Can you differentiate A from B using 1 H NMR in each pair?

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1 Can you differentiate A from B using 1 H NMR in each pair?

2 To be NMR active any nucleus must have a spin quantum number, different from zero (I 0) As in 1 H, the spin quantum number (I) of 13 C is 1/2 Two possible orientations of the nuclear spin in an external magnetic field.

3 Only one possible orientation under B 0 Only 13 C nuclei are NMR active Which is of low natural abundance and less sensitive than 1 H

4 DE = hgb 0 /2p Boltezman s excess for 13 C is less than that of 1 H Sensitivity is proportional to g 3 13 C/ 1 H signal intensity ratio is then (0.2514) 3 =

5 n = gb 0 /2p g 13 C = 0.25 X g 1 H DE = hgb 0 /2p B 0 (Tesla) 1 H (MHz) 13 C (MHz)

6 Signal intensity is proportional to the number of resonating nuclei Limitations: -Small NMR tube size (usually 5 mm), -Solubility of sample, -amount of sample available, -high concentration results in line broadening

7 Sensitivity can be increased slightly by lowering the temperature (relative population of the lower energy level is increased) Problems: -decrease in solubility of sample at lower temperature -Increase in viscosity results in line broadening High magnetic field results in increased sensitivity

8 DE = hgb 0 /2p Sensitivity can be enhanced by the use of stronger magnetic field 2.35T, 4.7T, 7.05T, 9.4T, 11.74T, 14.10T, 16.2, 18.4T Increasing order of sensitivity

9 Repeated recording allows the accumulation of thousands of spectra by digital computer Absorption signals are always positive, signals arising from noise vary in intensity and their sign Most noise signals will cancel each other out. This process is known as the CAT (computer-averaged transients) S/N = n 1/2, S is intensity of signal, N is the intensity of noise n is the number of scans. Recording 100 spectra of a sample will increase the signal to noise ratio 10 times

10 Continuous Wave (CW) NMR Spectrometer

11 solution of the sample in a uniform 5 mm glass tube is oriented between the poles of a powerful magnet, and is spun to average any magnetic field variations, as well as tube imperfections. Radio frequency radiation of appropriate energy is broadcast into the sample from an antenna coil (colored red). A receiver coil surrounds the sample tube, and emission of absorbed rf energy is monitored by dedicated electronic devices and a computer. An NMR spectrum is acquired by varying or sweeping the magnetic field over a small range while observing the rf signal from the sample (constant rf). An equally effective technique is to vary the frequency of the rf radiation while holding the external field constant.

12 A CW nmr spectrometer functions by irradiating each set of distinct nuclei in turn, independently. For a high resolution spectrum this must be done slowly,

13 Suppose the smallest line spacing (resolution) we would like to resolve is 1 Hz The uncertainty principle tells us: DEDt ~ h hdndt ~ h DnDt ~ 1 If Dn = 1, we need to perform the measurement during a time interval of 1 s We spend around 1 s measuring 1 Hz Sweep rate is 1Hz/s Typical width of 13 C NMR spectrum is 250 ppm which on 100 MHz is 25,000 Hz A complete scan requires 25,000 s (417 min or 7 hrs) 100 scan requires 700 hrs, 30 days!! Solution is Pulsed Fourier Transform Spectroscopy

14 Pulsed Fourier Transform Spectroscopy (Revisiting the NMR Phenomenon) n = gb 0 /2p (in cycles per second, Hz) w 0 = n2p = gb 0 (in radians per second) The frequency ω o is called the Larmor frequency. If rf energy having a frequency matching the Larmor frequency is introduced at a right angle of the external field (e.g. along the x-axis), the precessing nucleus will absorb energy and the magnetic moment will flip to its I = -1/2 state.

15 The energy difference between nuclear spin states is small and the +1/2 and -1/2 states are nearly equally populated. in a field of 2.34 T the excess population of the lower energy state is only six nuclei per million. the numerical excess in the lower energy state is sufficient for selective and sensitive spectroscopic measurements.

16 slight excess of +1/2 spin states precess randomly in alignment with the external field and a smaller population of -1/2 spin states precess randomly in an opposite alignment. An overall net magnetization therefore lies along the z-axis.

