Accelerated carbon-carbon bond-forming reactions in preparative electrospray

Article abstract of DOI:10.1002/anie.201206632

From analysis towards synthesis: Charged microdroplets act as microreaction vessels, extending the use of electrospray mass spectrometry from chemical analysis to synthesis. Application of this unique reaction conditions allows microscale carbon-carbon bo

Full text of DOI:10.1002/anie.201206632

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Angewandte
Communications
DOI: 10.1002/anie.201206632
Synthesis using a Mass Spectrometer
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Accelerated Carbon Carbon Bond-Forming Reactions in Preparative
Electrospray**
Thomas Mꢀller,* Abraham Badu-Tawiah, and R. Graham Cooks*
The chemistry of life occurs in spatially limited volumes—
cells—the structural and functional units of living organisms.
Biochemical reactions can also take place within the confines
of interfaces, for example, those between air and water[1] in
atmospheric aerosols. These unique chemical environments
can be mimicked by performing reactions in enclosed
volumes, for example, in micelles or microemulsions.[1f,2]
Inside these compartmentalized liquids, limiting phase boun-
daries as well as significant changes in local concentrations
can enhance reaction rates,[2a] induce regioselectivity,[3] and
help to overcome reagent incompatibilities.[2b] Although
electrospray has been used for the production of inorganic
nanoparticles[4] and thin organic polymer films,[5] it is most
widely associated with ionization in mass spectrometry
(MS).[6] Recent MS experiments have revealed that charged
microdroplets can serve as the locus for simple as well as
complex and multistep reactions.[7]
spectroscopy allows ready distinction of reagents 1 and 2 and
quantification of the product 2-(4-chlorobenzylidene)indan-
1-one (4). The freshly prepared methanolic reaction mixture
was treated in two contrasting ways: 1) the solution was
electrosprayed and the products were collected at a surface,
and 2) the reaction mixture was simply allowed to stand at
room temperature. In both the droplet and bulk experiments
the rates of product formation were determined by UV/Vis
spectroscopy and by using reversed-phase high-performance
liquid chromatography mass spectrometry (RP-HPLC-MS).
Note that the spray process (Figure 1) used the small droplet
experiment known as electrosonic spray ionization (ESSI).[6c]
Here we show that ordinary carbon–carbon bond reac-
tions can be performed on a microscale by collecting the
sprayed droplets. As a model system we investigated the base-
catalyzed Claisen–Schmidt condensation of 1-indanone (1)
and 4-chlorobenzaldehyde (2) (see Scheme 1). Absorption
Figure 1. Synthesis using an electrosprayer enclosed in a polypropylene
vessel bottom sealed with glass wool and silica. The high voltage was
applied through the stainless steel needle of the syringe, while
a grounded aluminum foil covered the vessel.
UV/Vis spectroscopy revealed (Figure 2A) remarkably
different extents of product formation in bulk solution versus
that in electrosonically generated droplets. The intensity of
the absorption band at 323 nm indicated a comparably slow
product formation in bulk solution, with complete reaction
occurring after several hours. On the other hand, the UV/Vis
spectrum of the electrosprayed and re-dissolved material
(Figure 2A) almost matched the spectrum of product 4
(Figure 2B), that is, the conversion appeared to be essentially
quantitative. In fact, when a solution of 0.83 mg of 1, 0.88 mg
of 2, and catalytic amounts of KOH was electrosprayed using
an array of four multiplexed ESSI sprayer tips (see Figure S1
in the Supporting Information), (1.47 Æ 0.09) mg or 92.2% of
the main product 4 was produced within 2.5 min. Even this
injection time (i.e. 2.5 min) was only required to spray this
amount of reaction mixture. Reaction is complete on a time
scale of less than 1 min.
Scheme 1. Mechanism of the base-catalyzed Claisen–Schmidt conden-
sation of 1-indanone (1) and 4-chlorobenzaldehyde (2) to 2-(4-chlor-
obenzylidene)indan-1-one (4). Negatively charged intermediates are
drawn in grey.
[*] Dr. T. Mꢀller
Institute of Organic Chemistry, University of Innsbruck
6020 Innsbruck (Austria)
E-mail: thomas.mueller@uibk.ac.at
Dr. A. Badu-Tawiah, Prof. R. G. Cooks
Department of Chemistry, Purdue University
West Lafayette, IN 47907 (USA)
E-mail: cooks@purdue.edu
[**] This research is supported by the National Science Foundation
under grant number CHE 0848650 (to R.G.C.)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206632.
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Figure 2. A) Time course of reactions in bulk solution (solid lines
analyzed after 0, 15, 30, and 60 min) and in preparative electrospray
after 10 min of spraying. Analysis is done by UV/Vis spectroscopy and
the spectra are normalized to equal amounts of reagents 1 and 2
