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Reaction Monitoring with NMR

Aitor Moreno

Bruker BioSpin, Switzerland

BeNeLux NMR User Meeting 2016, Brussels

25th of November 2016

Reaction Monitoring What is it and Why are we Doing it?

• Purpose:

– Reaction completion determination

– In-situ yield determination

– Reaction understanding: mechanistic information

– Extracting kinetic parameters from the time

course data: activation energy, rate constant

– Stability, degradation studies

– Dissolution

– Bio transformations

– …

• Calorimetry

• LC-UV

• MS, GC, GC-MS

• IR

• NMR

• Quantitative by default: ‘no need to calculate response factors’!

• Information rich: possible to elucidate the structure of starting materials, products, and intermediates.

Techniques for Reaction Monitoring

Clegg I.M., Gordon C.M., Smith D.S., Alzaga R., Codina A., Anal Methods, 2012, 4, 1498 // Foley D.A. et. al. J Org Chem, 2011,

76, 9630 // Khajeh M., Bernstein M.A., and Morris G.A., Magn Reson Chem, 2010, 48, 516

© Copyright Bruker Corporation. All rights reserved.

Innovation with Integrity

Copyright © 2011 Bruker Corporation. All rights reserved. www.bruker.com

Some Available Options

What’s missing?

1. A single interface for on-the-fly acquisition control, based on

real-time data processing and analysis

2. Hardware for online monitoring in real-time under real condition

InsightMR The Solution to Enhance Process Understanding

InsightMR flow tube

InsightMR software

InsightMR Flow Tube

December 5, 2016 7

Laboratory Setup for Chemical Applications

Bruker’s Current Offering

& Accessories

Laboratory Setup

NMR Signal Stability Testing

20 mM sucrose in H2O, 10% D2O 10 mM sucrose in H2O, 10% D2O

12

Delay of Transfer

(a) Integral corresponds to 15 mM composition

(b) @27.75 min Composition in pump was changed to 100%

(c) After 1 min @ 28.75 min change visible in NMR

(d) After 1.75 min @ 29.5 min 90% of target composition reached

(e) After ~3 min @ 30.5 min ~100% target composition reached

• <1-2 min is possible by adjusting the flow rate to 2-3ml/min

• Adjustment of hardware (length diameter) also possible.

• (4 m length, 1 ml/min flow, 0.5 mm i.d. capillaries)

Pump contributes ~100 ul to delay of concentration step propagation.

(b)

(a) (c)

(d)

(e)

Flow Behaviour

Hall A. et.al., Catalysis Science & Technology, 2016, DOI: 10.1039/C6CY01754A

Stopped flow, 16%

Flow 1 ml/min, 17%

Line Shape Test – 10 mM sucrose

Flow 1 ml/min, after re-shimming, 15%

DMF Maleic Anh. Product

CH3CN

25C

acetonitrile

Diels Alder Chemistry, NON-Deuterated Solvent

7 8

Diels Alder Chemistry, NON-Deuterated Solvent

7 8

InsightMR Software

Integration Acquisition - Analysis Click

Spectra Display

Click Acquisition

Answers to Chemical Questions Concentration Profiles

DMF Maleic Anh. Product

Visual, immediate

chemical information!!

Key Benefits

• Online reaction monitoring in real-time under real condition

• Compatible with Bruker 5 mm probes

• Complete temperature control from vessel to probe

• A single interface for automated acquisition control, and interactive processing

and analysis

• On-the-fly acquisition changes as needed based on real-time kinetic data

• Rapid and effortless handling of hundreds of stacked spectra

Professor Guy Lloyd-Jones, FRS

Are we Fast Enough?

Mixing

Acquisition

Standard NMR tubes Online – InsightMR (with batch reactor)

Transfer times in the order of minutes


When do we Need to go Faster?

1. Repeating the reaction varying conditions

Labour - intensive

Time consuming

0.000

0.005

0.010

0.015

0.020

0.025

0.030

0.035

0.040

0.045

0.050

0 5 10 15 20 25 30

Co

nc

(M

)

Time (s)

t½ ≈ 5 s mix

insert

lock

start….

2. Fast Reactions (seconds)


1. Flow Unit 2. High speed delivery

pumps 3. NMR system

The Solution for Fast Reaction Monitoring and Optimisation

InsightXpress Automated in-situ Monitoring

+ +


Stop-Flow with added Flexibility

• unlimited ‘shots’

• variable conc.

• variable reagents

• temp. control

• fast

• reproducible



Schematics

waste

130 msec deadtime

300 uL

600 uLshot

A B C

RESERVOIRS

DELIVERYMODULE

CONSOLE

W S

W

300 uL

trigger

C

A

BFlow cell

variable delay (D1 ). pluse, FIDvariable delay (D2)cycle

solvent flush ( n x 1ml)

ON TOP OFMAGNET

IN MAGNET

thermostattedby spectrometer

A B C

S

S

AWAY FROM MAGNET (e.g. in fume hood)

CONTROL SOFTWARE

i) VTOT

ii) velocity (ml / sec)

iii) fractions A, B, and C

SPECTROMETER

PRE-CONDITIONER(temp, magnetisation)

W

shotsignal

thermostattedby Reaction Express

IN MAGNET




4. attached flow lines to

reagent reservoirs

A, B, C, W




4. attached flow lines to

reagent reservoirs

5. connect to thermostatic circulator

A, B, C, W


Manual Sample Preparation

protodeboronation

aq. dioxane, KOH

BOH

OH

FF

F

H

FF

F

F F

14 Kobs (rate) values

X 20 data points = 280 NMR tubes

~ 1-2 weeks work

In-situ stop flow monitoring

0

0.0005

0.001

0.0015

0.002

0.0025

0.003

0.0035

0 0.5 1 1.5 2

Rat

e

equiv OH

14 Kobs (rate) values

3 h


max. signal without

pre-mag.19F with a 4 sec T1

t½ ≈ 1 second

Cox, P. A.; Leach, A. G.; Campbell, A. D.; Lloyd-Jones, G. C. J. Am. Chem. Soc. 2016 DOI: 10.1021/jacs.6b03283.

Cox, P. A.; Reid, M.; Leach, A. G.; Campbell, A. D.; King, E. G.; Lloyd-Jones, G. C. submitted, 2016.


InsightXpress Features at a Glance

• Used when needed seats on SampleXpress base

• Simple install 10-15 min

• Low sample vol a+b+c ≤ 600 uL / shot

• Time efficiency unlimited shots

• Variable ratios explore

• Temp. control detailed kinetics

• Pre-magnetisation quantitative

• Precise timing triggered pulse trains

• Reproducible stable measured vol.

• fast reactions <150 ms dead-time

• In-situ clean solvent flush line

Acknowledgments

• InsightMR team

• Anna Codina

• Peter Neidig

• Mark Garvey

• Martin Hofmann

• Ulrich Braumann

reaction monitoring with nmr - bruker · pdf filereaction monitoring with nmr aitor moreno...

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