Accelerated generation of (protonated) imines and quinoxalines by formation of C=N bonds in the microdroplets of a nebuliser

Article abstract of DOI:10.1177/1469066717737314

Ions corresponding to protonated imines appear in the positive ion electrospray mass spectra of mixtures of the parent aromatic aldehyde and arylamine. The formation of these imine products occurs readily in the electrospray source nebuliser, even without

Full text of DOI:10.1177/1469066717737314

In Memoriam of Peter Derrick
European Journal of Mass Spectrometry
0(00) 1–9
! The Author(s) 2017
Accelerated generation of (protonated) imines
and quinoxalines by formation of C¼N bonds
in the microdroplets of a nebuliser
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DOI: 10.1177/1469066717737314
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Amie Saidykhan1, Yasser Nazir1, William HC Martin1, Richard T Gallagher2
and Richard D Bowen1
Abstract
Ions corresponding to protonated imines appear in the positive ion electrospray mass spectra of mixtures of the parent
aromatic aldehyde and arylamine. The formation of these imine products occurs readily in the electrospray source nebuliser,
even without the application of a spray potential. This accelerated formation of C¼N bonds in the nebuliser has been
extended to encompass the preparation of quinoxalines from a range of substituted phenylenediamines and benzils. The
condensation may be induced either under conventional positive ion electrospray conditions (to give the protonated
quinoxalines) or when the nebuliser is disconnected from the mass spectrometer (to give the neutral quinoxaline). Ions
corresponding to intermediate adducts formed by condensation of the phenylenediamine component with the protonated
benzil are observed in many cases when the condensation occurs in the mass spectrometer. This finding supports an
interpretation based on nucleophilic addition in droplets generated by the nebuliser.
Keywords
Imines, quinoxalines, electrospray, C¼N bond formation, condensation
Received 14 August 2017; accepted 24 September 2017
Introduction
bonds is very important in synthetic organic chemistry,
Recent work has established that important organic especially in the preparation of nitrogen heterocycles.7,8
reactions, especially condensations, may be effected at Consequently, the possibility of forming C¼N bonds
an enhanced rate in the nebuliser of a conventional under ESIþ conditions was explored.
positive ion electrospray source.1–4 During the course
of a study involving liquid chromatography mass
spectrometry (LCMS) on model tricyclic indoles, unex-
Experimental procedures
pected [2M-H]þ ions were formed under standard posi- The reference compounds required in this study were
tive ion electrospray (ESIþ) conditions.5 These unusual prepared according to literature procedures from com-
adducts appeared to be formed under comparatively mercial starting materials of high purity. The imines9
mild conditions (approximately neutral pH and low were made by condensation of the parent aromatic
temperatures) in a nebuliser, even without applying a aldehyde and the appropriate substituted aniline; the
voltage to the nozzle. The elaboration of components quinoxalines10 were synthesised by condensation of
into larger species under such circumstances has obvi- the requisite (substituted) phenylenediamine and (sub-
ous synthetic potential, particularly when conventional stituted) benzil. All the phenylenediamines and most of
synthesis in solution frequently entails the use of strong
1School of Chemistry and Biosciences, Faculty of Life Sciences, University of
acids or bases, often at high temperature.
In view of the facility of certain indoles to undergo Bradford, Bradford, UK
2AstraZeneca, Oncology iMed, Macclesfield, UK
coupling reactions to form [2M-H]þ ions under ESIþ,
compared to the harsh conditions needed to effect simi-
lar processes in conventional solution methodology,6
the idea of forming other covalent bonds by similar
Corresponding author:
Richard D Bowen, University of Bradford, Great Horton Road, Bradford,
West Yorkshire BD7 1DP, UK.
means deserves attention. The formation of C¼N Email: r.d.bowen@bradford.ac.uk

