pharmaceutical Analysis Nuclear Magnetic Resonance (H1 NMR)
Lecture 4 48
Advanced Pharmaceutical Analysis Nuclear Magnetic Resonance (H1 NMR)
P 105
Dr. Baraa Ramzi

2. Nuclear Magnetic Resonance
NMR can determine the number of magnetically distinct atoms being studied.
For instance, one can determine the number of hydrogen nuclei as well as obtain information regarding the environment surrounding it .
Similar information can be determined for the carbon nuclei.

3. Principle
Many atomic nuclei have a property called spin: the nuclei behave as if they were spinning.
Any atomic nucleus that possesses either odd mass, odd atomic number, or both has a quantized spin.

4. Spinning

5. Principle
A nucleus is a charged particle, and any moving charge generates a magnetic field.
A hydrogen nucleus may have a clockwise (+) or counterclockwise (−) spin
The nuclear magnetic moments (m) in the two cases are pointed in opposite directions.

6. Principle
In an applied magnetic field, all protons have their magnetic moments either aligned with the field or opposed to it.

7. Principle

8. Principle

9. Principle

10. NMR Instrument

11. Principle

12. Principle
The nuclear magnetic resonance phenomenon occurs when nuclei aligned with an applied field are induced to absorb energy and change their spin orientation.
Applying energy would induce the nuclei 2 align itself against the field

13. Principle

14. Chemical Shift and Shielding Effect
Nuclear magnetic resonance has great utility because not all protons in a molecule have resonance at exactly the same frequency.
This depends on the difference in electronic environment surrounding them.
The protons are shielded by the electrons that surround them.

15. Chemical Shift and Shielding Effect
In an applied magnetic field, the valence electrons of the protons are caused to circulate.
This circulation, called a local diamagnetic current, generates a counter magnetic field that opposes the applied magnetic

16. Diamagnetic Shielding

17. Diamagnetic Shielding

19. Tetramethylsilane
A reference compound is placed in the solution of the substance to be measured.
The standard reference substance that is used universally is tetramethylsilane, (CH3)4Si, also called TMS.
This compound was chosen because the protons of its methyl groups are highly shielded.

20. Tetramethylsilane It would mark one end of the range.
Thus, when another compound is measured, the resonances of its protons are reported in terms of how far (in Hertz) they are shifted from those of TMS.
This is known as chemical shift (δ) the unit is in ppm.

21. Chemical Shift

22. NMR Sample Tube

23. Instrumentation The Continuous-Wave Instrument.
The Pulsed Fourier Transform (FT) Instrument.

24. The Continuous-Wave Instrument
The sample cell is a small cylindrical glass tube that is suspended in the gap between two poles of the magnet.
A coil attached to a 60-MHz radiofrequency (RF) generator. The coil surrounds the sample.
This coil supplies the electromagnetic energy used to change the spin orientations of the protons

25. The Continuous-Wave Instrument
When the sample absorbs energy, the instrument responds by recording this as a resonance signal, or peak.

26. The Continuous-Wave Instrument

27. NMR Spectrum

28. The Pulsed Fourier Transform (FT) Instrument
It uses a powerful but short burst of energy, called a pulse, that excites all of the magnetic nuclei in the molecule simultaneously.
All of the H1 nuclei are induced to undergo resonance at the same time.
It saves time and increases sensitivity.

29. Chemical Equivalence Molecules giving rise to one NMR absorption peak.
All protons chemically equivalent.

30. Chemical Equivalence
Molecules giving rise to two NMR absorption peaks.
Two different sets of chemically equivalent protons

31. Chemical Equivalence
Molecules giving rise to three NMR absorption peaks.
Three different sets of chemically equivalent protons.

32. Integration
In the NMR spectrum, the area under each peak is proportional to the number of hydrogens generating that peak.
It does this by tracing over each peak a vertically rising line, called the integral, which rises in height by an amount proportional to the area under the peak.

