Accelerated C-N bond formation in dropcast thin films on ambient surfaces

Article abstract of DOI:10.1007/s13361-012-0394-y

The aza-Michael addition and the Mannich condensation occur in thin films deposited on ambient surfaces. The reagents for both C-N bond formation reactions were transferred onto the surface by drop-casting using a micropipette. The surface reactions were

Full text of DOI:10.1007/s13361-012-0394-y

B American Society for Mass Spectrometry, 2012
J. Am. Soc. Mass Spectrom. (2012) 23:1461Y1468
DOI: 10.1007/s13361-012-0394-y
RESEARCH ARTICLE
Accelerated C–N Bond Formation in Dropcast
Thin Films on Ambient Surfaces
Abraham K. Badu-Tawiah, Dahlia I. Campbell, R. Graham Cooks
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
Abstract
The aza-Michael addition and the Mannich condensation occur in thin films deposited on
ambient surfaces. The reagents for both C–N bond formation reactions were transferred onto the
surface by drop-casting using a micropipette. The surface reactions were found to be much
more efficient than the corresponding bulk solution-phase reactions performed on the same
scale in the same acetonitrile solvent. The increase in rate of product formation in the thin film is
attributed to solvent evaporation in the open air which results in reagent concentration and
produces rate acceleration similar to that seen in evaporating droplets in desorption electrospray
ionization. This thin film procedure has potential for the rapid synthesis of reaction products on a
small scale, as well as allowing rapid derivatization of analytes to produce forms that are easily
ionized by electrospray ionization. Analysis of the derivatized sample directly from the reaction
surface through the use of desorption electrospray ionization is also demonstrated.
Key words: C–N bond formation, Aza-Michael addition, Mannich reaction, Surface chemistry,
Solvent effects, Ion chemistry, Microdroplets, Mass spectrometry
strictly anhydrous conditions), metal catalysts [4–6] [e.g.,
Yb(OTf)3, InCl3, FeCl3.7H2O/CO(OAc)2], oxidizing agents
Introduction
[7,8] (e.g., ceric ammonium nitrate) or N-heterocyclic
carbenes [9] generated by treating imidazolium salts with a
base). In this study, interfacial versions of the aza-Michael
addition and Mannich reactions were carried out under
ambient conditions in high yields (on a small scale) without
the use of catalyst. The synthetic procedure involves simple
drop-casting of the reagents onto a surface in the open air
and reaction is thought to be driven by reagent concentration
via solvent evaporation.
Solvent evaporation leading to rate enhancement of
chemical reactions has recently been reported for charged
microdroplets reactor systems generated in reactive desorp-
tion electrospray ionization (DESI) [1,10,11] and ambient
ion soft landing [12–14] experiments. Traditionally, the
advantages of microreactor systems are recognized to
include rapid mixing of reagents, effective control of
reaction time, and the ability to control interfacial chemistry
[15]. It has also become apparent that the larger surface areas
associated with microreactor systems favor physical pro-
cesses such as evaporation (when this is allowed) and
he formation of carbon-nitrogen (C–N) single bonds is
important in diverse areas of chemistry because of the
T
ubiquitous presence of nitrogen-containing compounds in
nature. For example, the formation of C–N bonds plays a
significant role in the synthesis of pharmacologically active
molecules as well being essential in such key biological
processes as peptide/protein synthesis. We have an ongoing
interest in chemical reactions in charged microdroplets [1],
which is extended here to the study of reactions in thin films.
Aza-Michael addition (Scheme 1a) is a direct approach to
the construction of C–N bonds. It represents a valuable
synthetic alternative to the established Mannich reaction
(Scheme 1b). Under bulk solution-phase conditions, the aza-
Michael addition is catalyzed by Lewis acids [2,3] (under
Electronic supplementary material The online version of this article
(doi:10.1007/s13361-012-0394-y) contains supplementary material, which
is available to authorized users.
Correspondence to: R. G. Cooks; e-mail: cooks@purdue.edu
Received: 20 February 2012
Revised: 11 April 2012
Accepted: 11 April 2012
Published online: 24 July 2012