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European Journal of Mass Spectrometry 0(00)
ꢃ
Scheme 1. Reagents and conditions: (i) 20–60 C, 0.5–3 h; (ii) thiazolium salt, C2H5OH, reflux, 2 h; (iii) conc. HNO3, O2, reflux, 1–4 h; (iv)
C2H5OH, reflux, 0.5–6 h.
the benzils were commercially available; the remaining C18, 1.7 mm, 2.1 mm ꢀ 100 mm. The sample was dis-
benzils were obtained by the benzoin condensation11,12 solved in methanol at ꢁ0.01 mg mLꢂ1 concentration,
of the relevant aryl aldehyde, with a thiazolium salt as and 10 mL was injected. The mobile phase flow rate
catalyst instead of cyanide anion, followed by oxidation was 0.45 mL minꢂ1. Mobile phase A was 0.05% aq.
of the resultant benzoin with nitric acid.13 These syn- formic acid, and mobile phase B was acetonitrile.
thetic routes are summarised in Scheme 1. The usual The UHPLC gradient was T ¼ 0.0, A ¼ 95%,
combination of 1H and 13C nuclear magnetic resonance B ¼ 5%, T ¼ 9.0, A ¼ 20%, B ¼ 80%, T ¼ 9.01,
spectroscopy, infrared spectroscopy and mass spec- A ¼ 2%, B ¼ 98%, T ¼ 11.0, A ¼ 2%, B ¼ 98%. At
trometry, together with melting point data, confirmed T ¼ 11.01 min, the system reverted to the starting con-
the identity and purity of all intermediates and prod- ditions and was held for 4 min to allow the column to
ucts prepared by conventional synthesis in this re-equilibrate. In later experiments, a freshly prepared
investigation.
solution of the phenylenediamine and benzil compo-
LC-MS analysis was carried out on a hybrid linear nents was introduced immediately and directly via the
ion trap–orbitrap mass spectrometer system (Thermo nebuliser without transmission through the LC
Scientific LTQ OrbiTrap XL) fitted with an ultra- system. The PDA was scanned from 210 to 350 nm
high-performance liquid chromatography (UHPLC) at 2 nm steps during the run. ESIþ was performed
system consisting of a binary pump, an autosampler with a capillary voltage of 3 kV, a sheath gas flow of
and a photodiode array (PDA) detector (Acquity: 50 and an auxiliary flow of 20 (arbitrary units) at a
Binary Solvent Manager, Sample Manager and PDA source capillary temperature of 250 ꢃC. The mass
Detector, respectively; Waters Ltd., Elstree, UK).14 spectrometer collected data every ꢁ0.25 s alternatively
The chromatography system and mass spectrometer recording a mass spectrum over the mass range 100–
were controlled by the software Xcalibur v1.4 800 amu and a product ion mass spectrum from the
(Thermo Scientific Ltd., Hemel Hempstead, UK). most intense ion detected in the mass spectrum. The
The LC column was a Waters Acquity UPLC BEH resolution was 7.5 K (full width at half maximum) for

Saidykhan et al.
3
Scheme 2. Formation of (2-bromophenyl)-1-phenylmethanimine, 3, from benzaldehyde, 1, and 2-bromoaniline, 2.
Figure 1. LC-MS of a nebulised mixture of benzaldehyde and 2-bromoaniline, showing formation of protonated (2-bromophenyl)-1-
phenylmethanimine (3, at m/z 260 [C13H1379BrN]þ, with the expected 81Br isotope satellite at m/z 262).
both scan modes; the collision energy was 35 eV in the respectively, formed by protonation of 2) and m/z 260
product ion experiments.15,16
and 262 (corresponding to [Ar1CH¼NAr2þH]þ formed
by protonation of 3) (Scheme 2, Figure 1). Accurate
mass measurements at high resolution confirmed the
ionic formulae of all four of these strong signals.
Parallel results were obtained when an equimolar
Results and discussion
When the ESIþ spectrum of an equimolar mixture of
an aryl aldehyde, Ar1CHO, with a slight excess of an mixture of benzaldehyde and other arylamines,
arylamine, Ar2NH2, was recorded, the expected signal including aniline, 4-methylaniline, 4-chloroaniline and
for the protonated amine was present in the spectrum, 4-bromoaniline were subjected to ESIþ, as evidenced
together with a strong signal corresponding to the by strong signals at m/z 182, 196, 216 and 260, respect-
protonated imine, Ar1CH¼NAr2, that would be ively, corresponding to C13H12Nþ, C14H14Nþ,
obtained by condensation of Ar1CHO and Ar2NH2. C13H1335ClNþ and C13H1379BrNþ, as confirmed by
However, the signals for the protonated aldehyde high-resolution measurements. Isotope satellites corres-
or
the
intermediate
tetrahedral
adduct, ponding to C13H1337ClNþ and C13H1381BrNþ, respect-
Ar1CH(OH)NHAr2, which would be formed initially ively, of the correct relative intensities were observed
by nucleophilic addition of Ar2NH2, usually were for the two protonated halogenoimines.
either extremely weak or not detectable at all. For
One obvious explanation for the ions at m/z 260 and
example, when a mixture of benzaldehyde, 1, and 262 is the nucleophilic attack of bromoaniline on pro-
2-bromoaniline, 2, was analysed, the spectrum showed tonated benzaldehyde, to form initially a protonated
pairs of peaks of nearly equal abundance at m/z 172 tetrahedral adduct; proton transfer, followed by elim-
and 174 ([Ar2NH2þH]þ containing 79Br and 81Br, ination of water, then generates the protonated imine.

