principles and selected applications of diffusion-ordered nmr spectroscopy stéphane viel, ph. d....
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Principles and selected applications of Principles and selected applications of Diffusion-Ordered NMR SpectroscopyDiffusion-Ordered NMR Spectroscopy
Stéphane Viel, Ph. D.Stéphane Viel, Ph. D.Assistant ProfessorAssistant Professor
Aix-Marseille UniversityAix-Marseille UniversityMolecular Sciences Institute II (UMR-6263)Molecular Sciences Institute II (UMR-6263)
Chemometrics and Spectroscopy LaboratoryChemometrics and Spectroscopy LaboratoryMarseilles (France)Marseilles (France)
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2Year
1992 1996 2000 2004 2008
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Diffusion Ordered NMR Spectroscopy
Web of Science, 12 / 2007
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Diffusion Ordered NMR Spectroscopy
Web of Science, 12 / 2007
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NMR and Diffusion…NMR and Diffusion…
19501950
19541954
PGSEPulsed Gradient Spin Echo19651965
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NMR and Diffusion…NMR and Diffusion…
19811981
19871987
DOSYDiffusion Ordered SpectroscopY
19921992
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NMR and Diffusion…NMR and Diffusion…
DOSYDiffusion Ordered SpectroscopY
19921992
PGSEPulsed Gradient Spin Echo19651965
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General outlineGeneral outline
• Part 1: Theory about molecular mobility
– Self-diffusion– Study of self-diffusion by NMR
• Principles of Pulsed Gradient Spin Echo (PGSE)• Diffusion ordered NMR spectroscopy (DOSY)
• Part 2: Selected applications of DOSY
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Self-diffusionSelf-diffusion
• Random translational motion of molecules or ions that arises from the thermal energy under conditions of thermodynamic equilibrium– No thermal gradient (convection)– No concentration gradient (mutual diffusion)
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self-diffusion coefficient
root mean square displacement
Self-diffusion by Brown, 1828Self-diffusion by Brown, 1828
time = time = tt
stime = 0time = 0
• « Random jostling of molecules which leads to their net displacement over time »
tDns 2
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•D self-diffusion coefficient
•k Boltzmann’s constant
•T absolute temperature
•f friction factorf
kTD
Self-diffusion coefficient Self-diffusion coefficient DD
• DD is related to the hydrodynamic volume of the diffusing particle through
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Self-diffusion coefficient Self-diffusion coefficient DD
• DD is related to the hydrodynamic volume of the diffusing particle through
•D self-diffusion coefficient
•k Boltzmann’s constant
•T absolute temperature
•f friction factor
Sphere
f
kTD
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• For a sphere diffusing in an isotropic and continuous medium of viscosity :
Stokes Einstein equationStokes Einstein equation
a
kTD
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Diffusion Molecular Size
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• PPulsed GGradient SSpin EEcho (PGSEPGSE)– Stejskal and Tanner, 1965– Gradients of magnetic field (Pulsed)
Study of self-diffusion by NMRStudy of self-diffusion by NMR
GradientPulses
OFF OFF OFF OFF
ON ON ON
Time
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1. Spatially label the nuclear spins using
gradients of magnetic field.
Study of self-diffusion by NMRStudy of self-diffusion by NMR
2. Monitor their displacement by measuring
their spatial positions at 2 distinct times.
Principle: 2 steps
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Nuclear magnetogyric ratio
Larmor frequencyLarmor frequency
In NMR, each nuclear spin is identified by its Larmor precession frequency 0
B0 00 B
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zegg
Magnetic field gradientMagnetic field gradient
Magnetic field gradient
Spatially dependentmagnetic field
For a single and constant gradient oriented along the z direction
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ze egg
Magnetic field gradientMagnetic field gradient
Magnetic field gradient
Spatially dependentmagnetic field
For a single and constant gradient oriented along the z direction
Notion of effective gradient
Coherenceorder
gpge
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Phase shift of nuclear spinsPhase shift of nuclear spins• Assume that the magnetic fieldgradient is active during a time
• A nuclear spin acquires a phase shift
)()( 0 zgBz e
Static Field
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• Assume that the magnetic fieldgradient is active during a time
Phase shift of nuclear spinsPhase shift of nuclear spins
• A nuclear spin acquires a phase shift
)()( 0 zgBz e
Gradient
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Phase shift of nuclear spinsPhase shift of nuclear spins• Assume that the magnetic fieldgradient is active during a time
• A nuclear spin acquires a phase shift
The spatial position of the nuclear spins is encoded into a phase shift
Nuclear spin spatial labellingNuclear spin spatial labelling
)()( 0 zgBz e
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zgz e)(
Rotating frameRotating frame• In NMR, a common simplification
consists in describing the evolution of the magnetization in a frame rotating at the Larmor frequency 0
• For nuclear spins on resonance, the phase shift reduces to
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Spin Echo or Hahn Echo (SE)Spin Echo or Hahn Echo (SE)Without magnetic field gradients
Echo
Signal
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23coding decoding
Spin Echo or Hahn Echo (SE)Spin Echo or Hahn Echo (SE)With magnetic field gradients
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24)( 1z )( 2z
Spin Echo or Hahn Echo (SE)Spin Echo or Hahn Echo (SE)With magnetic field gradients
Echo
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252)( zgp 1)( zgp
Spin Echo or Hahn Echo (SE)Spin Echo or Hahn Echo (SE)With magnetic field gradients
p = 1 p = - 1
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26 )( 21 zzg
Spin Echo or Hahn Echo (SE)Spin Echo or Hahn Echo (SE)With magnetic field gradients
Echo
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Spin Echo or Hahn Echo (SE)Spin Echo or Hahn Echo (SE)
)( 21 zzg
With magnetic field gradients
Attenuation factor
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3exp 2
0
qDI
Iecho
• Iecho: Intensity at the echo with gradients
• I0: Intensity at the echo without gradients
• D: Self-diffusion coefficient
• : gradient pulse duration
• : Diffusion time
• q: gradient pulse area
Attenuation factor Attenuation factor
gq
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29Gradient strength g (G.cm-1)
0 10 20 30
No
rma
lize
d in
ten
sity
0,0
0,2
0,4
0,6
0,8
1,0
How do we actually obtain How do we actually obtain DD? ? A
ttenu
atio
n fa
ctor
3exp 2 gD
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Gradient strength g (G.cm-1)
0 10 20 30
No
rma
lize
d in
ten
sity
0,0
0,2
0,4
0,6
0,8
1,0
How do we actually obtain How do we actually obtain DD? ?
