Applications of Solid-state NMR

Dewey H. Barich, Ph.D.Director of Solid-State NMR Facility

Molecular Structures Groupdhbarich@ku.edu

Outline Overview of Solid State NMR Spectroscopy (SSNMR) Advantages and Disadvantages Contribution Examples:

Environment characterization Physical form characterization Molecular conformation Reactive intermediates in catalysis

Summary

Solid-State NMR Spectroscopy

Analysis of Solids and Semi-solids Organics (Fine Chemicals, Pharmaceutics) Catalysts, Reactive Intermediates Mixtures (e.g., Pharmaceutical Formulations) Biomass (Plant Stalk, Leaves) Soils, Sediments Energy Materials (Coal, Shale, Battery Materials) Polymers, Proteins Membranes, Tissues, Gels

Solid-State NMR Spectroscopy

More information available from solids

Orientation-dependent interactions Dipolar Couplings Chemical Shift Anisotropy

Spectra more complicated Line broadening from multiple phenomena

Overview Research Areas Species Characterization

Chemical Shift Fingerprint

Material Characterization Crystalline polymorphs Crystalline vs. amorphous Influence of environment on spectra Analyzing mixture components

Molecular Structure Conformation Arrangement, degree of disorder

Advantages of Solid-State NMR Non-destructive

Non-invasive

Selective Nucleus specific (13C, 15N, 31P, 19F, etc) Mixture components

Quantitative

Disadvantages of SSNMR Expertise required to utilize properly

Insensitive (Analyses can be long)

Expensive

Automation is challenging

Common NMR Experiments

Solution 13C ObserveExcite the 13C nucleus,Decouple protons during acquisition

1H

13C

Decoupling

Common Solids ExperimentsCross Polarization (CP)

Excite the 1H nuclei,Transfer Magnetization to X nuclei (e.g., 13C)Decouple protons during acquisition

1H

13C

Decoupling

90y

CP advantages: For 13C, get 4x signal enhancementRepetition rate driven by 1H not 13C

CP

TCH Growth Followed by T1 Relaxation

500 ms

100 ms

40 ms

25 ms

5 ms

10 ms

16 ms

NMR Chemical Shifts

Result of electronic environment

Can distinguish functional groups Carboxylic acids, aromatics, aliphatics, etc.

11

22

33

iso

(iso is observed in solution)

In solids, can observe anisotropic chemical shift (x, y, z directions)

Magic Angle Spinning (MAS)

7 mm8 kHz

4 mm15 kHz

2.5 mm30 kHz

Magic Angle Spinning (MAS)

20406080100120140160

11

22

33

iso

Static SSNMR

MAS SSNMR

13C FIREMAT of Kanamycin A

0255075100125150

105.3102.7

92.976.575.974.272.271.570.269.366.862.254.853.649.843.736.5

CHCH

CHCHCHCHCHCHCHCHCH

NCHNCH

CH2

NCH2CH2

NCH

O

O

OH

OH

NH2

OHH

NH2NH2

OH

O

O

NH2

H

OH

OH

OH

13C CP/MAS TOSS SSNMR of3-Methylglutaric Acid (MGA)

O O

OHHOCOOH

CH3

CH2

CH

Crystalline Systems

SSNMR and X-Ray Diffraction (XRD) are complementary techniques:

XRD: long range order

SSNMR: short range order

Crystalline Systems

Unit cell: smallest repeatable unitnecessary to construct a crystallattice via translation

Asymmetric unit: smallest volumethat can be replicated to produce aunit cell (rotations or reflectionsrequired)

Crystalline Systems

Translation only fails to form unit cell:

Asymmetric units are magnetically equivalent

Contents of an asymmetric unit are magnetically inequivalent

SSNMR of Crystalline Systems

12

34

4a4b

8a 8b

5

6

78

4a, 4b, 8a, 8b

2, 3, 6, 7

1, 4, 5, 8

Barich, D. H. et al., J. Phys. Chem. A 2000, 104 (35), 8290–8295

Representation of Biphenylene Crystal

P

D

8b'1'

2'

3'4'

4a'

1 2

344a

56

7

88a

8b

4b

DD

D P

P

Barich, D. H. et al., J. Phys. Chem. A 2000, 104 (35), 8290–8295

13C FIREMAT of Ambuic Acid

050100150200250300

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

ppm from TMS

ppm from TMS

Ambuic Acid

O

O O

COOH

O

H H

H11C5

s-cis

O

O O

COOH

O

H H

H11C5

s-trans

Typically s-trans conformations are more stable; however, comparison of

the computed and experimental shifts for C8, C9, C11, and C12 finds the

s-cis to be the best fit at > 85 % confidence.

Bulk crystalline1H T1 = 243 s

Tablets1H T1 = 79 s

Spray-dried1H T1 = 4.1 s

120 100 80 40ppm

Lyophilized1H T1 = 3.8 s

60

O

OH

OH

H

HO

HH

HO

H

OH

O

OH

OH

H

HH

OHH

HO

H

Distinguishing Physical Forms:Crystalline vs. Amorphous Lactose

Quantitation of Mixtures:Neotame Monohydrate

Offerdahl, T. J. et al., J. Pharm. Sci. 2005, 94 (12), 2591–605

13C Solid-State NMR Spectra of Neotame Forms A and G

Form G

Form A

200 100 0150 50 ppm

135.