4
European Journal of Mass Spectrometry 0(00)
Scheme 3. Conventional acid-catalysed mechanism for formation of protonated (2-bromophenyl)-1-phenylmethanimine, 3Hþ, from
benzaldehyde and 1,2-phenylenediamine.
This mechanism is exactly analogous to the well-docu- ‘green chemistry’ credentials, have also been
mented mechanism by which aldehydes condense with reported.28–31 Therefore, the possibility of preparing
amines to form imines in solution, under either acid- or these important heterocycles under mild conditions,
base-catalysed conditions (Scheme 3). Alternatively, a without the use of heat or catalysts, in the microdro-
radical mechanism may operate, as appears to be prob- plets of a nebuliser is especially attractive.
able in the dimerisation of indoles5 mentioned in the
Introduction section.
In practice, various 2,3-diarylquinoxalines were
formed by infusing a solution of equimolar quantitites
Imines may be prepared in solution rather more of 1,2-phenylenediamines and benzils in methanol
readily than many organic chemists probably realise. through the earthed nebuliser, collecting the eluent
Nevertheless, the rate at which the signals correspond- and analysing it by LC-MS. Not only did the product
ing to protonated imines such as 3Hþ appeared under have the correct molecular formula, as determined by
ESIþ conditions was exceptionally rapid. The prepar- accurate mass measurements at high resolution on the
ation of imines in microdroplets, such as those formed derived [MþH]þ ion, but the CID spectrum of this
in a nebuliser, has clear synthetic potential, especially in [MþH]þ ion matched that formed from authentic
cases in which the corresponding condensation in solu- material prepared by conventional methods in solution.
tion is slow or in which one reactant or the product is All these reactions occurred far more rapidly in the
acid or base sensitive.
nebuliser than under standard solution conditions.
In view of the ease with which C¼N bond formation Thus, 2,3-diphenylquinoxaline, 6, was obtained by con-
to produce imines occurred in the nebuliser, the possi- densation of 1,2-phenylenediamine, 4, with benzil, 5, in
bility of enhancing the rate at which suitable hetero- an off-line nebuliser (Scheme 4, Figure 2).
cycles may be formed from their constituent
precursors was explored. Quinoxalines were chosen in the ESIþ spectrum of a solution of 4 and 5.
In addition, [6þH]þ was directly observed at m/z 283
for several reasons. Firstly, quinoxalines are an import-
Moreover, the relative retention time of the peak in
ant and ubiquitous class of aromatic heterocycles17,18 the LC, and the formula (C20H15N2þ) and the CID
occurring in a variety of biologically active materials spectrum of this ion all matched those of [MþH]þ
(including echinomycin and related antibiotics19,20), formed from authentic 6 prepared in solution. In gen-
giving them a wide range of applications in pharma- eral, these CID spectra were dominated by elimination
ceutical and medicinal settings,21,22 and in polymer sci- of ArH containing the aromatic substituent in the 2 or 3
ence, particularly in optical and electrical contexts.23–27 position of the substituted quinoxaline. Thus, when this
Secondly, their formation would entail creating two substituent was a phenyl group, the base peak in the
C¼N bonds (as opposed to only one in imines). spectrum of [MþH]þ formed from the quinoxaline pre-
Thirdly, studying the preparation of an aromatic het- pared either in solution or by condensation of the con-
erocyclic ring (in this case, a pyrazine) is facilitated by stituent phenylenediamine and benzil in the nebuliser
the availability of stable precursors, 1,2-phenylenedia- usually was [MþH-C6H6]þ. Similarly, when there was
mines and benzils, which may condense to form qui- a halogeno substituent in the aromatic ring, a strong
noxalines. The classical synthesis of quinoxalines in signal was present corresponding to [MþH-C6H5X]þ,
solution typically involves elevated temperature (reflux- where X ¼ F, Cl or Br. The spectra of the dimethoxy
ing the precursors in chloroform or ethanol, sometimes analogues were more complicated because elimination
for several hours) and/or catalysis (usually with an of a neutral species having a (total) mass of 15 (CH3),
acid)10. Various catalytic approaches, some with 32 (CH3OH) and 45 (CH3 and CH2O) units competed