FIT
D
Atte
nuat
ion
fact
or
3exp 2 gD
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31coding decoding
Stimulated Echo (STE)Stimulated Echo (STE)With magnetic field gradients
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BPP-STE-LED sequenceBPP-STE-LED sequence
Stimulated Echo (STE) with Bipolar gradient (BPP) pulses and longitudinal eddy current delay (LED)
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The BPP-STE-LED sequenceThe BPP-STE-LED sequence
• Stimulated Echo (STE): – T1 relaxation vs. T2 relaxation– No artefacts due to J modulation
• Bipolar gradient pulses (BPP):– Reduced eddy currents
• Longitudinal Eddy currents Delay (LED):– Less spectral distortions due to eddy currents
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Stimulated Echo (STE) with Bipolar gradient (BPP) pulses and longitudinal eddy current delay (LED)
The BPP-STE-LED sequenceThe BPP-STE-LED sequence
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The BPP-STE-LED sequenceThe BPP-STE-LED sequence
• Stimulated Echo (STE): – T1 relaxation vs. T2 relaxation– No artefacts due to J modulation
• Bipolar gradient pulses (BPP):– Reduced eddy currents
• Longitudinal Eddy currents Delay (LED):– Less spectral distortions due to eddy currents
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Stimulated Echo (STE) with Bipolar gradient (BPP) pulses and longitudinal eddy current delay (LED)
The BPP-STE-LED sequenceThe BPP-STE-LED sequence
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The BPP-STE-LED sequenceThe BPP-STE-LED sequence
• Stimulated Echo (STE): – T1 relaxation vs. T2 relaxation– No artefacts due to J modulation
• Bipolar gradient pulses (BPP):– Reduced eddy currents
• Longitudinal Eddy currents Delay (LED):– Less spectral distortions due to eddy currents
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Stimulated Echo (STE) with Bipolar gradient (BPP) pulses and longitudinal eddy current delay (LED)
The BPP-STE-LED sequenceThe BPP-STE-LED sequence
Echo Signal
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Stimulated Echo (STE) with Bipolar gradient (BPP) pulses and longitudinal eddy current delay (LED)
SéquenceSéquenceBPP-STE-LEDBPP-STE-LED
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How can we use PGSE data?How can we use PGSE data?
A B C
NMR spectrum (frequency scale, ppm)
DA > DC > DB
DADA
DB
DC
DC
ppm
S I Z ES I Z E
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NMR spectrum (ppm scale)
A B C DA > DC > DB
DADA
DB
DC
DC
A AB Cppm C
SIZE
James & McDonald, 1978Stilbs & Moseley, 1978-80
S I Z ES I Z E
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Size Resolved SpectrometrySize Resolved Spectrometry
NMR spectrum (ppm scale)
A B C DA > DC > DB
B CCA Appm
Stilbs, 1981
S I Z ES I Z E
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ppm
DA
DC
DB
D
High
Low
AB
C
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ppm A AB C C
DA
DC
DB
DOSY
D
AB
C
High
Low
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• DDiffusion OOrdered NMR SSpectroscopYY– Morris & Johnson, 1992
DOSYDOSY
Antalek, B. Concepts in Magn. Reson 2002, 14, 225-258
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DOSYDOSY
Many processings available:- MaxEnt (Delsuc, M. –A.)- DECRA (Antalek, B.)- CORE (Stilbs, P.)- MCR (van Gorkom, L. C. M.)- MULVADO (Huo, R.)- iRRT (Mandelstham, V.)
• DDiffusion OOrdered NMR SSpectroscopYY– Morris & Johnson, 1992– Signal processing
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DOSYDOSY
Many processings available:- MaxEnt (Delsuc, M. –A.)- DECRA (Antalek, B.)- CORE (Stilbs, P.)- MCR (van Gorkom, L. C. M.)- MULVADO (Huo, R.)- iRRT (Mandelstham, V.)
• DDiffusion OOrdered NMR SSpectroscopYY– Morris & Johnson, 1992– Signal processing
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DOSY mapDOSY map
Adapted from Nilsson et al.
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Distortions due to spectral overlapDistortions due to spectral overlap
Adapted from Nilsson et al.