1462
A. K. Badu-Tawiah et al.: Thin Film Reactions at Ambient Surfaces
(a)
(b)
Scheme 1. (a) Aza-Michael addition; Y=CONH2, CN, COMe, CO2Et (Me), and (b) general reaction scheme depicting the
Mannich reaction
partitioning of solutes from the bulk to the surface [16–18],
which should increase those reactions that are dependent on
surface active species. In the special case of charged
microdroplets, the increase in product yield is ascribed to
solvent evaporation, which causes moderate pH values in the
starting droplet to reach extreme values while reagent
concentrations also increase [1,19]. Such a system might
be particularly suitable for accelerating acid/base catalyzed
bimolecular reactions. Aside from microreactors, solid films
of reactants containing microscopic quantities of solvent
have been reported to serve as efficient reaction media in
which organic reactions can be accelerated [12,20]. Otera
and coworkers generated solid films through the use of a
rotary evaporator [20], and reaction was observed to be more
efficient than that under the corresponding bulk solution-
phase conditions when the solid film was allowed to stand
under ambient conditions. This procedure was applied to
imine synthesis, the Wittig reaction, and quaternization of
tertiary phosphine, and pyridine [20]. Gentle deposition of
electrospray [21,22] droplets at ambient surfaces has
been shown to afford organic solid films in which the
Girard condensation is accelerated compared with the
bulk solution-phase reaction conducted on the same scale
[12]. In this paper, we show that similar enhancement in
product yield can be achieved for C–N bond forming
reactions in nominally dry mixtures generated by simple
drop-casting of reactant solutions onto ambient surfaces.
The drop-casted products are easily collected or directly
analyzed using surface analysis techniques such as DESI
without dissolution.
Barnstead/Thermolyne deionizer unit (Barnstead Mega-Pure
System, Dubuque, IA, USA).
(a)
100% = 1.68E7
98
86
100
m/z 157
100
[M+H]+
50
157
0
90
115
140
165
m/z
157
0
60
120
180
240
(b)
100% = 1.36E7
100
157
m/z 157
98
100
157
50
0
90
0
100
125
155
m/z
60
120
180
240
m/z
Experimental
Chemicals and Reagents
Figure 1. Nanospray-MS of piperidine (M) (33 mM) and
acrylamide (28 mM) reaction mixture after (a) 1 h bulk
solution-phase reaction, and (b) 10 min surface reaction. In
both cases 2, μL of each reagent in acetonitrile was used
without catalyst. After 10 min reaction time, the surface
reaction mixture was dissolved in 10 μL of methanol/water
(1:1, vol/vol) and analyzed using nanospray ionization
(1.8 kV). Similarly, after 1 h bulk-phase reaction, 10 μL of
methanol/water (1:1, vol/vol) was added to the reaction
mixture for MS analysis. Inserts indicate MS/MS product
ion spectrum of reaction product at m/z 157
Acrylamide, acrylonitrile, methyl acrylate, morpholine,
piperidine, cycloheptylamine, benzaldehyde, cyclohexanone,
and chloroform were purchased from Sigma-Aldrich (Mil-
waukee, WI, USA), ethanolamine was obtained from Acros
Organics (Geel, Belgium), and methanol and acetonitrile
(HPLC grade) from Mallinckrodt Baker Inc. (Phillipsburg,
NJ, USA). Deionized/distilled water was obtained using a

A. K. Badu-Tawiah et al.: Thin Film Reactions at Ambient Surfaces
1463
Nanospray Ionization Mass Spectrometry
for Product Analysis
analysis. All MS experiments were performed using a
Thermo Fisher Scientific LTQ mass spectrometer (San Jose,
CA, USA). Typical MS parameters used included averaging
of 3 microscans, 100 ms maximum ion injection time, 15 V
capillary voltages, 150 °C capillary temperature, and 65 V
tube lens voltage. Data were acquired and processed using
Xcalibur 2.0 software (Thermo Fisher Scientific, San Jose,
CA, USA). The identification of analyte ions was confirmed by
tandem mass spectrometry using collision-induced dissociation
(CID). An isolation window of 1.5 Th (mass/charge units) and
a normalized collision energy of 30 %–35 % (manufacturer’s
unit) was selected for the CID experiments. Reagent (e.g.,
piperidine) consumption was calculated based on nor-
malized product ion intensities [IP/(IP + IR)], where IP
and IR represent protonated product and reagent ion
intensities, respectively.
Surface reaction was achieved by depositing appropriate
volumes (typically 2 μL) of each of the reagent solutions to
be reacted separately (but at the same spot) onto a surface,
and allowing the resulting drop to dry under ambient
conditions. After surface reaction, the dried material was
dissolved into 10 μL of methanol/ water (1:1, vol/vol) and
characterized using nanoelectrospray ionization-MS (nano-
spray-MS or nESI-MS). A nanospray was generated using
an emitter (E Series Microelectrode Holder, with Ag wire
electrode; Warner Instruments, LLC, Hamden, CT, USA)
and applying a voltage of 1.8 kV (~20 nL/min flow rate).
These sample analysis conditions involve short ionization
periods, and so significant reaction cannot occur during
Table 1. Acrylamide Reaction with Amines (in Acetonitrile Solution) at Ambient Surface in the Open Air
aPercent reagent consumption was calculated based on normalized product ion intensities [IP/(IP + IR)], where IP and IR represent protonated product and
reagent ion intensities, respectively. The same amounts of reactants (acrylamide/amine mole ratio of 1:1.2) were used for the surface reaction as for the bulk
solution-phase reaction
bIncluding 9 % of bis-addition product
cIncluding 2 % of bis-addition product