Saidykhan et al.
5
Scheme 4. Synthesis of 2,3-diphenylquinoxaline, 6, from 1,2-phenylenediamine, 4, and benzil, 5.
Figure 2. LC-MS of a nebulised solution of a mixture of 1,2-phenylenediamine and benzil. Accurate mass chromatograms show 1,2-
phenylenediamine (top left), benzil (middle left) and 2,3-diphenylquinoxaline (bottom left) with corresponding mass spectrum for the
latter (right).
with loss of 108 units (anisole, CH3OC6H5). However, 4,5-dimethyl-1,2-phenylenediamine. Similarly, ‘BF2’,
these competing processes are typical or the fragmen- ‘BCl2’, ‘BBr2’ and ‘B(OMe)2’ denote, respectively,
tation of methoxy-substituted aromatic compounds, 4,40-difluoro-, 4,40-dichloro-, 4,40-dibromo- and 4,40-
thus lending further support to the interpretation that dimethoxybenzil or their 3,30-disubstituted isomers.
quinoxalines containing methoxyphenyl substituents The corresponding substituted quinoxalines are
are being formed. Representative CID spectra are defined by the appropriate combination of prefixes
shown in Figure 3.
and suffixes.
Further investigation revealed that the formation of
In some cases, analysis of mixtures of phenylenedi-
protonated quinoxalines, [QþH]þ, from substituted amine and benzil components under ESIþ conditions
benzils, B, and the appropriate substituted phenylene- gave not only signals corresponding to the protonated
diamine, P, in the nebuliser by this method is general quinoxalines but also those attributable to ions at the
(Table 1). In this system of abbreviation, a prefix or intermediate stages of condensation. It was convenient
suffix defines one or more substituent(s) in either the to do the mass spectrometric analysis of mixtures of
benzil of the phenylenediamine; similarly, a prefix and/ phenylenediamine and benzils by introducing an equi-
or a suffix indicate(s) any substituent(s) in the proto- molar mixture of the constituent precursors in metha-
nated quinoxaline. Thus, ‘MeP’, ‘FP’, ‘ClP’ and ‘BrP’ nol directly into the nebuliser when connected to the
refer to 4-methyl-, 4-fluoro-, 4-chloro- and 4-bromo- mass spectrometer, without transmitting the solution
1,2-phenylenediamine, respectively, and ‘Me2P’ denotes through the LC column.