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iRRTinverseRegularized ResolventTransform
Mixture of 2 isomers
V. MandelshtamA. J. Shaka
Thureau, P.; Thévand, A.; Ancian, B.; Escavabaja, P.; Armstrong, G. S.; Mandelshtam, V. A., ChemPhysChem 2005, 6, 1
Armstrong, G. S.; Loening, N. M.; Curtis, J. E.; Shaka, A. J.; Mandelshtam, V. A., J. Magn. Reson. 2003, 163, 139
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• Part 1: Theory about molecular mobility
– Self-diffusion– Study of self-diffusion by NMR
• Principles of Pulsed Gradient Spin Echo (PGSE)• Diffusion ordered NMR spectroscopy (DOSY)
• Part 2: Selected applications of DOSY
General outlineGeneral outline
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Chiral recognitionChiral recognition
Chiral recognition of dipeptides in a biomembrane model
C. Bombelli, S. Borocci, F. Lupi, G. Mancini, L. Mannina, A. L. Segre, S. Viel
J. Am. Chem. Soc. 2004, 126, 13354-13362
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IntroductionIntroduction• The organization of biomembranes is based
on molecular recognition phenomena (chiral recognition)
• To investigate the non covalent interactions involved in such systems, models are used
C. Bombelli, S. Borocci, F. Lupi, G. Mancini, L. Mannina, A. L. Segre, S. VielJ. Am. Chem. Soc. 2004, 126, 13354-13362
we used Sodium N-doceanoyl-L-prolinate (SDP)
Here N
O
CO2
H
Na+-
C11H23
N
CO2
H
C11H23
O
Na+-
Z E
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Introduction (2)Introduction (2)• We studied by NMR the chiral recognition
in SDP micelles of 2 dipeptides
Ditryptophan (1)-
N
N
N
O
H
CO2
NH3
H
H
+2
3a
45
6
77a
2'
3'a
4'5'
6'
7'7'a
''
NMR techniques: 1H, PGSE, ROESY+Molecular mechanic calculations
-
+N
O
H
CO2
NH3
Diphenylalanine (2)
C. Bombelli, S. Borocci, F. Lupi, G. Mancini, L. Mannina, A. L. Segre, S. VielJ. Am. Chem. Soc. 2004, 126, 13354-13362
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11H experiments: H experiments: LLLL//DDDD couple couple
Ditryptophan (1)+SDP micelles
Diphenylalanine (2)
+SDP micelles
C. Bombelli, S. Borocci, F. Lupi, G. Mancini, L. Mannina, A. L. Segre, S. VielJ. Am. Chem. Soc. 2004, 126, 13354-13362
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11H experiments: H experiments: LDLD//DLDL couple couple
Ditryptophan (1)
+SDP micelles
Diphenylalanine (2)
+SDP micelles
C. Bombelli, S. Borocci, F. Lupi, G. Mancini, L. Mannina, A. L. Segre, S. VielJ. Am. Chem. Soc. 2004, 126, 13354-13362
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PGSE experimentsPGSE experiments
• Monitor the D values of the dipeptides by PGSE experiments
• 2-site model: dipeptide in equilibrium between the bound (b) and free (f) phase
SDPD + D
FreeState
BoundState
C. Bombelli, S. Borocci, F. Lupi, G. Mancini, L. Mannina, A. L. Segre, S. VielJ. Am. Chem. Soc. 2004, 126, 13354-13362
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PGSE experimentsPGSE experiments
Monitor the D values of the dipeptides by PGSE experiments
2-site model: dipeptide in equilibrium between the bound (b) and free (f) phase
SDPD + D
fbbbobs DxDxD )1( C. Bombelli, S. Borocci, F. Lupi, G. Mancini, L. Mannina, A. L. Segre, S. VielJ. Am. Chem. Soc. 2004, 126, 13354-13362
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PGSE experimentsPGSE experiments
• Determine the partition coefficient of the dipeptides in the 2 phases
aqueous
micellar
DP
DPp
micellar
aqueous
b
b
V
V
x
xp
1C. Bombelli, S. Borocci, F. Lupi, G. Mancini, L. Mannina, A. L. Segre, S. VielJ. Am. Chem. Soc. 2004, 126, 13354-13362
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PGSE experimentsPGSE experimentsBound molar fractions xb and partition coefficients p
82 ± 120.69 ± 0.03LL-22
82 ± 120.69 ± 0.03DD-22
138 ± 250.79 ± 0.03DL-22
138 ± 250.79 ± 0.03LD-22
931 ± 1000.962 ± 0.004LL-11
860 ± 870.959 ± 0.004DD-11
1900 ± 4070.981 ± 0.004DL-11
1900 ± 4070.981 ± 0.004LD-11
pXbDipeptide:
C. Bombelli, S. Borocci, F. Lupi, G. Mancini, L. Mannina, A. L. Segre, S. VielJ. Am. Chem. Soc. 2004, 126, 13354-13362
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82 ± 120.69 ± 0.03LL-22
82 ± 120.69 ± 0.03DD-22
138 ± 250.79 ± 0.03DL-22
138 ± 250.79 ± 0.03LD-22
931 ± 1000.962 ± 0.004LL-11
860 ± 870.959 ± 0.004DD-11
1900 ± 4070.981 ± 0.004DL-11
1900 ± 4070.981 ± 0.004LD-11
pXbDipeptide:
PGSE experimentsPGSE experimentsBound molar fractions xb and partition coefficients p
C. Bombelli, S. Borocci, F. Lupi, G. Mancini, L. Mannina, A. L. Segre, S. VielJ. Am. Chem. Soc. 2004, 126, 13354-13362
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82 ± 120.69 ± 0.03LL-22
82 ± 120.69 ± 0.03DD-22
138 ± 250.79 ± 0.03DL-22
138 ± 250.79 ± 0.03LD-22
931 ± 1000.962 ± 0.004LL-11