17 changes in net macroscopic magnetization occurs as energy is introduced by rf irradiation at right angles to the external field. The net magnetization shifts away from the z-axis and toward the y-axis. After irradiation the nuclear spins return to equilibrium in a process called relaxation. Short and strong rf irradiation is called PULSE.

18 Pulsed Fourier Transform Spectroscopy: Allows the possibility of extracting the complete frequency response in ONE GO Measuring all frequencies simultaneously instead of one after the other. From uncertainty principle: DEDt ~ h hdndt ~ h DnDt ~ 1 If the irradiation is applied for a time Dt, the normally monochromic irradiation is uncertain in frequency by about 1/Dt if we only apply it for Dt s Dt 1ms, corresponds to Dn = 1/10-3 s = 1000 Hz

19 By exposing the sample to a very short (10 to 100 μsec), relatively strong (about 10,000 times that used for a CW spectrometer) burst of rf energy (pulse) along the x-axis,. all of the nuclei in the sample are excited simultaneously. The overlapping resonance signals generated as the excited nuclei relax are collected by a computer and subjected to a Fourier transform mathematical analysis.

20 The rf signal emitted by the sample decays exponentially, and is called a Free Induction Decay (FID). FID signal collected after one pulse, may be stored and averaged with the FID's from many other identical pulses prior to the Fourier Transform (FT), spectra from low abundance isotopes, such as 13 C can thus be analyzed FT

21 CH 3 -CH 2 -OH 13 C peaks are not integrated

22 O Multiplicity of signals H 3 C CH 3 A m X n 1 J C,H = Hz 2 J C,H = 5.5 Hz 1 H, 13 C coupled spectrum 1 H, 13 C decoupled spectrum

23 H O H H 3 H 2 6 O CH O CH H 3 H O H H Diethyl phthalate 1 H, 13 C coupled spectrum Signal overlapping

24 1 H, 13 C decoupled spectrum H O H H 3 H 2 6 O CH O CH H 3 H O H H Diethyl phthalate Distinct peaks for different sets of Equivalent carbon atoms The intensities of quaternary carbon signals are always much lower than protonated carbon atoms.

25 FACTORS AFFECTING CHEMICAL SHIFT IN 13 C NMR s i = s dia + s para + s N s i magnetic shielding constant s dia diamagnetic shielding constant accounts for local electrons around the nucleus induced by B 0 s dia r -1 The diamagnetic term decreases with distance r between nucleus and circulating electrons. s electrons will cause stronger shielding than p electrons s dia is dominant in hydrogen with only s electrons

26 s N is anisotropic effect (most important in triple bonds) For 13 C, the paramagnetic term s para predominates. It opposes s dia and is deshielding DE = average electronic excitation energy = inverse cube of the distance between 2p electron and the nucleus Q AA number of electrons in p orbital SQ AA multiple bond contribution s para increases with a decrease in DE and the inverse cube of r

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28 O OCH 2 CH 3 OCH 2 CH 3 O p s s n

29 Increasing order of p electron density at carbon causes electron repulsion The bonding orbital expands, r increases s para decreases Carbons are more shielded.

30 Hybridization of Carbon The hybridization of carbon determines to a greater extent the range within which its 13 C signal is found. sp 3 carbons resonate at highest field (-10 to 80 ppm) followed by sp carbons (60 to 95 ppm), s N, anisotropic effect is shielding for sp carbon - sp 2 hybridized centres are low field ( ppm) Carbonyl ( ppm) The hybridization effect in 13 C NMR thus parallels the effect in 1 H NMR

31 Inductive Effect Electronegativity of substituents that are attached at the carbon atom changes the resonance frequency The effect is transmitted through bonds.

32 Effect of halogen substituents on chemical shift in n-pentane derivatives X g g These are additive parameters to values where X=H

33 The -effect increases with increasing electronegativity of the substituent (F, Cl, Br). The effect of iodine (-7.4 ppm) is an exception to the pattern. The bond polarization due to electronegative substituents should propagate along the carbon chain. However there is no correlation between the substituent electronegativities and the observed chemical shift of -and g-carbon resonance. Inductive effect decreases with inverse cube of distance and the effect should be smaller at - and g-positions. The shielding of g-position is called g-gauche effect

34 The up-field chemical shift produced by iodine and bromine atoms is called heavy atom effect. The effect increases with multiple substitution. This is attributed to increased diamagnetic shielding caused by the large number of electrons introduced by heavy atoms. Z is the atomic number r is the internuclear distance m e is the electron mass e is the electron charge

35 Steric Effect (g-gauche effect) Steric interactions arise from an overlapping of van der-waals radii of substituents which are closely spaced. The carbon atom is always shielded if substituents are introduced at the g-position. This is observed in both acyclic and cyclic systems.