6
European Journal of Mass Spectrometry 0(00)
Figure 3. CID spectrum of m/z 317 formed by (top) ESIþ of the product of condensing 4-chloro-1,2-phenylenediamine with benzil in the
nebuliser and bottom ESIþ of 6-chloro-2,3-diphenylquinoxaline prepared by conventional solution synthesis.
Thus, when a mixture of 4-chloro-1,2-phenylenedia- condensation of phenylenediamine with 4,40-
mine and benzil was investigated, peaks were observed dimethoxybenzil (Scheme 5).
at
m/z
335
and
353
corresponding
to
Attempts to study the influence of substituents in
[35ClQþHþ2H2O]þ and [35ClQþHþH2O]þ, respect- either the phenylenediamine or benzil on the efficiency
ively, accompanied by their 37Cl isotope satellites at of the condensation under ESIþ conditions gave only
m/z 337 and 355 of approximately one-third relative qualitative results, partly because the relative intensity
intensity (Figure 4).
of the [X2QY2þHþ2H2O]þ, [X2QY2þHþH2O]þ and
Furthermore, the CID spectra of these ions typically [X2QY2þH]þ signals was dependent on the precise
contained signals for loss of H2O, as illustrated in experimental conditions. Under such circumstances,
Figure 5, which shows how [35ClQþHþH2O]þ (at m/z only tentative conclusions are justified until at least
335) eliminates H2O (to form [35ClQþH]þ at m/z 317), semi-quantitative analysis can be attempted. For
Cl (to form m/z 307), CO and Cl. (to form m/z 257) and instance, the presence of one or two electron-donating
CO and C6H6 (to form m/z 229).
methyl substituents in the phenylenediamine compo-
Similarly, in the condensation of 1,2-phenylenedia- nent perhaps favoured the condensation, as might be
mine with 4,40-dimethoxybenzil under ESIþ conditions, expected given the enhancement of the nucleophilicity
the ions at m/z 343, 361, and 379 had the formulae of this species by electron-donating substituent(s). In
C22H19N2O2, C22H21N2O3 and C22H23N2O4, which contrast, the condensation possibly occurred slightly
matched those expected for the first and second inter- more readily for a mixture of a given phenylenediamine
mediate and protonated 2,3-di(4-methoxyphenyl)qui- with 3,30-dimethoxybenzil than with 4,40-dimethoxy-
noxaline, [Q(OMe)2þHþ2H2O]þ and [Q(OMe)2þHþ benzil. This effect, if significant, could be attributed to
H2O]þ and [Q(OMe)2þH]þ, respectively. Moreover, more effective reduction of the electrophilicity of the
the CID spectrum of the ion at m/z 343 was essentially carbonyl groups by p-conjugation through the aro-
identical for that generated by protonation of an matic ring when the electron-donating methoxy sub-
authentic sample of 4,40-2,3-di(4-methoxyphenyl)qui- stituents are in the 4- and 40-positions, rather than the
noxaline obtained by the conventional condensation 3- and 30-positions. However, other factors, including
of phenylenediamine with 4,40-dimethoxybenzil in the lower solubility of the 4,4-disubstituted benzils,
solution. All these results support the proposal that especially in dibromo series, are relevant and may be
these species were genuine intermediates in the more important.