860 ± 870.959 ± 0.004DD-11
1900 ± 4070.981 ± 0.004DL-11
1900 ± 4070.981 ± 0.004LD-11
pXbDipeptide:
PGSE experimentsPGSE experimentsBound molar fractions xb and partition coefficients p
C. Bombelli, S. Borocci, F. Lupi, G. Mancini, L. Mannina, A. L. Segre, S. VielJ. Am. Chem. Soc. 2004, 126, 13354-13362
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Conformations of Conformations of 11 isomers by NMR and isomers by NMR and Molecular mechanic calculations (1)Molecular mechanic calculations (1)
Buffer
DL-1 1 + BufferLL-1 1 + Buffer
C. Bombelli, S. Borocci, F. Lupi, G. Mancini, L. Mannina, A. L. Segre, S. VielJ. Am. Chem. Soc. 2004, 126, 13354-13362
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Conformations of Conformations of 11 isomers by NMR and isomers by NMR and Molecular mechanic calculations (2)Molecular mechanic calculations (2)
SDP micelles (LL/DD couple)
LL-1 1 + SDPSDP micelles DD-1 1 + SDPSDP micelles
C. Bombelli, S. Borocci, F. Lupi, G. Mancini, L. Mannina, A. L. Segre, S. VielJ. Am. Chem. Soc. 2004, 126, 13354-13362
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Conformations of Conformations of 11 isomers by NMR and isomers by NMR and Molecular mechanic calculations (3)Molecular mechanic calculations (3)
SDP micelles (DL/LD couple)
DL-1 1 + SDPSDP micelles LD-1 1 + SDPSDP micelles
C. Bombelli, S. Borocci, F. Lupi, G. Mancini, L. Mannina, A. L. Segre, S. VielJ. Am. Chem. Soc. 2004, 126, 13354-13362
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Binding modes of Binding modes of 11 isomers isomers to SDP micellesto SDP micelles
LL/DD couple
C. Bombelli, S. Borocci, F. Lupi, G. Mancini, L. Mannina, A. L. Segre, S. VielJ. Am. Chem. Soc. 2004, 126, 13354-13362
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Binding modes of Binding modes of 11 isomers isomers to SDP micellesto SDP micelles
LD/DL couple
C. Bombelli, S. Borocci, F. Lupi, G. Mancini, L. Mannina, A. L. Segre, S. VielJ. Am. Chem. Soc. 2004, 126, 13354-13362
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Chemical exchangeChemical exchange
Determining chemical exchange rates in nucleobases
P. Thureau, B. Ancian, S. Viel, A. ThévandChem. Comm. 2006, 200-202
P. Thureau, B. Ancian, S. Viel, A. ThévandChem. Comm. 2006, 1884-1886
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Hydrogen bonding in nucleic acidsHydrogen bonding in nucleic acids
P. Thureau, B. Ancian, S. Viel, A. Thévand Chem. Comm. 2006, 200-202P. Thureau, B. Ancian, S. Viel, A. Thévand Chem. Comm. 2006, 1884-1886
DNA
RNA
Thymine – Adenine
AdenineUracil –
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Effect of chemical exchange in DOSYEffect of chemical exchange in DOSY
Uridine
P. Thureau, B. Ancian, S. Viel, A. Thévand Chem. Comm. 2006, 200-202P. Thureau, B. Ancian, S. Viel, A. Thévand Chem. Comm. 2006, 1884-1886
O
OO
NN
OO
O
H
H
H H
H2O
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ModelModel
Simple 2-site exchange
P. Thureau, B. Ancian, S. Viel, A. Thévand Chem. Comm. 2006, 200-202P. Thureau, B. Ancian, S. Viel, A. Thévand Chem. Comm. 2006, 1884-1886
N-H +H2O HOH+N-H
T = 50 ms T = 200 ms T= 900 ms
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ModelModel
Simple 2-site exchange
P. Thureau, B. Ancian, S. Viel, A. Thévand Chem. Comm. 2006, 200-202P. Thureau, B. Ancian, S. Viel, A. Thévand Chem. Comm. 2006, 1884-1886
N-H +H2O HOH+N-H
T = 50 ms T = 200 ms T= 900 ms
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ModelModel
Simple 2-site exchange
P. Thureau, B. Ancian, S. Viel, A. Thévand Chem. Comm. 2006, 200-202P. Thureau, B. Ancian, S. Viel, A. Thévand Chem. Comm. 2006, 1884-1886
N-H +H2O HOH+N-H
T = 50 ms T = 200 ms T= 900 ms
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Uracil exchange constants KUracil exchange constants Kaa
Simple 2-site exchange
P. Thureau, B. Ancian, S. Viel, A. Thévand Chem. Comm. 2006, 200-202P. Thureau, B. Ancian, S. Viel, A. Thévand Chem. Comm. 2006, 1884-1886
N-H +H2O HOH+N-H
H1 ka= 8 s-1
H3 ka= 18 s-1
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Thymine exchange constants KThymine exchange constants Kaa
Simple 2-site exchange
P. Thureau, B. Ancian, S. Viel, A. Thévand Chem. Comm. 2006, 200-202P. Thureau, B. Ancian, S. Viel, A. Thévand Chem. Comm. 2006, 1884-1886
N-H +H2O HOH+N-H
H1 ka= 5 s-1
H3 ka= 7 s-1
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Self-aggregationSelf-aggregation
Investigations of complexes in solution
S. Viel, L. Mannina, A. L. SegreTetrahedron Lett. 2002, 43, 2515-2519
C. Sanna, C. La Mesa, L. Mannina, P. Stano, S. Viel, A. L. SegreLangmuir 2006, 22, 6021-6031
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stacking interactions are important in organic chemistry and for biological systems