1464
A. K. Badu-Tawiah et al.: Thin Film Reactions at Ambient Surfaces
the nESI-MS data for the bulk reaction to that of the surface
reaction indicates that the surface products were formed before
Results and Discussion
dissolution and not during MS analysis of the product. The
complete list of amines reacted with acrylamide under the drop-
casting conditions is provided in Table 1. Note that primary
amines such as ethanolamine and cycloheptylamine also
yielded bis-addition products by reaction of two mole-
cules of acrylamide instead of one, which was the only
reaction in the case of secondary amines. Among all the
aliphatic amines tested (Table 1), the reaction involving
the sterically hindered cycloheptylamine and acrylamide
was found to be exceptionally slow, with a product yield
of 94 % in 50 min reaction time compared with 99 %
yield for morpholine, piperidine, and ethanolamine in
10 min of surface reaction with acrylamide.
Initial investigations involved the reaction between piperidine
(33 mM) and acrylamide (28 mM) using a micropipette to
deposit 2 μL of each of the reagent solutions in acetonitrile onto
a stainless steel surface (each reagent solution was separately
deposited at the same spot). About 99 % of piperidine (6 μg
absolute, starting amount) was converted into product after
10 min of surface reaction time, whereas 1 h of solution-phase
reaction in acetonitrile allowed only 5 % piperidine conversion
in the absence of a catalyst (Figure 1a) using the same
quantities and starting concentrations of reagent as utilized
for the surface reaction. Note that the surface products were
typically dissolved into methanol/water (1:1, vol/vol) and then
analyzed using nanospray-mass spectrometry. Comparison of
142
m/z142
100
124
98
81
(a)
142
100
50
0
60
100
140
180
m/z
m/z150
132
100
105
150
79.25
117.17
84.25 88.33
99.08 103.17
113.75
130.17
151.50
170.42 173.67
0
80
110
140
170
150
62
m/z
0
60
120
180
240
300
360
m/z
150
100
m/z248
248
0
130
170
210
250
150
(b)
m/z
100
50
0
150
100
m/z248
m/z150
248
132
105
0
80
110
140
170
m/z
368
60
120
180
240
300
360
m/z
Figure 2. Mannich reaction involving benzaldehyde (10 mM), ethanolamine (16 mM), and cyclohexanone (0.1 M) in acetonitrile
(a) under bulk solution-phase and (b) at ambient surface. For the bulk phase reaction, 1 μL each of benzaldehyde and
ethanolamine was premixed for 1 h before adding 16 μL of cyclohexanone. At the surface, however, the benzaldehyde/
ethanolamine drop (1 μL each) was allowed to stand in the open air for 2 min before adding 16 μL of cyclohexanone. Only
10 min of reaction time was allowed after cyclohexanone was added for bulk-phase reaction after which 10 μL of methanol/
water (1:1, vol/vol) was added for MS analysis. Similarly, the surface reaction was allowed an extra 10 min after cyclohexanone
was added to the dry benzaldehyde/ethanolamine mixture. The surface reaction mixture was then (re)dissolved into 10 μL of
methanol/water (1:1, vol/vol) and analyzed using nanospray-MS. Inserts indicate MS/MS product ion spectrum of reaction
product at m/z 248, and also for intermediates at m/z 142 and 150. The MS3 product ion spectrum of m/z 248 via m/z 150 ion is
also provided. Ion at m/z 368 in (b) is an unrelated background ion

