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Diffusion Ordered SpectroscopyPowerPoint Presentation

Diffusion Ordered Spectroscopy

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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

- 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)

- 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 relates to molecular size!

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

- larmour frequency,T2, rotating frame of reference

How to measure diffusion coefficients?

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

- 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

- 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

Attenuation of Signal as Gz Increases

Stokes-Einstein

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

What can we study with DOSY?

- Analysis of Mixtures
- Intra-molecular interactions
- Supra and biomolecular complexes
- Affinity
- Chemical exchange

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
- Exchange

Host-Guest Complexes

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

Solving for Ka – for small molecule and large Host

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

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 Complexes

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

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 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.

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

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

Determination of Precursors:

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

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

Limitations

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

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.

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