Here we consider 2 types of organic molecules bearing an aromatic ring and characterized by a:
IntroductionIntroduction
- low molecular weight (< 400 Da)
Studied by: - NMR (1H, PGSE, NOESY)- DLS- Physicochemical measurements
- low H2O solubility
S. Viel et al. Tetrahedron Lett. 2002, 43, 2515-2519C. Sanna et al. Langmuir 2006, 22, 6021-6031
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Molecules under studyMolecules under studyClass A
Class B
CH3CH3H1DHHOCH31CHHCH31BHHH1AZZYYXXNameName
CH2CH2OCH2CH2CH3CH2CH3PRETCH2OCH2CH3CH3ACET
CH(CH3)CH2OCH3CH3METOYYXXNameName
X
N
Y
O
Y
X
H
O
O
NO2
z
S. Viel et al. Tetrahedron Lett. 2002, 43, 2515-2519C. Sanna et al. Langmuir 2006, 22, 6021-6031
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Monomeric resonances
1H spectra of dilute aqueous solutions of METOMETO, ACETACET and PRETPRET, (Conc < sol)
11H experimentsH experiments
6.97.07.17.27.37.4 ppm 0.91.01.11.2 ppm
a b
S. Viel et al. Tetrahedron Lett. 2002, 43, 2515-2519C. Sanna et al. Langmuir 2006, 22, 6021-6031
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1H spectra of dilute aqueous solutions of METOMETO, ACETACET and PRETPRET, (Conc > sol)
11H experimentsH experiments
6.97.07.17.27.37.4 ppm 0.91.01.11.2 ppm
a b
Monomeric resonances
Extra resonances
S. Viel et al. Tetrahedron Lett. 2002, 43, 2515-2519C. Sanna et al. Langmuir 2006, 22, 6021-6031
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11H experimentsH experiments1H spectra of dilute aqueous solutions of METOMETO, ACETACET and PRETPRET, (Conc > sol)
6.97.07.17.27.37.4 ppm 0.91.01.11.2 ppm
a b•Well resolved
•Upfield shifted
S. Viel et al. Tetrahedron Lett. 2002, 43, 2515-2519C. Sanna et al. Langmuir 2006, 22, 6021-6031
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ppm
7 6 5 4 3 2 1 ppm
-9.0
-9.5
-10.0
-10.5
Aggregate
Monomer
Log D
(m s )2 -1
PGSE experiments (DOSY display)PGSE experiments (DOSY display)
PGSE on a dilute aqueous solution of ACETACET
Much lower diffusion coefficient
S. Viel et al. Tetrahedron Lett. 2002, 43, 2515-2519C. Sanna et al. Langmuir 2006, 22, 6021-6031
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PGSE experimentsPGSE experiments
(nm)(10-11 m2 s-1)(mM)
101.943PRETPRET 151.346METOMETO 111.750ACETACET
Aggregate
0.45043PRETPRET 0.45146METOMETO 0.45350ACETACET
Monomer
RHDNMRConc
Hydrodynamic radiiHydrodynamic radii(Stokes Einstein,Sphere)
S. Viel et al. Tetrahedron Lett. 2002, 43, 2515-2519C. Sanna et al. Langmuir 2006, 22, 6021-6031
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NOESY experimentsNOESY experimentsNOESY spectrum of a dilute aqueous solution of ACETACET
400 ms400 ms
Color of cross peaks:
Blue : NegativeGreen/Yellow : Positive
S. Viel et al. Tetrahedron Lett. 2002, 43, 2515-2519C. Sanna et al. Langmuir 2006, 22, 6021-6031
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NOESY experimentsNOESY experimentsNOESY spectrum of a dilute aqueous solution of ACETACET
400 ms400 ms
Color of cross peaks:
Blue : Negative cross-peakGreen/Yellow : Positive cross-peak
Spin Diffusion
S. Viel et al. Tetrahedron Lett. 2002, 43, 2515-2519C. Sanna et al. Langmuir 2006, 22, 6021-6031
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NOESY experimentsNOESY experimentsNOESY spectrum of a dilute aqueous solution of ACETACET
10 ms10 ms
Color of cross peaks:
Blue : NegativeGreen/Yellow : Positive
S. Viel et al. Tetrahedron Lett. 2002, 43, 2515-2519C. Sanna et al. Langmuir 2006, 22, 6021-6031
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DLS experimentsDLS experiments
Hydrodynamic radiiHydrodynamic radii of the aggregates were also estimated by DLS
(nm)(10-13 m2 s-1)(mM)
3006.52ACETACET 2507.83PRETPRET 7002.813METOMETO
Aggregate
RHDConc
METOMETO
PRETPRET
ACETACET
S. Viel et al. Tetrahedron Lett. 2002, 43, 2515-2519C. Sanna et al. Langmuir 2006, 22, 6021-6031
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Physico-chemical propertiesPhysico-chemical propertiesSurface Surface TensionTension
Activity Activity CoeffCoeff
Osmotic Osmotic CoeffCoeff
Rel. viscosityRel. viscosity
S. Viel et al. Tetrahedron Lett. 2002, 43, 2515-2519C. Sanna et al. Langmuir 2006, 22, 6021-6031
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Diffusion-Ordered NMR Spectroscopy: a versatile tool for the molecular weight
determination of uncharged polysaccharides
Molecular weightMolecular weight
S. Viel, D. Capitani, L. Mannina, A. L. SegreBiomacromolecules 2003, 4, 1843-1847
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IntroductionIntroduction•Polysaccharides constitute a major class of biomacromolecules and play key roles in biological recognition processes.