A. K. Badu-Tawiah et al.: Thin Film Reactions at Ambient Surfaces
1465
1.2
The Mannich reaction (Scheme 1b), which represents
another reaction in which C–N (and C–C) bonds are formed,
was also attempted at ambient surfaces using the drop-
1
casting method. Under bulk solution-phase conditions, this
multi-component condensation of a non-enolizable alde-
hyde, primary or secondary amine, and an enolizable
carbonyl compound (i.e., carbonyl compound having one
Drying Time (min.)
Chloroform 0.5
0.8
Acetonitrile
2
Water
50
0.6
or more α-hydrogen atoms) affords β-amino carbonyl
products. Often, the desired Mannich product is generated
by indirect procedures in which either the enolate or the
0.4
imine (i.e., the Schiff base) is preformed [23–25]. Direct
one-pot Mannich reactions have been reported, however,
catalysts and long reaction times are typically needed
[26,27]. The thin film approach presented here represents a
0.2
0
10
20
30
40
50
60
Reaction Time (min.)
rapid form of indirect Mannich reaction. No unwanted
products are detected as shown by the dissolution of the
surface product and analysis via nESI-MS. Specifically, only
2 min of reaction time was needed to generate the desired
Schiff base (m/z 150) by drop-casting 1 μL each of
ethanolamine (16 mM) and benzaldehyde (10 mM) solutions
from acetonitrile onto a surface. Subsequently, addition of
16 μL of cyclohexanone solution (0.1 M) in acetonitrile to
the resultant and nominally dry reaction spot on the surface
provided the expected Mannich product at m/z 248 in an
extra 10 min (Figure 2b). The formation of this product was
confirmed through collision-induced dissociation (CID), as it
fragmented to give an ion at m/z 150 via the loss of
cyclohexanone (MW 98). Note that the intermediate species
(m/z 150) and the reaction product (m/z 248) have different
ionization efficiencies so their intensities as represented in
the mass spectrum (Figure 2b) do not reflect the relative
amounts present in the collected material. However, almost
all reactants (ethanolamine and benzaldehyde) were con-
verted into the intermediate before cyclohexanone was
added. Under bulk solution-phase conditions, by contrast,
1 h reaction time involving benzaldehyde and ethanolamine
in acetonitrile (the same quantities as used for the surface
reaction) did not yield a significant amount of the desired
Schiff base needed for reaction with the enolizable carbonyl
compound (i.e., cyclohexanone) in the second step. Instead,
the subsequent addition of cyclohexanone to this reaction
mixture consisting of unreacted ethanolamine and benzalde-
hyde produced predominantly a second Schiff base at m/z
142 via reaction of cyclohexanone with ethanolamine
(Figure 2a). Again, CID confirmed the absence of the
Mannich product at m/z 248.
Figure 3. Yield of morpholine reaction with acrylamide
(1.2:1 mol ratio) at surface in different solvents. In all cases,
2 μL of each reagent in the respective solvents was used
without addition of catalyst. Normalized product ion intensity
was calculated based on the ratio: IP/[IP + IM], where IP and IM
represent protonated product (m/z 159) and morpholine (m/z
88) ion intensities respectively
slowest in water. This is simply ascribed to the differences in
the rates with which the respective solvents evaporate. For
example, it takes 30 s to generate a nominally dry reaction
mixture when chloroform is used as the solvent, compared
with 2 and 50 min. for acetonitrile and water, respectively.
This indicates that solvent evaporation causes reagent
concentration, which leads to more effective collisions. This
increased reaction rate attributable to the reduced number of
solvent molecules is analogous to the effect of solvent
removal on gas-phase SN2 reactions in which essentially no
activation energy is required and where every collision
results in product formation [28,29]. Michael acceptors
having higher vapor pressures such as acrylonitrile and
methyl acrylate were found not to be useful in this procedure
since solvent evaporation leading to reagent concentration
could not be achieved—the solvent and reagents all
evaporated together leaving only the amine, with no reaction
product at the surface.
The possibility of there being surface effects on reaction
efficiency were also investigated. First, chemical effects in
the form of possible structural changes of reagent at surfaces
due to the absence of solvent were investigated using
infrared spectroscopy (Thermo-Nicolet Nexus FTIR, with
ATR optics). FTIR spectrum recorded on the nominally dry
acrylamide (in the absence of amine) showed a band at about
1670 cm–1, which is attributed to C = O stretching of amides
[30] (Figure S1, Supporting Information) just as is observed
in solution-phase and indicating no structural changes at the
surface in the absence of solvent. This result suggests that
the increase in surface product yield compared with that
obtained under bulk conditions is simply due to solvent
evaporation leading to reagent concentration. In this regard,
the influence of the physical properties of the surface itself
on solvent evaporation was further investigated by utilizing
The general increase in reaction rate observed in the thin
films, compared with bulk solution-phase reactions with no
added catalyst, is attributed to increased reagent concentra-
tion due to solvent and surface effects. This was investigated
for the aza-Michael addition by preparing reagents in
different solvents (chloroform, acetonitrile, and water) and
comparing the yield of the surface reaction as a function of
reaction time. The results, shown in Figure 3, indicate that
the morpholine reaction at the surface with acrylamide was
fastest when the reactants were prepared in chloroform and