Saidykhan et al.
7
Table 1. Summary of important signals in the ESIþ spectra of mixtures of substituted phenylenediamines and benzils.
Reagents
Product signals
m/z
317
355
Assignment
[QþHþ2H2O]þ
m/z
301
337
Assignment
[QþHþH2O]þ
m/z
283
319
353
441
343
301
317
361
361
377
421
297
333
365
357
311
347
379
371
Assignment
[QþH]þ
P
B
a
P
BF2
[QF2þHþ2H2O]þ
[QF2þHþH2O]þ
[QF2þH]þ
b,c
P
BCl2
[QCl2þH]þ
[QBr2þH]þ
[Q(OMe)2þH]þ
[FþQH]þ
b,d
P
BBr2
a
P
B(OMe)2
379
337
353
397
397
413
457
335
367
[Q(OMe)2þHþ2H2O]þ
[FQþHþ2H2O]þ
361
319
335
379
379
395
439
317
351
[Q(OMe)2þHþH2O]þ
[FQþHþH2O]þ
FP
B
ClPb
BrPc
FP
B
[ClQþHþ2H2O]þ
[ClQþHþH2O]þ
[ClþQH]þ
B
[BrQþHþ2H2O]þ
[BrQþHþH2O]þ
[BrQþH]þ
b
b
b
B(OMe)2
B(OMe)2
B(OMe)2
B
[FQ(OMe)2þHþ2H2O]þ
[ClQ(OMe)2þHþ2H2O]þ
[BrQ(OMe)2Hþ2H2O]þ
[MeQþHþ2H2O]þ
[FQ(OMe)2þHþH2O]þ
[ClQ(OMe)2þHþH2O]þ
[BrQ(OMe)2HþH2O]þ
[MeQþHþH2O]þ
[FQ(OMe)2þH]þ
ClQ(OMe)2Hþ
BrQ(OMe)2Hþ
[MeQþH]þ
[QF2þH]þ
ClPa
BrPb
MeP
MeP
MeP
MeP
Me2P
Me2P
Me2P
Me2P
[MeQF2þHþ2H2O]þ
[MeQF2þHþH2O]þ
b
BF2
e
BCl2
[QFCl2þH]þ
[Q(OMe)2þH]þ
[Me2QþH]þ
[Me2QF2þH]þ
[Me2QCl2þH]þ
[MeQ(OMe)2þHþ2H2O]þ
[Me2QþHþ2H2O]þ
375
329
365
[MeQ(OMe)2þHþH2O]þ
[Me2QþHþH2O]þ
e
B(OMe)2
B
393
347
[Me2QF2þHþH2O]þ
b
BF2
b
BCl2
[Me2Q(OMe)2þHþ2H2O]þ
389
[Me2Q(OMe)2þHþH2O]þ
[Me2Q(OMe)2þH]þ
e
B(OMe)2
407
aBoth the 3,30 and 4,40 isomer were studied.
bOnly the 4,40 isomer was studied.
cThe signals in this row refer to ions containing the 35Cl isotope; corresponding satellite signals containing the 37Cl isotope were also present.
dThe signals in this row refer to ions containing the 79Br isotope; corresponding satellite signals containing the 81Br isotope were also present.
eOnly the 3,30 isomer was studied.
Figure 4. ESIþ spectrum of an equimolar mixture of 4-chloro-1,2-phenylenediamne and benzil showing first and second intermediate
ions [35ClQþHþ2H2O]þ and [35ClQþHþH2O]þ.

8
European Journal of Mass Spectrometry 0(00)
Figure 5. CID spectrum of [35ClQþHþH2O]þ (m/z 335) showing elimination of H2O to form [35ClQþH]þ at m/z 317.
Scheme 5. Proposed mechanism for formation of protonated 2,3-di(4-methoxyphenyl)quinoxaline from 1,2-phenylenediamine and 4,4’-
dimethoxybenzil.
Despite these caveats, the substantial enhancement time (typically up to several hours in some cases, partly
of the rate of formation of the (protonated) quinoxa- because of low solubility of one or both components in
lines in the nebuliser relative to that in conventional protic solvents such as ethanol) or the use of catalysts.
solution experiments is clearly established. Reactions In contrast, the corresponding process in the nebuliser
that required an hour or more reflux in ethanol (at appears to occur very rapidly for at least 21 combin-
approximately 80 ꢃC) took place almost instantan- ations of 1,2-phenylenediamines with 3,30-disubstituted
eously at ambient temperature in the nebuliser, either and 4,40-disubstituted benzils. The potential for synthe-
when it was disconnected from the ESIþ source (to sising nitrogen heterocycles such as quinoxalines by
form the parent quinoxaline) or as part of an operating accelerated formation of C¼N bonds in microdroplets
mass spectrometer (to give the protonated quinoxaline, such as those formed in the nebuliser is obvious.
often with intermediate ions formed on route to this Provided that certain technical challenges, including
protonated heterocycle).
devising means of effectively scaling up the process,
can be overcome, this methodology may offer great
advantages over conventional solution synthesis.
Conclusion
The formation of C¼N bonds is greatly accelerated in Dedication
the nebuliser of an ESIþ source compared to the situ-
Dedicated to Professor Peter J Derrick in recognition of his
outstanding contribution to the development and application
ation in solution. Condensation of phenylenediamines
with benzils in solution sometimes requires heating and of mass spectrometry in many scientific disciplines.

Saidykhan et al.
9
18. Sato N. Pyrazines and their benzo derivatives.
In: Katritzky AR, Ramsden CA, Scriven EFV, et al.
(eds) Comprehensive heterocyclic chemistry III. Vol. 8,
Oxford: Elsevier, 2008, pp.273–331.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
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Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
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