•Their structural elucidation relies mainly on NMR, but a complete characterization may also require the molecular weight (MW).
•Available techniques: Photonic Correlation Spectroscopy, Gel Permeation Chromatography
Drawbacks: sample manipulation
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91S. Viel, D. Capitani, L. Mannina, A. L. SegreBiomacromolecules 2003, 4, 1843-1847
Diffusion and MassDiffusion and Mass•Strictly, diffusion relates to molecular size. A calibration is hence required to establish the relationship between diffusion coefficient and molecular weight
Pullulan (linear polysaccharide)
6 fractions (kDa): 5.8; 12; 28.3; 100; 180 and 853Studied by PGSE experiments
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92S. Viel, D. Capitani, L. Mannina, A. L. SegreBiomacromolecules 2003, 4, 1843-1847
Diffusion and MassDiffusion and Mass
853 kDa5.8 kDa 100 kDa
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100 1000 10000 100000 10000001E-11
1E-10
1E-9
Pullulan
S. Viel, D. Capitani, L. Mannina, A. L. SegreBiomacromolecules 2003, 4, 1843-1847
Determination of Molecular Weight:Determination of Molecular Weight:Pullulan as a Model SamplePullulan as a Model Sample
MW(Da)
D(m2/s)
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94S. Viel, D. Capitani, L. Mannina, A. L. SegreBiomacromolecules 2002, 4, 1843-1847
Determination of Molecular Weight:Determination of Molecular Weight:Calibration curveCalibration curve
100 1000 10000 100000 10000001E-11
1E-10
1E-9
Pullulan Calibration Curve
D(m2/s)
MW(Da)
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95S. Viel, D. Capitani, L. Mannina, A. L. SegreBiomacromolecules 2002, 4, 1843-1847
Determination of Molecular Weight:Determination of Molecular Weight:Check with another polysaccharideCheck with another polysaccharide
D(m2/s)
MW(Da)100 1000 10000 100000 1000000
1E-11
1E-10
1E-9
Calibration Curve Dextran
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96S. Viel, D. Capitani, L. Mannina, A. L. SegreBiomacromolecules 2003, 4, 1843-1847
Determination of Molecular Weight:Determination of Molecular Weight:Check with oligosaccharidesCheck with oligosaccharides
D(m2/s)
MW(Da)100 1000 10000 100000 1000000
1E-11
1E-10
1E-9
Calibration Curve Dextran Cyclodextrins - Oligosaccharide
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97S. Viel, D. Capitani, L. Mannina, A. L. SegreBiomacromolecules 2003, 4, 1843-1847
Determination of Molecular Weight:Determination of Molecular Weight:Check with saccharidesCheck with saccharides
D(m2/s)
MW(Da)100 1000 10000 100000 1000000
1E-11
1E-10
1E-9
Calibration Curve Dextran Cyclodextrins - Oligosaccharide Saccharides
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98
Use of Pulsed Field Gradient Spin-Echo NMR as a tool in MALDI method
development for polymer Mw determination
Molecular WeightMolecular Weight
M. Mazarin, S. Viel, B. Allard-Breton, A. Thévand, L. CharlesAnal. Chem. 2006, 78, 2758-2764
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99
PolymersPolymers
M. Mazarin, S. Viel, B. Allard-Breton, A. Thévand, L. CharlesAnal. Chem. 2006, 78, 2758-2764
pMAMpMAM
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Concentration (mg.mL-1)
0.0 1.0 2.0 3.0 4.0
D (
m2 .s
-1)
0.0
2.0e-10
4.0e-10
6.0e-10
8.0e-10
1.0e-9
1.2e-9
1.4e-9
Mw 309 (D0 = 1.172e-9)
Mw 972 (D0 = 6.596e-10)
Mw 3460 (D0 = 3.405e-10)
Mw 9830 (D0 = 1.973e-10)
Mw 23800 (D0 = 1.189e-10)
Mw 74500 (D0 = 5.903e-11)
D=f[PS] D0PS=f(Mw)
Molecular weight Mw (Da)
10 100 1000 10000 100000 1000000
D0
(m2 .s
-1)
1e-11
1e-10
1e-9
1e-8
0.54122.721448e-8
Polymers Polymers PSPS
CDCl3
D = k Mw -a
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PS : Comparison Mw : SEC, NMR and MS
12.012.1(Fluka)
83416 2038353974500PS 70000
-3.8-3.8(Fluka)
22890 492290723800PS 20000
-4.6-8.6(Fluka)
9375 1089869830PS 10000
0.3-5.2(Fluka)
3470 432783460PS 3000
-5.6-0.6(Fluka)
918 6966972PS 1000
40.5-8.1(Sigma-Aldrich)
434 10334309PS 400
MALDI-TOF-MSNMRSEC (provider)PS standards
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102
Analysis of mixtures (part I)Analysis of mixtures (part I)
Improved 3D DOSY-TOCSY experiment for mixture analysis
S. Viel, S. CaldarelliChem. Comm. 2008, in press
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103S. Viel, S. Caldarelli
Chem. Comm. 2008, in press
IntroductionIntroduction
•Overlapping signals severely complicate DOSY analysis
•A typical solution is the addition of another frequency dimension to spread the signals out
Drawback: time consuming experiments due to the requirement of sampling the indirect frequency dimension
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104
Speeding up 3D NMR Speeding up 3D NMR experimentsexperiments
•Various methodologies have been proposed to speed up 3D NMR experiments (FDM)
S. Viel, S. Caldarelli
Chem. Comm. 2008, in press
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105
Speeding up 3D NMR Speeding up 3D NMR experimentsexperiments
•Various methodologies have been proposed to speed up 3D NMR experiments (FDM)
•One possibility is Hadamard (there are other ones
S. Viel, S. Caldarelli
Chem. Comm. 2008, in press
………...….….3D iRRT would be great!)