1466
A. K. Badu-Tawiah et al.: Thin Film Reactions at Ambient Surfaces
gold, Teflon, stainless steel, paper, and aluminum foil as
substrates for the aza-Michael addition. (Highly hydrophilic
surfaces like glass could not be used because of the extent to
which the solvent acetonitrile spreads, making collection of
product from the surface particularly difficult). Again, all
surfaces provided the expected reaction product, indicating
the lack of chemical effects, except for the differences in
efficiency of the surface reaction. For example, more
products were collected from the inert gold surface than
from Teflon (see Figure S2, Supporting Information for
detail). Different surfaces yielded products at distinctive
rates because hydrophilic surfaces such as gold produced
larger surface areas than Teflon, which in turn afforded
faster solvent evaporation and, eventually, reagent concen-
tration and more effective collisions in a unit time.
benzaldehyde reactants used in the aza-Michael addition
(as Michael acceptor) and the Mannich reaction (as non-
enolizable carbonyl compound) are not effectively ionized
by ESI (suppose the goal was to specifically analyze them
by ESI-MS). However, through chemical derivatization,
such compounds can be converted into forms that are easily
ionized by ESI [31,32]. A rapid method of chemical
derivatization is thus desirable in order not to significantly
increase the ESI-MS analysis time. Unfortunately, traditional
derivatization via wet chemistry often involves harsh
conditions (e.g., high temperatures and acidic media), with
long reaction times. The drop-casting conditions have
proven to be useful in providing specific derivatives in a
matter of a few minutes (Figures 1, 2, and Table 1). Even
more interesting is the ability to analyze the nominally dry
reaction mixture (after drop-casting) directly from the
surface using a surface analysis technique such as DESI,
without dissolving it into solution. This capability was
Aside from the relevance of the drop-casting method in
synthesis, it also has some inherent advantages in analytical
mass spectrometry. For example, the acrylamide and
(a)
[PRODUCT+H]+
157
100
157
100
m/z157
98
[M+H]+
86
50
140
0
74
50
150
m/z
250
0
60
160
260
360
460
(b)
[PRODUCT+H]+
157
100
157
86
100
m/z157
[M+H]+
98
0
50
0
50
150
m/z
250
247
m/z
60
160
260
360
460
m/z
Figure 4. (a) Desorption electrospray ionization (DESI)-MS analysis of drop-casting products directly from Teflon surface: 2 μL
each of acrylamide (28 mM) and piperidine (M, 33 mM) solutions in acetonitrile were deposited at the surface and 6 min was
allowed for mixture to dry before DESI analysis using methanol/water (1:1, vol/vol) spray solvent; (b) reactive DESI using
~0.4 mM piperidine in methanol/water (1:1,vol/vol) solution as DESI spray directed at dry acrylamide (4 μg absolute amount).
Inserts in (a) and (b) indicate MS/MS product ion spectra at m/z 157

A. K. Badu-Tawiah et al.: Thin Film Reactions at Ambient Surfaces
1467
demonstrated by using DESI to analyze the aza-Michael
Acknowledgment
addition product directly from Teflon surface after drop-
casting 2 μL each of acrylamide and piperidine solutions in
acetonitrile onto the Teflon surface. The resulting spot was
dried in the open air for 6 min, and the DESI-MS recorded
using MeOH/H2O (1:1, vol/vol) spray solvent is as shown in
Figure 4a. The product was detected at m/z 157 and its
identity was confirmed via CID. Unreacted piperidine was
also detected at m/z 86. Analysis of Mannich reaction
products directly from the reaction surface using DESI was
also achieved, and the result is provided in (Figure S3,
Supporting Information). It is also recognized that with
DESI, no derivatization step may be needed in the MS
analysis; it can be operated in a reactive mode (i.e., reactive
DESI [10,11]) in which the sample to be analyzed (e.g.,
acrylamide) is placed on the surface and then directly
analyzed with a DESI spray solvent containing a reactive
reagent (e.g., piperidine). In this case, derivatization occurs
in-situ during the DESI analysis at ambient conditions.
Figure 4b shows the result of reactive DESI analysis of
acrylamide using piperidine solution (0.4 mM) in MeOH/
H2O (1:1, vol/vol) as the DESI spray solvent. Here too, the
derivatized product is observed in the MS at m/z 157.
The authors acknowledge funding for this work by the
National Science Foundation (CHE NSF 0848650 and
0852740).
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An interfacial version of the aza-Michael addition has been
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ment over the conventional bulk solution-phase reactions
performed on the same scale with no added catalyst. The
increase in reaction yield is attributed to reagent concentra-
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