Química Orgânica I. Nuclear Magnetic Resonance Spectroscopy (II) Ciências Farmacêuticas Bioquímica Química AFB QO I 2007/08 1 AFB QO I 2007/08 2

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1 Química Orgânica I Ciências Farmacêuticas Bioquímica Química AFB QO I 2007/08 1 Nuclear Magnetic Resonance Spectroscopy (II) AFB QO I 2007/08 2 1

2 Adaptado de Organic Chemistry, 6th Edition; L.G. Wade, Jr. Leitura complementar recomendada: Espectroscopia de Ressonância Magnética Nuclear; A.M.d A.R. Gonsalves, T.M.V.D. Pinho e Melo, 2007 AFB QO I 2007/08 3 (rev) Desvio químico (ambiente electrónico) Nº de sinais (grupos de protões equivalentes) Intensidade (nº de protões equivalentes) Multiplicidade de sinal (protões adjacentes) AFB QO I 2007/08 4 2

3 Chemical shift Strength of Field: Operating Frequency: Shift From TMS: δ value: B 0 = 1.41 Tesla 60 MHz 162 Hz 2.70 ppm B 0 = 2.35 Tesla 100 MHz 270 Hz 2.70 ppm AFB QO I 2007/08 5 AFB QO I 2007/08 6 3

4 Me-H; Me-F AFB QO I 2007/08 7 Electronegativity effects on proton chemical shifts Compound CH 3 X Element X Electronegativity of X Chemical Shift δ CH 3 H H CH 3 I I CH 3 Br Br CH 3 Cl Cl CH 3 F F AFB QO I 2007/08 8 4

5 AFB QO I 2007/08 9 δ AFB QO I 2007/

6 Number of Signals Equivalent hydrogens have the same chemical shift. AFB QO I 2007/08 11 Intensity of Signals The area under each peak is proportional to the number of protons. Shown by integral trace. AFB QO I 2007/

7 1,1,2-Tribromoethane Nonequivalent protons on adjacent carbons. AFB QO I 2007/08 13 Doublet: 1 Adjacent Proton AFB QO I 2007/

8 Triplet: 2 Adjacent Protons AFB QO I 2007/08 15 Explain observed signals AFB QO I 2007/

9 J distance between split peaks = 1.26 ppm ppm = 0.12 ppm J = 0.12 ppm * (60 Hz / 1 ppm) = 7.2 Hz AFB QO I 2007/08 17 Values for Coupling Constants AFB QO I 2007/

10 The N + 1 Rule If a signal is split by N equivalent protons, it is split into N + 1 peaks. AFB QO I 2007/08 19 Range of Magnetic Coupling Equivalent protons do not split each other. Protons bonded to the same carbon will split each other only if they are not equivalent. Protons on adjacent carbons normally will couple. Protons separated by four or more bonds will not couple. AFB QO I 2007/

11 Splitting for Ethyl Groups AFB QO I 2007/08 21 Splitting for Isopropyl Groups AFB QO I 2007/

12 Coupling Constants (rev.) Distance between the peaks of multiplet Measured in Hz Not dependent on strength of the external field Multiplets with the same coupling constants may come from adjacent groups of protons that split each other. AFB QO I 2007/08 23 Complex Splitting Signals may be split by adjacent protons, different from each other, with different coupling constants. Example: H a of styrene which is split by an adjacent H trans to it (J = 17 Hz) and an adjacent H cis to it (J = 11 Hz). H a C C c H Hb AFB QO I 2007/

13 H a Splitting Tree C C c H Hb AFB QO I 2007/08 25 Spectrum for Styrene AFB QO I 2007/

14 Stereochemical Nonequivalence Usually, two protons on the same C are equivalent and do not split each other. If the replacement of each of the protons of a -CH 2 group with an imaginary Z gives stereoisomers, then the protons are nonequivalent and will split each other. AFB QO I 2007/08 27 Some Nonequivalent Protons H a C C c H Hb H ah CH 3 Cl Hb d H c H a OH H b Cl AFB QO I 2007/

15 (S)-1,2-dichloropropane H Cl 3.74H H3.49 Cl 4 3 PPM AFB QO I 2007/ conformers AFB QO I 2007/

16 Time Dependence Molecules are tumbling relative to the magnetic field, so NMR is an averaged spectrum of all the orientations. Axial and equatorial protons on cyclohexane interconvert so rapidly that they give a single signal. Proton transfers for OH and NH may occur so quickly that the proton is not split by adjacent protons in the molecule. AFB QO I 2007/08 31 Hydroxyl Proton Ultrapure samples of ethanol show splitting. Ethanol with a small amount of acidic or basic impurities will not show splitting. AFB QO I 2007/