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106
Speeding up 3D NMR Speeding up 3D NMR experimentsexperiments
•Various methodologies have been proposed to speed up 3D NMR experiments
•One possibility is Hadamard (there are other ones
S. Viel, S. Caldarelli
Chem. Comm. 2008, in press
………...….….3D iRRT would be great!)
•In Hadamard NMR spectroscopy, the evolution time in the indirect dimension of the 2D block is replaced by phase-encoded multisite selective excitation
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107
Hadamard encodingHadamard encoding
S. Viel, S. Caldarelli
Chem. Comm. 2008, in press
Hadamard family matrices HMatrix dimension N:N = 2k (k = 1, 2, 3…)
+––+––++–+–+++++
Pulse 1
Pulse 2
Pulse 3
Pulse 4
A B C D
– HHHH
M chemical sites NM
–+++
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108
Hadamard encodingHadamard encoding
S. Viel, S. Caldarelli
Chem. Comm. 2008, in press
Hadamard family matrices HMatrix dimension N:N = 2k (k = 1, 2, 3…)
+––+––++–+–+++++
Pulse 1
Pulse 2
Pulse 3
Pulse 4
A B C D
M chemical sites NM – HHHH
–+++
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109
Hadamard encodingHadamard encoding
S. Viel, S. Caldarelli
Chem. Comm. 2008, in press
Hadamard family matrices HMatrix dimension N:N = 2k (k = 1, 2, 3…)
+––+––++–+–+++++
Pulse 1
Pulse 2
Pulse 3
Pulse 4
A B C D
M chemical sites NM – HHHH
–+++
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110
Hadamard encodingHadamard encoding
S. Viel, S. Caldarelli
Chem. Comm. 2008, in press
Hadamard family matrices HMatrix dimension N:N = 2k (k = 1, 2, 3…)
+––+––++–+–+++++
Pulse 1
Pulse 2
Pulse 3
Pulse 4
A B C D
Signal B = + 1 – 2 + 3 – 4M chemical sites NM – HHHH
–+++
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111
Proposed pulse sequenceProposed pulse sequence
S. Viel, S. Caldarelli
Chem. Comm. 2008, in press
Thrippleton, M. J.; Keeler, J., Angew. Chem. Int. Ed. 2003, 42, 3938-3941.
Cano, K. E.; Thrippleton, M.; Keeler, J.; Shaka, A. J., J. Magn. Reson. 2004, 167, 291-297.ZQC filters
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112
Proof of principle (1)Proof of principle (1)
S. Viel, S. Caldarelli
Chem. Comm. 2008, in press
TOCSY spectrum of a mixture of:
- Methanol (M)- Ethanol (E)- Propanol (P)- Valine (V)
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113
Proof of principle (2)Proof of principle (2)
S. Viel, S. Caldarelli
Chem. Comm. 2008, in press
M
P
E
V
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114
Effect of signal overlappingEffect of signal overlapping
S. Viel, S. Caldarelli
Chem. Comm. 2008, in press
Propanol
OH
OH
2-Butanol
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115
Effect of signal overlapping (2)Effect of signal overlapping (2)
S. Viel, S. Caldarelli
Chem. Comm. 2008, in press
OHOH
Time saving factor: 64
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116
Analysis of mixtures (part II)Analysis of mixtures (part II)
Enhanced diffusion-edited NMR spectroscopy of mixtures using
chromatographic stationary phases
S. Viel, F. Ziarelli, S. CaldarelliProc. Natl. Acad. Sci. U. S. A. 2003, 100, 9696-9698
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117
Can we selectively slow down the diffusion of some components of the mixture?
