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Nuclear Magnetic Resonance 2. Lecture Date: February 13 th , 2008. Selected Applications of NMR. Structural analysis Stereochemical and conformational analysis Quantitative analysis Solid-state analysis. NMR Experiments. NMR experiments fall into some basic categories: - PowerPoint PPT Presentation
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Lecture Date: February 13 th , 2008 Nuclear Magnetic Resonance 2
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Page 1: Nuclear Magnetic Resonance 2

Lecture Date: February 13th, 2008

Nuclear Magnetic Resonance 2

Page 2: Nuclear Magnetic Resonance 2

Selected Applications of NMR

Structural analysis

Stereochemical and conformational analysis

Quantitative analysis

Solid-state analysis

Page 3: Nuclear Magnetic Resonance 2

NMR Experiments

NMR experiments fall into some basic categories:– Basic pulse methods

Single pulse Selective pulse or selective decoupling Solvent suppression

– 2D and multi-dimensional experiments unravel complex spectra by separation of overlapping signals,

control of “mixing” between signals (to obtain more data)

– Multiple resonance (heteronuclear techniques) Are often 2D or nD sequences

– Diffusion, dynamics and relaxation experiments

Page 4: Nuclear Magnetic Resonance 2

Common Solution-state NMR Experiments for Organic Structural Analysis

Experiment AcronymInformation

Provided

GASPE

DEPT

Gated-spin echo

Distortionless editing by polarization transfer

13C multiplicity

(C, CH, CH2, CH3)

COSY correlated spectroscopy 1H-1H covalent bonding, 2-4

bonds

HMQC heteronuclear multiple quantum coherence

1H-13C covalent bonding, 1 bond

HMBC heteronuclear multiple bond correlation

1H-13C covalent bonding, 2-4

bonds

NOE difference, NOESY, ROESY

nuclear Overhauser effect spectroscopy

1H-1H proximity in space, 1.8-4.5 A

Page 5: Nuclear Magnetic Resonance 2

Pulse Sequences

Modern NMR involves flexible spectrometers that can implement pulse sequences, which are designed to extract and simplify relevant information for the spectroscopist

Designed to harness a property or properties of the nuclear spin Hamiltonians

– J-coupling

– Chemical shift

– Quadrupolar coupling

– Dipolar coupling

Or, are designed to measure a bulk effect– Relaxation

– Diffusion

– Chemical exchange or dynamics

Page 6: Nuclear Magnetic Resonance 2

An Example of 1D NMR

Top – 1H spectrum

Middle – Selective pulse

Bottom – homonuclear decoupling

Page 7: Nuclear Magnetic Resonance 2

Structural Analysis – 13C NMR and Editing

13C spectra of cholesteryl acetate:

(a) continuous 1H decopling

(b) 1H during acquisition (no NOE)

(c) GASPE (APT)

(d) DEPT-135

Page 8: Nuclear Magnetic Resonance 2

Multi-dimensional NMR

The general scheme of 2D and multi-dimensional NMR:

Evolution (t1) Detection (t2)Preparation Mixing (tm)

Experiment Time

2D NMR data has two frequency dimensions:

Can include NOE or J-coupling mixing

FT(t1) FT(t2)

Page 9: Nuclear Magnetic Resonance 2

A Simple 2D NMR Spectrum

Diagonal Peak

Cross peak(“correlation”)

1

2

3

4

5

12345

F1 (ppm)

F2 (ppm)

Page 10: Nuclear Magnetic Resonance 2

An Example of 2D NMR – the COSY Experiment

Correlations are observed between J-coupled protons!

(Example is a sample of sucrose in D2O)

Page 11: Nuclear Magnetic Resonance 2

Structural Analysis: 1H –13C Correlation

The 1H-13C HSQC analysis of clarithromycin:

Page 12: Nuclear Magnetic Resonance 2

Structural Analysis: Long-range 1H –13C Correlation

The 1H-13C HMBC analysis of carvedilol:

Page 13: Nuclear Magnetic Resonance 2

Structural Analysis: 1H –15N Correlation

The 1H-15N long-range HMQC analysis of telithromycin:

Page 14: Nuclear Magnetic Resonance 2

Determination of Relative StereochemistryNOE difference spectroscopy

Page 15: Nuclear Magnetic Resonance 2

Determination of Absolute Stereochemistry

Remember the ring current effect?

J. A. Dale and H. S. Mosher, J. Am. Chem. Soc., 95, 512-519 (1973).C. E. Johnson and F. A. Bovey, J. Chem. Phys., 29, 1012 (1958).

Chemical Shielding around the Benzene Ring

-2

0

2

4

6

8

10

12

0.0 2.0 4.0 6.0 8.0Distance from Ring Center (A)

Ab

so

lute

Iso

tro

pic

Sh

ield

ing

(p

pm

)

Above Ring

In Ring Plane

Chemical Shielding around the Benzene Ring (Expanded View)

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

4.0 5.0 6.0 7.0 8.0Distance from Ring Center (A)

Ab

so

lute

Iso

tro

pic

Sh

ield

ing

(p

pm

)

Above Ring

In Ring Plane

shielding (opposes field)

deshielding (aligned with field)

Page 16: Nuclear Magnetic Resonance 2

Determination of Absolute Stereochemistry by Mosher-Dale Method

Procedure: Derivatize a chiral alcohol with MPTA, -methoxy-- (trifluoromethyl)phenyl acetic acid

Because a phenyl group’s deshielding effects drop off more rapidly with distance than its shielding effects, protons close to a phenyl should be more shielded!