33. Integration

34. Integration

35. Integration

36. Chemical environment & Chemical shift
Every type of proton has only a limited range of δ values over which it gives resonance.
Being attached to aromatic rings or the electronegative element such as oxygen gives rise to protons that are more deshielded.

37. Chemical environment & Chemical shift

39. Chemical Shift
The chemical shift increases as the electronegativity of the attached element increases.
The influence of the substituent drops off rapidly with distance, an electronegative element having little effect on protons that are more than three carbons distant.

40. Chemical Shift

41. Ring Current
When an aromatic ring is placed in a magnetic field, the ∏ electrons in the aromatic ring system are induced to circulate around the ring, this circulation is called a ring current.
It deshields the hydrogen atoms attached to the ring giving high chemical shift.

43. Ring Current

44. Shielding In Acetylene

45. Shielding
Protons falling within the conical areas are shielded, and those falling outside the conical areas are deshielded.

46. Shielding VS Deshielding

47. Spin-Spin Splitting
1,1,2-trichloroethane has two resonance peaks in the NMR spectrum (integral ratio of 2:1).
High-resolution NMR spectrum of this compound has five peaks: a group of three peaks (called a triplet) at 5.77 ppm and a group of two peaks (called a doublet) at 3.95 ppm.

48. 1,1,2-trichloroethane
It shows a group of doublet and a group of triplet.

49. Spin-Spin Splitting
N + 1 = Number of multiplets

50. Spin-Spin Splitting
This phenomenon, called spin-spin splitting, can be explained by the so-called n + 1 Rule.
Each type of proton senses the number of equivalent protons (n) on the carbon atom(s) next (neighbor) to the one to which it is bonded, and its resonance peak is split into (n + 1) components.

51. 1,1,2-trichloroethane

52. Ethyl Iodide (CH3CH2I)

53. Ethyl iodide (CH3CH2I)

54. 2-nitropropane

55. 2-nitropropane

56. Examples

57. Examples

58. The Origin of Spin-Spin Splitting
The hydrogen on carbon A can sense the spin direction of the hydrogen on carbon B.
In some molecules the hydrogen on carbon B has spin + (X-type molecules), in other molecules the hydrogen on carbon B has spin (Y-type molecules).
Proton A is said to be coupled to proton B.

59. The Origin of Spin-Spin Splitting
Proton A absorbs at a slightly different chemical shift value in type X molecules than in type Y molecules.
In X-type molecules, proton A is slightly deshielded, while in Y-type molecules, proton A is slightly shielded .
Because of that two absorptions of nearly equal intensity are observed for proton A.

60. The Origin of Spin-Spin Splitting

61. The Origin of Spin-Spin Splitting

62. Pascal’s Triangle
We can easily verify that the intensity ratios of multiplets derived from the n + 1 Rule follow the entries in the mathematical mnemonic device called Pascals triangle.

63. Pascal’s Triangle

64. Pascal’s Triangle
1:3:3:1
1:2:1

65. Coupling Constant
The distance between the peaks in a simple multiplet is called the coupling constant J .
The coupling constant is a measure of how strongly a nucleus is affected by the spin states of its neighbor.

66. Coupling Constant

67. Alkanes

68. Example

69. Alkenes

70. Example
Mistake

71. Shielding
Protons falling within the conical areas are shielded, and those falling outside the conical areas are deshielded.

72. Aromatic Compounds

73. Aromatic Compounds

74. Alkynes

75. Example
It is shifted upfield because of the shielding provided by the ∏ electron
It is a doublet of triplet.

76. Shielding
Protons falling within the conical areas are shielded, and those falling outside the conical areas are deshielded.

77. Alkyl Halides

78. Example

79. Alcohol

80. Example
OH can be anywhere

81. Amines

82. Amines
The position of the resonance is affected by temperature, acidity, amount of hydrogen bonding, and solvent.
In addition to this variability in position, the N-H peaks are often very broad and weak without any distinct coupling to hydrogens on an adjacent carbon atom.

83. Example

84. Aldehydes

85. Example

86. Ketones

87. Example

88. Carboxylic Acids

89. Example

90. Amides

91. Example

92. Examples