Reaction Monitoring with NMR - Bruker · PDF fileReaction Monitoring with NMR Aitor Moreno...

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

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