6 pp

m13

8.6

ppm

Offerdahl, T. J. et al., J. Pharm. Sci. 2005, 94 (12), 2591–605

13C SSNMR Spectrum of a 50/50 Mixture of Neotame Forms A and G

Offerdahl, T. J. et al., J. Pharm. Sci. 2005, 94 (12), 2591–605

13C SSNMR of a 50/50 Mixture ofAmorphous Neotame and Form G

120125135145 130140

83

100

Offerdahl, T. J. et al., J. Pharm. Sci. 2005, 94 (12), 2591–605

13C SSNMR of Oil Shales

Miknis, F. P.; Smith, J. W. Org. Geochem. 1984, 5, 193–201

15N SSNMR of Crosslinked Polymer

13C SSNMR of Soils

Courtesy, Prof. Sharon Billings

29Si CP/MASCharacterization of Catalysts

Courtesy, A. Ramanathan and B. Subramaniam

Q2 Q3 Q4

Material (Q3+Q2)/Q4 Q3/Q4Zr-200 5.3 4.0Zr-100 5.5 4.2Zr-40 4.1 3.2Zr-20 3.1 2.4Zr-20 Silylated 1.9 1.5

29Si CP/MASCharacterization of Catalysts

Courtesy, A. Ramanathan and B. Subramaniam

Material (Q3+Q2)/Q4 Q3/Q4Ce-100 6.1 4.6Ce-50 6.8 5.2Ce-25 5.5 4.2Ce-10 5.5 4.2SiK5 6.5 5.0

Q2 Q3 Q4

ppm200 150 100 50 0

50 15 1045 40 35 30 25 20ppm

Line Width as a Probe of Bulk Environment:13C SSNMR of Ibuprofen

37 3935

31 3233

Barich, D. H.; et al., J. Pharm. Sci. 2006, 95 (7), 1586–1594

50 45 40 35 30 25 20 15 10ppm

13C Solid-State NMR Spectra of Ibuprofen Preparations

51 52 4945

47 48

47 47 44 4142 43

38 38 35 31 32 33

37 39 35 3131 33

Ibuprofen Recrystallized from Acetonitrile

Cryoground Ibuprofen

Manually Ground Ibuprofen

Bulk Ibuprofen

Barich, D. H.; et al., J. Pharm. Sci. 2006, 95 (7), 1586–1594

SEM and PXRD of Ibuprofen Preparations

Cryoground IbuprofenBulk Ibuprofen

NMR Line Width = 42.2 HzNMR Line Width = 31.5 Hz

Crystallized From Acetonitrile

NMR Line Width = 47.0 Hz

30 m

5 10 20 30 4015 25 35 45 5 10 20 30 4015 25 35 45

Degrees 2 Degrees 2Degrees 2

30 m 30 m

5 10 20 30 4015 25 35 45

≈

Summary

Solid State NMR is a powerful technique for analyzing abroad range of materials and phenomena Species identification

Catalyst composition

Reactive intermediates

Physical form identification and quantitation

Influence on bulk environment

Acknowledgements Researchers

Jacob Davis Dr. Eric Gorman Dr. Joe LubachDr. Tom Offerdahl Dr. Loren Schieber Jon SalsburyDr. Patrick Goguen Dr. Teng Xu Dr. Weiguo SongDr. Mark Zell Prof. Jim Harper Prof. Eric MunsonProf. Sharon Billings Dr. Jianwei Li Dr. Anita OrendtDr. A. Ramanathan Prof. B. Subramaniam

FundingPhRMA Foundation NutrasweetUniversity of Kansas PfizerNSF CHE0840515 National Institutes of Health

Nuclei Accessible at Facility H He

Li Be B C N O F Ne

Na Mg Al Si P S Cl Ar

K Ca Sc Ti V Cr Mn Fe Co Ni Cu Zn Ga Ge As Se Br Kr

Rb Sr Y Zr Nb Mo Tc Ru Rh Pd Ag Cd In Sn Sb Te I Xe

Cs Ba La Hf Ta W Re Os Ir Pt Au Hg Tl Pb Bi Po At Rn

Fr Ra Ac Rf Db Sg Bh Hs Mt

Ce Pr Nd Pm Sm Eu Gd Tb Dy Ho Er Tm Yb Lu

Th Pa U Np Pu Am Cm Bk Cf Es Fm Md No Lr

Accessibility at Facility: Yes Maybe

Types of Materials Studied at theKU SSNMR Facility

Soil Biomass Battery Materials Catalysts Organometallic

Pharmaceutics Biological Inorganic Polymers

Quantitation of Mixtures

Ideally, peak area is proportional to the number of nuclei

Challenge: Cross polarization spectra are rarely quantitative Peak area depends on cross polarization rates and

relaxation rates (TCH and T1)

At short-to-optimum contact times (CT), cross polarization rates (TCH) increase the signal intensity. At longer CT, signal decays by proton T1 relaxation