Online monitoring of a photocatalytic reaction by real-time high resolution FlowNMR spectroscopy

Article abstract of DOI:10.1039/c7cc07059d

We demonstrate how FlowNMR spectroscopy can readily be applied to investigate photochemical reactions that require sustained input of light and air to yield mechanistic insight under realistic conditions. The Eosin Y mediated photo-oxidation of N-allylbenzylamine is shown to produce imines as primary reaction products from which undesired aldehydes form after longer reaction times. Facile variation of reaction conditions during the reaction in flow allows for probe experiments that give information about the mode of action of the photocatalyst.

Full text of DOI:10.1039/c7cc07059d

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and U. Hintermair, Chem. Commun., 2017, DOI: 10.1039/C7CC07059D.
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DOI: 10.1039/C7CC07059D
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Online Monitoring of a Photocatalytic Reaction by Real-time High
Resolution FlowNMR Spectroscopy
Received 00th January 20xx,
Accepted 00th January 20xx
Andrew M. R. Hall,a Rachael Broomfield-Tagg,b Matthew Camilleri,a David R. Carbery,b* Anna
Codina,c David T. E. Whittaker,d Steven Coombes,d John P. Lowe,b and Ulrich Hintermaira*
DOI: 10.1039/x0xx00000x
www.rsc.org/
We demonstrate how FlowNMR spectroscopy can readily be techniques are incompatible with photochemical reactions due to
applied to investigate photochemical reactions that require the difficulties in irradiating the sample once it is inside the
sustained input of light and air to yield mechanistic insight under magnet.13, 14
realistic conditions. The Eosin Y mediated photo-oxidation of N- For this reason, most NMR monitoring of photochemical reactions is
allylbenzylamine is shown to produce imines as primary reaction performed off-line, but the delays and sample work-up procedures
products from which undesired aldehydes form after longer between reaction and analysis often entail compositional changes.
reaction times. Facile variation of reaction conditions during the In-situ approaches including setups where light is guided from an
reaction in flow allows for probe experiments that give information external source to the sample inside the spectrometer using mirrors
about the mode of action of the photocatalyst.
or fibre-optic cables,18, 19 special sample tubes with miniature LED
light sources inside the spectrometer20, 21 and modified NMR probes
Photochemical reactions are an important part of the modern
synthetic chemists’ repertoire due to the unique chemistry occurring
in the excited state.1-5 Visible light photo(redox)catalysis is of
particular current interest due to the potential for utilization of
sunlight as sustainable energy source in chemical synthesis.6-11 In
order to gain an understanding of the mechanisms involved in these
reactions it is necessary to have a means of producing high quality
kinetic data under realistic conditions. Spectroscopic techniques
such as Ultra-violet visible (UV-vis), Infrared (IR) and fluorescence
spectroscopies have been widely used for monitoring photochemical
reactions, however, these techniques are only able to provide limited
structural information about reaction species and require calibration
before use.1, 12-15 Mass Spectrometry represents a complimentary
technique with higher sensitivity and resolution, but structural
information may still be limited for novel compounds where
14
have been developed13,
but these require custom-made
equipment and are the domain of specialists. In addition, these
setups do not allow for mixing of the sample or changes in reaction
conditions,22 and often deliver light at one point only.14, 19-21 The lack
of control of light intensity across the sample means that recreating
realistic conditions is difficult, which may result in different rates
or/and mechanisms for reactions that are limited by photon density.
The use of NMR as online monitoring technique has been known for
some years, primarily as a detection method in HPLC-NMR coupled
analysis,23, 24 but only recently gained interest as a method for real-
time reaction monitoring. This has been spurred on by the recent
commercialisation of a number of dedicated FlowNMR monitoring
systems25-28 accompanied by several reports detailing general
29, 30
considerations for their use.26,
Online FlowNMR techniques
utilize an external reaction vessel, situated outside of the influence
of the magnetic field, with sample continuously pumped into the
spectrometer through a dedicated NMR flow tube located within a
standard NMR probe before returning to the reaction vessel (Figure
1).25, 29 This setup permits full control over the reaction conditions
during the analysis, including mixing, addition of reagents,
temperature regulation as well as irradiation of the sample.22
Advanced solvent suppression techniques allow the use of non-
deuterated reaction solvents without compromising data quality,
reducing cost and avoiding unwanted isotope effects.31 Two recent
papers have explored the possibility of utilizing online NMR reaction
monitoring to study photochemical reactions, with one study
investigating the photochemical degradation of environmental
fragmentation patterns are unknown, and calibration is required
before quantitative results may be attained.16,
sensitive, Nuclear Magnetic Resonance (NMR) spectroscopy provides
a wealth of structural information over a wide detection range and
does not require external calibration. However, conventional NMR
17
Although less
a.Centre for Sustainable Chemical Technologies, University of Bath, Claverton
Down, Bath BA2 7AY, United Kingdom.
b.Department of Chemistry, University of Bath, Claverton Down, Bath BA2
7AY, United Kingdom.
c. Bruker UK Ltd., Banner Lane, Coventry CV4 9GH, United Kingdom.
d.AstraZeneca, Charter Way, Macclesfield SK10 2NA, United Kingdom.