17 N-H Proton Moderate rate of exchange. Peak may be broad. AFB QO I 2007/08 33 Identifying the O-H or N-H Peak Chemical shift will depend on concentration and solvent. To verify that a particular peak is due to O-H or N- H, shake the sample with D 2 O. Deuterium will exchange with the O-H or N-H protons. On a second NMR spectrum the peak will be absent, or much less intense. AFB QO I 2007/

18 Modern NMR AFB QO I 2007/08 35 Carbon C has no magnetic spin. 13 C has a magnetic spin, but is only 1% of the carbon in a sample. The gyromagnetic ratio of 13 C is one-fourth of that of 1 H. Signals are weak, getting lost in noise. Hundreds of FT-NMR spectra are taken, averaged. AFB QO I 2007/

19 Fourier Transform NMR Radio-frequency pulse given. Nuclei absorb energy and precess (spin) like little tops. A complex signal is produced, then decays as the nuclei lose energy. Free induction decay is converted to spectrum. AFB QO I 2007/08 37 AFB QO I 2007/

20 AFB QO I 2007/08 39 Hydrogen and Carbon Chemical Shifts AFB QO I 2007/

21 Combined 13 C and 1 H Spectra AFB QO I 2007/08 41 Differences in 13 C Technique Resonance frequency is ~ onefourth, 15.1 MHz instead of 60 MHz. Peak areas are not proportional to number of carbons. Carbon atoms with more hydrogens absorb more strongly. AFB QO I 2007/

22 Spin-Spin Splitting It is unlikely that a 13 C would be adjacent to another 13 C, so splitting by carbon is negligible. 13 C will magnetically couple with attached protons and adjacent protons. These complex splitting patterns are difficult to interpret. AFB QO I 2007/08 43 AFB QO I 2007/

23 O O O 14.1 O 61.3 calculated AFB QO I 2007/08 45 Proton Spin Decoupling To simplify the spectrum, protons are continuously irradiated with noise, so they are rapidly flipping. The carbon nuclei see an average of all the possible proton spin states. Thus, each different kind of carbon gives a single, unsplit peak. AFB QO I 2007/

24 Two 13 C NMR Spectra AFB QO I 2007/08 47 Proton-decoupled 13C spectra for ethyl phenylacetate AFB QO I 2007/

25 Off-Resonance Decoupling 13 C nuclei are split only by the protons attached directly to them. The N + 1 rule applies: a carbon with N number of protons gives a signal with N + 1 peaks. AFB QO I 2007/08 49 Off-resonance proton-coupled 13C spectra for ethyl phenylacetate AFB QO I 2007/

26 DEPT Distortionless Enhancement by Polarization Transfer 1H magnetization is generated first, then transferred to 13C. This "polarization transfer" enhances sensitivity. Also, the experiment repetition rate is dependent on relaxation of 1H, rather than 13C, so a shorter delay is needed. AFB QO I 2007/08 51 DEPT - codeine DEPT-135 CH and CH3 peaks up, CH2 peaks inverted DEPT-90 CH peaks only DEPT-45 all protonated carbons normal 13C spectrum AFB QO I 2007/

27 solvents Solvent acetic acid - d 4 acetone - d 6 acetonitrile - d 3 benzene - d 6 carbon tetrachloride chloroform - d dimethylsulfoxide - d (singlet) ethanol - d , 3.56, 5.19 methanol - d (singlet), 4.78 (singlet) methylene chloride - d 2 water - d 2 δ (ppm) 2.0 (singlet), 11.7(singlet) 2.09 (singlet) 1.93 (singlet) 7.15 (singlet) none 7.25 (singlet) 5.32 (singlet) 4.82 (singlet) AFB QO I 2007/08 53 Solvents for 13C-NMR Solvent acetone benzene chloroform dimethylsulfoxide dioxane methanol δ (ppm) 206.0, AFB QO I 2007/

28 MRI Magnetic resonance imaging, noninvasive Nuclear is omitted because of public s fear that it would be radioactive. Only protons in one plane can be in resonance at one time. Computer puts together slices to get 3D. Tumors readily detected. AFB QO I 2007/08 55 AFB QO I 2007/

29 ext/spectrpy/nmr/nmr1.htm#nmr1 eaching/316/index.html /nmrtheory/main.html AFB QO I 2007/