S. Viel, F. Ziarelli, S. Caldarelli
Proceedings of the National Academy of Sciences of the United States of America 2003, 100, 9696-9698
IntroductionIntroduction
•PGSE experiments allow compounds to be discriminated according to differences in their effective size (mixture analysis)
•Corollary: similar sized compounds CANNOT be resolved by PGSE
Chromatographic phases
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118S. Viel, F. Ziarelli, S. Caldarelli
Proceedings of the National Academy of Sciences of the United States of America 2003, 100, 9696-9698
PrinciplePrinciple
•A chromatographic phase interacts selectively with some of the mixture components (for instance: polarity/apolarity)
•Discrimination is achieved according to apparent diffusion rates(instead of free self-diffusion coefficients)
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119S. Viel, F. Ziarelli, S. Caldarelli
Proceedings of the National Academy of Sciences of the United States of America 2003, 100, 9696-9698
Problem: spectral resolution!Problem: spectral resolution!1H of Sol. + Stationary phase
Conventional NMRHHigh RResolutionMMagic AAngle SSpinning: solid state technique
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120S. Viel, F. Ziarelli, S. Caldarelli
Proceedings of the National Academy of Sciences of the United States of America 2003, 100, 9696-9698
Problem: spectral resolution!Problem: spectral resolution!1H of Sol. + Stationary phase
Conventional NMRHHigh RResolutionMMagic AAngle SSpinning: solid state technique
HRMAS NMR
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121S. Viel, F. Ziarelli, S. Caldarelli
Proceedings of the National Academy of Sciences of the United States of America 2003, 100, 9696-9698
HRMASHRMAS
HRMAS rotorHRMASprobe
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122S. Viel, F. Ziarelli, S. Caldarelli
Proceedings of the National Academy of Sciences of the United States of America 2003, 100, 9696-9698
Example 1Example 1
Mixture 1:Mixture 1:- Dichlorophenol- Ethanol- Heptane
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123S. Viel, F. Ziarelli, S. Caldarelli
Proceedings of the National Academy of Sciences of the United States of America 2003, 100, 9696-9698
Example 1Example 1
Mixture 1:Mixture 1:- Dichlorophenol- Ethanol- Heptane
+
SiO2
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124S. Viel, F. Ziarelli, S. Caldarelli
Proceedings of the National Academy of Sciences of the United States of America 2003, 100, 9696-9698
Example 2Example 2
Mixture 2:Mixture 2:- Naphtalene- Dec-1-ene - Ethanol
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125S. Viel, F. Ziarelli, S. Caldarelli
Proceedings of the National Academy of Sciences of the United States of America 2003, 100, 9696-9698
Example 2Example 2
Mixture 2:Mixture 2:- Naphtalene- Dec-1-ene - Ethanol
+
C18
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126S. Viel, F. Ziarelli, S. Caldarelli
Proceedings of the National Academy of Sciences of the United States of America 2003, 100, 9696-9698
Research directionsResearch directions
• Improve resolution of complex mixtures
• Characterize new chromatographic phases
• Investigate chromatographic phenomenon
• Discriminate stereoisomers
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PFG MAS diffusion PFG MAS diffusion measurementsmeasurements
Pulsed field gradient magic angle spinning NMR self-diffusion
measurements in liquids
S. Viel, F. Ziarelli, G. Pagès, C. Carrara, S. CaldarelliJ. Magn. Reson. 2008, 190, 113-123
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128
Gradients and MAS probesGradients and MAS probes
S. Viel, F. Ziarelli, G. Pagès, C. Carrara, S. Caldarelli
J. Magn. Reson. 2008, 190, 113-123
Courtesy of Bruker Instruments
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129
Magic gradientMagic gradient
S. Viel, F. Ziarelli, G. Pagès, C. Carrara, S. Caldarelli
J. Magn. Reson. 2008, 190, 113-123
Courtesy of Bruker Instruments
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130S. Viel, F. Ziarelli, G. Pagès, C. Carrara, S. Caldarelli
J. Magn. Reson. 2008, 190, 113-123
Courtesy of Bruker Instruments
Stator
Gradients
Magic gradientMagic gradient
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131S. Viel, F. Ziarelli, G. Pagès, C. Carrara, S. Caldarelli
J. Magn. Reson. 2008, 190, 113-123
Gradient calibration: Gradient calibration: ProfileProfileHahn echo on a H2O/D2O sample with gradient during acquisition
Adapted from Hurd et al.
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132S. Viel, F. Ziarelli, G. Pagès, C. Carrara, S. Caldarelli
J. Magn. Reson. 2008, 190, 113-123
Gradient calibration: Gradient calibration: ProfileProfile
6%
95%
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133
Gradient calibration: strengthGradient calibration: strength
S. Viel, F. Ziarelli, G. Pagès, C. Carrara, S. Caldarelli
J. Magn. Reson. 2008, 190, 113-123
Rotor:
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134S. Viel, F. Ziarelli, G. Pagès, C. Carrara, S. Caldarelli
J. Magn. Reson. 2008, 190, 113-123
Rotor:
V = 50 LV = 12 L
G = 6.0 G cm-1 A-1
Gradient calibration: strengthGradient calibration: strength
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Effect of spinningEffect of spinning
S. Viel, F. Ziarelli, G. Pagès, C. Carrara, S. Caldarelli
J. Magn. Reson. 2008, 190, 113-123
Water
Water ACN
ACN
12 L
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Effect of spinningEffect of spinning
S. Viel, F. Ziarelli, G. Pagès, C. Carrara, S. Caldarelli
J. Magn. Reson. 2008, 190, 113-123
Water
Water ACN
ACN
50 L
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Results: ACN 4 kHzResults: ACN 4 kHz
S. Viel, F. Ziarelli, G. Pagès, C. Carrara, S. Caldarelli
J. Magn. Reson. 2008, 190, 113-123
50 L12 L
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138S. Viel, F. Ziarelli, G. Pagès, C. Carrara, S. Caldarelli
J. Magn. Reson. 2008, 190, 113-123
ResultsResults
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ResultsResults
S. Viel, F. Ziarelli, G. Pagès, C. Carrara, S. Caldarelli
J. Magn. Reson. 2008, 190, 113-123
PEO 116kDa D2O 4 kHz PEO 116kDa CDCl3 3 kHz
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140S. Viel, F. Ziarelli, S. Caldarelli
Proceedings of the National Academy of Sciences of the United States of America 2003, 100, 9696-9698
Research directionsResearch directions
• Improve resolution of complex mixtures
• Characterize new chromatographic phases
• Investigate chromatographic phenomenon
• Discriminate stereoisomers
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HPLC
PFG MAS
ODS phase Silica gel
G. Pagès et al. Anal. Chem. 2006, 78, 561-566
G. Pagès et al. Angew. Chem. Int. Ed. 2006, 45, 5950-5953
Mixture of:
- Benzene- Naphthalene- Anthracene(ACN/H2O, 90/10)
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Merci
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Grazie
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Thank you !
A
BC
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A
BC