* Corresponding authors: D.Carbery@bath.ac.uk, U.Hintermair@bath.ac.uk
† Electronic Supplementary Information (ESI) including experimental details
and additional figures available online: See DOI: 10.1039/x0xx00000x
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Figure 1: FlowNMR setup for monitoring photochemical reactions (not to scale).
pollutants,13 and another using a low-field NMR spectrometer for
analysis of products exiting from a photochemical flow reactor.32
Neither study reports reaction kinetics or mechanism, and to the
best of our knowledge, no examples of high-resolution FlowNMR
reaction monitoring for kinetic and mechanistic investigations of
photochemical reactions have thus far been reported.
Figure 2: Off-line and on-line FlowNMR reaction profiles of N-allylbenzylamine (1) in
MeCN (6.4 mM) at 20°C in the presence of Eosin Y catalyst (1 mol%) under green LED
illumination (633 µW) to form 2, 3 and 4. (On-line: 100 mL, 4 mLmin-1 flowrate, WET
solvent suppression, 1.64 s acquisition time, 3 s relaxation delay, 12 scans. Off-line: 300
mL, 3 s acquisition time, 1 s relaxation decay, 16 scans. 20 mL samples were periodically
withdrawn from the reaction mixture and concentrated under reduced pressure before
Examples of visible light photocatalysis are abundant in nature,
2,
5
forming the basis of many key biological processes.1,
Flavins,
based on a tricyclic isoalloxazine ring system, are an important class dissolving in CDCl3 for analysis). See the supporting information for details.
of natural photocatalysts.2, 33-35 Synthetic fluorescent dyes mimicking
increase in concentration of products 2 and 3 in a 1:1 ratio at virtually
identical rates. The rate of the reaction was constant until about 65%
conversion, indicating pseudo-zero order kinetics in 1 under the
conditions applied. Interestingly, no benzaldehyde formation was
observed by FlowNMR during the initial stages of the reaction; the
associated peaks did not appear until about 2 hours into the reaction,
corresponding to >80% substrate consumption. This clearly showed
benzaldehyde to be a secondary reaction product formed from
imines 2 and 3 rather than from amine 1, which appeared much more
pronounced in the off-line reaction monitoring data due to
degradation between sampling and data acquisition. Under the
conditions applied, substrate conversion reached completion after
~4 hours, after which the concentration of benzaldehyde continued
to increase at the expense of both 2 and 3, although degradation of
the core structure of flavins have been developed as staining agents
for biological systems, including compounds such as Fluorescein,
Eosin and Rose Bengal. In the presence of visible light and air, Flavin
and Eosin Y have been found to catalyse reactions of secondary
amines to give a mixture of inter- and intramolecular oxidation
products (Scheme 1).36 The reaction proceeds at room temperature
in acetonitrile solution under white or green light irradiation in air
(Scheme 1). Sampling off-line 1H NMR analysis of the reaction
showed the major products to be oxidation product 2 and
intermolecular coupling product 3 (Figure 2). Small amounts of
benzaldehyde were also observed throughout the reaction as an
undesired by-product. Even with utmost care, data from off-line
sampling was always scattered and difficult to reproduce due to
slight variations between different samples and the need for work-
up before the analysis (Figure 2). Monitoring the reaction under the
same conditions by online 1H FlowNMR spectroscopy however
(Figure 1) yielded smooth and highly reproducible concentration
profiles of all components from a single experiment (Figure 2). The
~30 second time lapse between leaving the continuously illuminated
vessel and reaching the NMR probe was sufficient to avoid adverse
effects on NMR data acquisition by photo-generated radicals, and
the returning aliquot resumed turnover once returned to the
illuminated vessel. The data obtained revealed a steady consumption
of the N-allylbenzylamine starting material with corresponding
allylphenylimine
benzylphenylimine 3.
Increasing the concentration of
2 was slightly faster than the more stable
1
seven-fold resulted in a
lengthening of the reaction time, again with constant rates during
the first 6 hours up to ~65% conversion indicative of saturation
kinetics (Figure S2). Over these longer reaction times a number of
other (currently unidentified) by-products were observed to form at
low concentration, as evidenced by the appearance of a variety of
small peaks in the 1H spectra (Figure S3). Sum integration of the
aromatic region remained constant over the course of the reaction,
however, demonstrating that the reaction mass-balance was
maintained (Figure S4).