Example: 5-nitro-2-pentanol

F3C

O

PhH3CO

O H

CH3

(R)-alcohol

NO2

(S)-MPTA-Cl=> (R)-MPTA ester

1

2

3

4

4.45t

2.02m

1.69m1.26d

5.15m

3.51q 7.4-7.5m

89

1011

567

|5JH9,F10| = 1.2 Hz

|3JH11,H5| = 6.2 Hz

|3JH2,H3| = 6.9 Hz

|4JH2,H4| = 0 Hz

F3C

O

PhH3CO

O H

(S)-alcohol

H3C

(S)-MPTA-Cl=> (R)-MPTA ester

1

2

3

4

4.34dt

1.83m

1.62m

1.35d

5.15m

3.55q 7.4-7.5m

89

10

11

567

NO2

|5JH9,F10| = 1.1 Hz

|3JH11,H5| = 6.3 Hz

|3JH2,H3| = 6.8 Hz

|4JH2,H4| = 2.2 Hz

J. A. Dale and H. S. Mosher, J. Am. Chem. Soc., 95, 512-519 (1973).A. Guarna, E. O. Occhiato, L. M. Spinetti, M. E. Vallecchi, and D. Scarpi, Tetrahedron, 51, 1775-1788 (1995).

Page 17: Nuclear Magnetic Resonance 2

19F Quantitative Analysis: TFA Salt Stoichiometry

Page 18: Nuclear Magnetic Resonance 2

Solid-state Nuclear Magnetic Resonance

NMR in solids, like solution-state, relies on the behavior of nuclear spin energy levels in a magnetic field. However, the interactions that affect NMR spectra act differently.

In liquids, molecules reorient and diffuse quickly, leading to narrow isotropic resonances.

In solids, the fixed orientation of individual crystallites leads to a range of resonance frequencies for anisotropic interactions.

E

m=+1/2

m=-1/2

No field Field = B0

E=(h/2)B0

Page 19: Nuclear Magnetic Resonance 2

Solid-state NMR: Magic-Angle Spinning

These can be averaged away over time by spinning at a root of the scaling factor:

The result of magic angle spinning (often combined with dipolar decoupling):

1cos3 cos

2

2

P

broadening

E. R. Andrew, A. Bradbury, and R. G. Eades, Nature, 183, 1802 (1959).I. J. Lowe. Phys. Rev. Lett. 2, 285 (1959).

The following anisotropic interactions are dependent on their orientation with respect to the large magnetic field (B0):

– dipolar (homo- and heteronuclear) coupling

– 1st-order quadrupolar coupling

– anisotropic chemical shift

Page 20: Nuclear Magnetic Resonance 2

Cross-Polarization Cross-polarization is an example of a double resonance experiment

– Two resonances, typically two different nuclei, are excited in a single experiment.

Cross-Polarization combined with MAS (CP-MAS):

– Enhancement of signal from “sparse” spins via transfer of polarization from “abundant” spins

– The “Hartmann-Hahn condition” allows for efficient energy transfer between the two spins, usually via dipolar interactions

– The basic CP pulse sequence for 1H to 13C experiments:

1H

13CCP

CP

90

CW Decoupling

E. O. Stejskal and J. D. Memory. “High Resolution NMR in the Solid State,” Oxford University Press, New York (1994).A. Pines, M. G. Gibby and J. S. Waugh. J. Chem. Phys., 59, 569 (1973).

Page 21: Nuclear Magnetic Resonance 2

An Example: Polymorphism in Carvedilol

13C CP-TOSS spectra of the polymorphs of SKF105517 free base

Amorphous forms generally give broadened spectra

NH

O

NH

O

OH

O

H3C 1

2

3

45

6

7

8

9

10

11

12

13

14

15 16

17

1819

20

21 22

23

2425

26

Page 22: Nuclear Magnetic Resonance 2

An Example: Polymorphism in Carvedilol 15N SSNMR spectroscopy also shows similar effects.

Advantages: simple and easy-to-interpret spectra, valuable information about the nitrogen chemical environment

Disadvantage: much lower sensitivity

NH

O

NH

O

OH

O

H3C 1

2

3

45

6

7

8

9

10

11

12

13

14

15 16

17

1819

20

21 22

23

2425

26

Page 23: Nuclear Magnetic Resonance 2

LC-SPE-NMR for Impurity Analysis

LC separation and solid-phase extraction (SPE) concentration

Page 24: Nuclear Magnetic Resonance 2

Magnetic Resonance Imaging

• The basic idea: a linear magnetic field gradient imposes a linear spread of Larmor frequencies on a sample.

Figure from S. W. Homans, A Dictionary of Concepts in NMR, Oxford, 1989.For more details, see P. G. Morris, NMR Imaging in Medicine and Biology, Oxford University Press, 1986.

00 B Gradient00 B

Page 25: Nuclear Magnetic Resonance 2

Magnetic Resonance Force Microscopy

Rugar, D.; et al. Nature 2004, 430, 329–332.R. Mukhopadhyay, Anal. Chem. 2005, 449A-452A.

A “combination” of AFM and EPR/NMR

Uses a nano-scale cantilever to detect spin motion induced by RF via in an magnetic field

Page 26: Nuclear Magnetic Resonance 2

Nuclear Spin Optical Rotation (NSOR)

Nature 2006, 442, 1021

Measures NMR signals by detecting phase shifts induced in a laser beam as a the beam passes through a liquid

Gives excellent spatial resolution

Currently lacks sensitivity

Developed by Romalis group at Princeton


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