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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
1.0.3
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
Professor Guy Lloyd-Jones, FRS
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)
Professor Guy Lloyd-Jones, FRS
1. Flow Unit 2. High speed delivery
pumps 3. NMR system
The Solution for Fast Reaction Monitoring and Optimisation
InsightXpress Automated in-situ Monitoring
+ +
Professor Guy Lloyd-Jones, FRS
InsightXpress Automated in-situ Monitoring
Professor Guy Lloyd-Jones, FRS
Stop-Flow with added Flexibility
• unlimited ‘shots’
• variable conc.
• variable reagents
• temp. control
• fast
• reproducible
InsightXpress Automated in-situ Monitoring
Professor Guy Lloyd-Jones, FRS
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
© Copyright Bruker Corporation. All rights reserved.
Innovation with Integrity
Copyright © 2011 Bruker Corporation. All rights reserved. www.bruker.com
4. attached flow lines to
reagent reservoirs
A, B, C, W
© Copyright Bruker Corporation. All rights reserved.
Innovation with Integrity
Copyright © 2011 Bruker Corporation. All rights reserved. www.bruker.com
4. attached flow lines to
reagent reservoirs
5. connect to thermostatic circulator
A, B, C, W
© Copyright Bruker Corporation. All rights reserved.
Innovation with Integrity
Copyright © 2011 Bruker Corporation. All rights reserved. www.bruker.com
4. attached flow lines to
reagent reservoirs
5. connect to thermostatic circulator
A, B, C, W
Professor Guy Lloyd-Jones, FRS
Professor Guy Lloyd-Jones, FRS
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
Professor Guy Lloyd-Jones, FRS
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.
Professor Guy Lloyd-Jones, FRS
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
© Copyright Bruker Corporation. All rights reserved.
Innovation with Integrity
Copyright © 2011 Bruker Corporation. All rights reserved. www.bruker.com
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