Having access to the reaction vessel during FlowNMR experiments
means that the mode and power of illumination may easily be
changed while ensuring even light input across the sample, as a way
of investigating whether the reaction is limited by the availability of
photons. When using a more powerful light source (250 mW halogen
lamp) the reaction became much faster, reaching completion in just
30 minutes at 0˚C (Figure 3), with fewer by-products formed than
with lower power LED light sources that required longer reaction
Scheme 1: Structure of Eosin Y and photocatalytic oxidation of allylic amines.
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Figure 1: 1H FlowNMR reaction profiles of N-allylbenzylamine (1) in MeCN (6.4 mM) at
0°C in the presence of Eosin Y catalyst (1 mol%) under halogen light illumination (250
mW) to form 2, 3 and 4 (200 mL, 4 mLmin-1 flowrate, WET solvent suppression, 4 s
acquisition time, 1 s relaxation delay, 16 scans).
Figure 5: 1H FlowNMR reaction profiles of N-allylbenzylamine (1) in MeCN (6.4 mM) at
20°C in the presence of Eosin Y catalyst (1 mol%) under chopped green LED illumination
(633 µW) and different atmospheres (argon to dry air) to form 2, 3 and 4 (50 mL, 4
mLmin-1 flowrate, WET solvent suppression, 1.46 s acquisition time, 3 s relaxation delay,
16 scans).
times. Since the Eosin Y exhibits a sharp absorption peak around 535
nm with minimal absorption at other wavelengths emitted by the
halogen lamp (Figure S5), this difference in reaction rate is attributed
to the greater light intensity ~535 nm rather than the presence of
higher energy UV photons. This was confirmed by performing the
reaction using a UV filter, which yielded a virtually identical reaction
rate (Figure S6). The formation of benzaldehyde was not significantly
affected by light intensity, proceeding at roughly the same rate
regardless of light source once appreciable amounts of 2 and 3 had
formed in the reaction mixture.
Varying light intensity further revealed the reaction to be photon-
limited under typical conditions, with higher lamp powers yielding
increased initial reaction rates (Table S1 & Figure S7). While under
photon-limited conditions, 2 and 3 appeared to form in parallel
(Figure 2), under high illumination conditions 2 formed as soon as the
light was switched on, but formation of 3 occurred only after an
induction period of 2-3 minutes (Figure 3). This observation suggests
the formation of 3 to proceed via reaction of 2 with 1 activated by
the excited photocatalyst system (most likely an α-aminoradical),36
leading to coupling and loss of two allylic groups. No allylic signals
other than those from 1 were ever observed by NMR, but spiking a
reaction mixture with allylamine showed it to rapidly disappear from
the spectra as soon as the reaction was restarted by illumination
(Figure S8), showing likely by-products of the formation of 3 and 4 to
be undetectable under the conditions applied.
To investigate the nature of the photo-initiated radical reaction
system, variations of atmosphere and illumination were undertaken
during the reaction. A chopped illumination experiment performed
in air (Figure 4) revealed that no further reaction took place in the
absence of light after initial irradiation, showing the photo-generated
reactive species to have short lifetimes and only operate under
sustained input of photons. Product distribution profiles were
identical to experiments performed under continuous illumination.
Altering reaction atmospheres during light variation showed that
some product formed very slowly in an illuminated reaction mixture
under dry argon, and no reaction took place when air was introduced
but the light switched off (Figure 5). Only when illuminated under
aerobic conditions product formation occurred, and the reaction
stalled immediately when the light was switched off again.
The formation of benzaldehyde 4 seemed to occur only under
illumination in air (Figure 5). Test reactions showed the imine
products 2 and 3 to be resistant to hydrolysis in the absence of Eosin
Y,37 and addition of water to an anhydrous photocatalytic FlowNMR
Figure 4: 1H FlowNMR reaction profiles of N-allylbenzylamine (1) in MeCN (6.4 mM) at
20°C in the presence of Eosin Y catalyst (1 mol%) under chopped green LED illumination
(633 µW) to form 2, 3 and 4 (100 mL, 4 mLmin-1 flowrate, WET solvent suppression, 1.46
s acquisition time, 3 s relaxation delay, 12 scans).
Scheme 2: Reaction network based on experimentally observed product and by-product
formation profiles, and conditions.
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7. J.-T. Li, J.-H. Yang, J.-F. Han and T.-S. Li, Green Chem., 2003, 5,
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experiment did not affect the amount of benzaldehyde formation
(Figure S9). Thus, product degradation to the undesired aldehydes
must be a parallel photo-initiated process rather than a simple
hydrolysis reaction. This may proceed via the formation of the
corresponding iminoradicals,36 or due to the presence of singlet
oxygen formed upon excitation of Eosin Y.38 Combining all these
observations leads to the proposed reaction network shown in
Scheme 2.
433.
DOI: 10.1039/C7CC07059D
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This work was supported by a Research Grant from the Royal Society
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