36 Because of the necessity of the confirmation, this is called the g-gauche steric effect. gauche

37 Due to steric interactions, the chemical shift of the g-carbon atoms will move up-field. The nonbonding interaction causes a polarization of the C-H bonds increasing the electron densities at carbon atoms (up-field shift) H 3 C CH H 3 C 30.6 H H 20.1 H H

38 endo, endo endo, exo exo, exo g-effect is additive

39 Sterically induced up-field shift is d trans > d cis at the allylic carbon in cis and trans alkenes

40 CH 4 H 3 C CH 3 H H 3 C H CH 3 CH 3 H 3 C H CH 3 H CH 3 C 3 H 3 C CH methane primary secondary tertiary quaternary Increasing order of substitution by more electron withdrawing group causes a successive down-field shift

41 Electron deficiency at a carbon causes drastic de-shielding If the positive charge is dispersed, electron deficient carbon will be less de-shielded 248 ppm

42 Mesomeric Effect (Resonance Effect) ppm Ipso 54.8 OMe : OMe + : OMe - H + OMe H H O H H - H H

43 Mesomeric Effect (Resonance Effect) Electron releasing substituents increase electron density at ortho and para positions (shield) meta not affected Electron withdrawing substituents decrease electron density at ortho and para positions (de-shield) meta not affected

44 a,b-unsaturated Carbonyl O -carbon is de-shielded Decrease in bond order and results in shielding of the central carbon atoms

45 166.4 The carbonyl carbon of a,b-unsaturated carbonyl compounds are shielded by about 10 ppm

46 Steric Effect on Conjugation Ф is tortional angle between phenyl and carbonyl bonding Steric repulsion between alkyl groups may oppose conjugation and cancel the up-field shift characteristic of conjugated state.

47 s i = s dia + s para + s N s N neighbouring anisotropy term H 5.6 ppm H 7.3 ppm = 1.7 ppm in a 10 ppm scale % difference Important in 1 H NMR =1.5 ppm in a 200 ppm scale 0.75% difference NOT as important in 13 C NMR What would you use to differentiate alkenes from aromatics? 1 H NMR

48 Intramolecular Hydrogen Bonding chelation Intra-molecular Hydrogen bonding, carbonyl is more polarised, carbonyl carbon become more positive (De-shielded)

49 1 H NMR is of 10 ppm scale 13 C NMR is of 200 ppm scale Knowledge of the relationship between chemical shift and molecular structure is more important in 13 C NMR than in 1 H NMR. Empirical rules with substituent constants or increments are available, to help predict resonance positions of carbon atoms.

50 ALKANES Carbon is sp 3 hybridized Alkanes resonate between -10 to 80 ppm As the number of carbon substituents is increased the chemical shift move downfield. After analyses of a large number of hydrocarbons, empirical rule have been developed d k is the chemical shift of carbon of interest -2.3 chemical shift of CH 4 n kl number of carbon atoms at position l with respect to atom k A l additive shift parameter S kl steric correction parameter

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55 3,5 2,6 m C =2nI+1 I for D is 1, n=1 m =(2X1X1)+1= 3 CDCl 3 (t) 4 1,

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57 SUBSTITUTED ALKANES Substituents have influence on chemical shift. -effect correlates with substituent electronegativity -effect is much smaller and is always de-shielding but no-direct relationship with electronegativity. g-effect is shielding due to steric g-gauche interaction. To calculate the value of chemical shift position in substituted alkanes: 1)Calculate the value in the parent hydrocarbon. 2)Shift and steric correction parameters are added.

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59 CDCl 3 HO

60 (RH) chemical shift of the parent hydrocarbon

61 (parent hydrocarbon)

62 CYCLOALKANES

63 -3.8 ppm Torsional strain because of eclipsed hydrogen atoms Anisotropic effect, ring strain cause shielding

64 Hax 1 Heq 4 Hax CH 3 1 ring flip ring flip The ring inversion can be frozen out at lower temperature (-100ºC) The two different conformers can be observed separately by NMR spectroscopy. The shift parameters of substituents can be determined for each conformation Heq CH 3

65 27.60 ppm

66 ALKENES s para is important for alkenes p- p* transition occurs DE is small sp 2 hybridized centres are low field ( ppm) Electronic nature and the number of substituents attached to alkene carbon can affect the resonance frequency. Shift parameters of alkyl groups determine chemical shift position.

