Diffusion ordered spectroscopy
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Diffusion Ordered Spectroscopy. Diffusion Ordered Spectroscopy. Provides a way to separate different compounds in a mixture based on the differing translational diffusion coefficients (differences in the size and shape of a molecule)

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Diffusion Ordered Spectroscopy

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Diffusion ordered spectroscopy

Diffusion Ordered Spectroscopy


Diffusion ordered spectroscopy1

Diffusion Ordered Spectroscopy

  • Provides a way to separate different compounds in a mixture based on the differing translational diffusion coefficients (differences in the size and shape of a molecule)

  • Achieved by radio-frequency pulses as used in routine NMR spectroscopy and magnetic field gradients that encode spatial information


Self diffusion

Self-Diffusion

  • Random translational motion of molecules or ions through the surrounding media driven by thermal energy (Brownian motion)

  • NO thermal gradient (convection)

  • NO concentration gradient (mutual diffusion)


Diffusion coefficient d

Diffusion Coefficient (D)

  • Quantifies this motion as a measure of the rate of mean square displacement of the molecule (Units of m2s-1)

  • We can measure diffusion by NMR if we can map the location of a molecule in solution and how this varies as a function of time


Diffusion and mass

Diffusion and Mass

  • Diffusion relates to molecular size!


Study of self diffusion

Study of Self-Diffusion

Two steps:

  • Spatially label the nuclear spins using gradients of magnetic field

  • Monitor their displacement by measuring their spatial positions at 2 distinct times


Refresher nmr basics

Refresher: NMR Basics

  • larmour frequency,T2, rotating frame of reference


How to measure diffusion coefficients

How to measure diffusion coefficients?

  • Short period (~1ms) in which magnetic field experienced by the NMR sample is made inhomogeneous!


Pulse sequence pulsed field gradient echo

Pulse Sequence – Pulsed Field Gradient Echo


Diffusion ordered spectroscopy

  • DOSY uses two PFG pulses separated by a diffusion time Δ

  • First PFG destroys (dephases) all signals

  • Second PFG acts in opposition to first & may recover (rephase) signals

  • IF NO MOVEMENT during Δ – FULL signal recovered

  • IF MOVEMENT OCCURS during Δ, signal is NOT fully rephased leading to loss of signal


Diffusion nmr

Diffusion NMR

  • Movement of molecules during Δ leads to LOSS of resonance intensity

  • Diffusion profile is obtained by increasing magnitude of field gradient Gz for repeated 1D experiments

  • Faster molecular diffusion corresponds to faster signal attentuation as a function of Gz


Diffusion magnetic field gradient

Diffusion & Magnetic Field Gradient


Attenuation of signal as g z increases

Attenuation of Signal as Gz Increases


Dosy nmr

DOSY NMR


Stokes einstein

Stokes-Einstein

  • Stokes- Einstein relation relates the Diffusion coefficient, D, of a particle to its molecular shape via a friction coefficient f (FOR SPHERE)


Diffusion spectra

Diffusion Spectra


What can we study with dosy

What can we study with DOSY?

  • Analysis of Mixtures

  • Intra-molecular interactions

  • Supra and biomolecular complexes

  • Affinity

  • Chemical exchange


Diffusion applications

Diffusion Applications

  • Aggregation

    Slower Diffusion as molecules self-aggregate

  • Host-guest formation

    Binding of small “guest” molecules within larger host leads to slower diffusion

  • Supramolecular chemistry

    Assessment of molecular size


Complexes and exchange

Complexes and Exchange

  • Complexes

  • Exchange


Host guest complexes

Host-Guest Complexes

Cameron,K., Fielding, L. 2001. J. Org. Chem. 66, 6891.


Solving for k a for small molecule and large host

Solving for Ka – for small molecule and large Host

Cameron,K., Fielding, L. 2001. J. Org. Chem. 66, 6891.


Dosy k a

DOSY: Ka

  • Approximations remove need to perform titrations, and Ka in principle can be derived from a single experiment.

  • Assumption is sound for small molecules binding to macro(biological molecules)

  • However for smaller Host-Guest chemistry – this assumption is not always true


Host guest complexes1

Host-Guest Complexes

Cameron,K., Fielding, L. 2001. J. Org. Chem. 66, 6891.


Aggregation

Aggregation

  • Simplest form of oligomerization is dimerization

  • Two monomers come together to form a dimer

    Similar to H + G HG

    2A A2

    Kdimer= [A2]/[A]2


Dosy nmr analysis of ring closing metathesis rcm products from lactam precursors

DOSY-NMR analysis of ring-closing metathesis (RCM) products from β-lactam precursors

  • Limitation of RCM for formation of intramolecular ring-closed products is the occurrence of side products from intermolecular oligomerization!

  • Identification of reaction products is not straightforward: 1H 13C NMR data may be inconclusive because of complexity. Mass spec – inconclusive.

  • DOSY is the answer!

Sliwa, A., Marchand-Brynaert, J., Luhmer, M. 2011 Magn. Reson. Chem. 49, 812.


Diffusion ordered spectroscopy

Sliwa, A., Marchand-Brynaert, J., Luhmer, M. 2011 Magn. Reson. Chem. 49, 812.


Diffusion ordered spectroscopy

Sliwa, A., Marchand-Brynaert, J., Luhmer, M. 2011 Magn. Reson. Chem. 49, 812.


Determination of precursors

Determination of Precursors:

Sliwa, A., Marchand-Brynaert, J., Luhmer, M. 2011 Magn. Reson. Chem. 49, 812.


Limitations

Limitations

  • Measuring accurate diffusion constants required a high quality gradient coil. Gradients have to be linear.

  • Good temperature stability required

  • Assumptions of spherical shape often used – not always accurate

  • 2D Transformation Errors – diffusion coefficients should differ as much as possible from one another & Standard errors should be marginal


Limitations1

Limitations

Cohen, Y., Avram, L., Frish, L., 2005. Angew. Chem. 44, 520


In summary dosy

In Summary: DOSY

  • Powerful method for the NMR analysis of many types of mixtures

  • Measure diffusion coefficients which reflect size and shape of molecular species

  • Applications: association constants, investigating aggregation, encapsulation, intermolecular interactions in multi-component systems and size and structure of labile systems.


Questions

Questions?


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