67 n kl number of carbon atoms at position l with respect to atom k A l additive shift parameter S kl steric correction parameter

68 +,

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70 CYCLOALKENES

71 AROMATIC COMPOUNDS Anisotropy is important in 1 H NMR Spectroscopy. In 1 H NMR Spectroscopy, aromatic protons resonate at lower field (1-2 ppm) as compared to olefinic protons. 1 H NMR is the best criteria for aromaticity. Aromatic carbons appear in the same region as those of olefinic carbons. Generally between 100 and 150 ppm. On attachment of electron-withdrawing and electronreleasing substituents, the shift may extend, to ppm.

72 Factors affecting the chemical shift position of aromatic compounds: 1)Mesomeric effect (resonance) 2)Inductive effect 3)Field effect (arising from through-space polarization of p-system by the electric field of a substituent 4)Steric (g) effect on the ortho-carbon nuclei. 5)Anisotropic effect of triple bonds (alkynyl and cyano) on ipso carbon 6)Heavy atom effect which is shielding.

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74 Mesomeric Effect (Resonance Effect) Electron releasing substituents increase electron density at ortho and para positions (shield) meta not affected Electron withdrawing substituents decrease electron density at ortho and para positions (de-shield) meta not affected

75 CH ppm meta ortho Hyperconjugation (shielding at ortho & para) -effect (de-shielding) at ortho ipso para Ar-CH 3

76 Resonance (shielding at ortho & para) g-effect (shielding at ortho) meta para ortho O CH H OCH 3 ipso

77 Resonance (de-shielding at ortho & para) CHO ortho meta para ipso H O H Field effect (shielding at ortho)

78 H O N + O H I Heavy atom effect High electron density at oxygen will force the bonding electron density towards the carbon atom and shielding the ortho-carbon atoms (field effect).

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82 Polyaromatic Compounds An increase in conjugation will decrease the p-bond order of a double bond, will result in a shift towards low frequency

83 CARBONYL COMPOUNDS Absorb in the characteristic region of ppm. Substituents at carbonyl influence resonances. Aldehydes and ketones resonate at low field (between ppm) due to structure B. Carboxylic acids and derivatives (including amides) appear at higher field ( ppm) due to structure B.

84 O O C + Electron density at the carbonyl carbon has increased, shift towards higher field due to resonance The introduction of a second double bond causes further shift towards higher field

85 C=O in ketones appear at lower field than aldehydes and -carbons results in a shift towards lower field g-carbon results in a shift towards high field.

86 Hig

87 Properties of Some Deuterated NMR Solvents Solvent B.P. C Residual 1 H signal (δ) 13 C signal (δ) acetone-d ppm & 30.5 ppm acetonitrile-d ppm & 1.3 ppm benzene-d ppm ppm chloroform-d ppm 77.0 ppm cyclohexane-d ppm 26.4 ppm dichloromethane-d ppm 53.8 ppm dimethylsulfoxide-d ppm 39.5 ppm nitromethane-d ppm 62.8 ppm pyridine-d , 7.55 & 8.71 ppm 150, & ppm tetrahydrofuran-d & 3.58 ppm 67.4 & 25.2 ppm

88 Spin-Spin Coupling in 13 C NMR 13 C - 13 C coupling is not important because: The probability of having two 13 C atoms next to each other is only 0.01% 1 H - 13 C coupling is what is normally considered. A m X n m= n+1

89 Coupling can be through: One bond ( 1 J C,H ), two bonds ( 2 J C,H ) or three bonds ( 3 J C,H ) Four bond ( 4 J C,H ) coupling can also occur provided zigzag arrangement( W-coupling ) Empirical relationship between J CH and fractional s-character (denoted by s)

90 For sp 3 carbon 1 J CH is between Hz For sp 2 carbon 1 J CH is between Hz For sp carbon 1 J CH is between Hz For sp 3 carbon 2 J CH is -6 to -4 Hz For sp 2 carbon 2 J CH is Hz For sp carbon 2 J CH is Hz