(A=absorbance). B) UV/Vis spectra (A at lmax =1) of 1 (dotted line), 2
(dashed line), and product 4 (solid line).
Figure 3. HPLC-APCI-MS product analysis with UV detection (DAD) at
270 nm: A) reaction mixture and B) product of the preparative electro-
spray. C) Total ion current (TIC) chromatogram for the HPLC analysis
depicted in (B). For more details see Figure S2 and Tables S2 to S5 in
the Supporting Information.
LC-MS analyses using atmospheric pressure chemical
ionization (APCI) were performed to obtain more informa-
tion about the composition and purity of the bulk and sprayed
reaction product mixtures (Figure 3). In the case of reaction
in bulk solution, the minor side products 5 and 5b were
identified as methanol adducts of compound 4. The m/z
values of the protonated molecules ([M+H]+) increased by
32 Da compared to their precursors (see Tables S2 and S3 in
the Supporting Information).
10c (m/z 509). The extended p conjugation of 4, which is
responsible for the absorption maximum at 323 nm, is no
longer present. Exemplary mass spectra and proposed con-
stitutional formulae of 9 and 10 are depicted in Figure 4 (see
Tables S2 to S5 in the Supporting Information).
In contrast, the analysis of the electrosprayed material
(after washing from the collection surface) revealed a com-
pletely different pattern of minor products (Figure 3B and C).
Besides the main product 4 (m/z 255) and residual reagents
1 and 2, nine different compounds were observed in the
product mixture (for a comprehensive summary of UV/Vis
and APCI-MS data see Tables S2 to S5 in the Supporting
Information). The formation of the side products 4b, 7, 8, 9,
9b, 9c, 10, 10b, and 10c could readily be rationalized after
their identification with the help of MS. Only 4b (m/z 255),
detected in traces, was found to be an isomer of 4 (most likely
the Z-isomer of 4) because of its similar m/z value and UV
absorption properties. All eight other compounds had three
features in common: 1) an UV spectrum similar to that of the
reagent 1, but 2) m/z values higher than that of 4 and
3) [4+H]+ as a fragment ion. These eight minor compounds
are clearly products of secondary reactions, which exclusively
can be observed in the charged microdroplet experiment. In
the progression of the reaction and with decreasing concen-
trations of reagent 2, negatively charged enolates of 1 also
react with 4 to give 7 (m/z 401), 9, 9b, or 9c (m/z 387).
Moreover, the deprotonated 4 reacts further with 2 to form 8
(m/z 395) or with another molecule of 4 to give 10, 10b and
Continuous and rapid solvent evaporation gives rise to
increasing reagent concentrations which increase the rate of
reaction—perhaps entirely through a concentration effect.
The side products observed during preparative electrospray
(even though in low yield) were not observed in solution
experiments although their occurrence in the late stages of the
reaction and at high concentrations is not precluded.
Optimization of the conditions to avoid side products and
increase specificity and the overall yield of product 4 above
the current 92.2% level should be straightforward. Since
velocities between 100–200 msÀ1 are reported for charged
droplets 2 mm from the spray source[8] and the distance from
the sprayer to the collection surface was in the range of 3 to
5 cm, the effective lifetime of a droplet is in the millisecond
range. This is orders of magnitude less than a time scale of
many minutes for the corresponding bulk solution experi-
ment. The reaction rate (not rate constant) therefore must be
dramatically enhanced up to several orders of magnitude, in
agreement with recently published data[7a] and this ration-
alizes the observation that the spray time in the electrospray
experiment (minutes) did not influence the composition of
the product mixture (see Figure S4 in the Supporting
Information). Several other experimental variables were
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time. The scale-up was realized by use of an array of four
multiplexed sprayer tips and could easily be further
expanded. The use of an enclosed spray head together with
an inert sheath gas enables oxygen- or moisture-sensitive
compounds to be injected as reagents. If necessary, the silica
adsorbent should allow an in situ purification or separation of
the product. Due to the extraordinary chemical environment
of evaporating charged microdroplets accelerated product
formation was observed.
Experimental Section
Claisen–Schmidt condensation: A 1.8m methanolic KOH solution
(5 mL) was added to 25 mm methanolic solutions of 1 and 2 (500 mL).
Aliquots of the freshly prepared solution were simultaneously used
for reaction in bulk solution at room temperature as well as for
preparative electrospray.
Preparative electrospray: An ESSI sprayer tip setup was used as
previously reported.[6c] The argon or nitrogen pressures were at 120 to
145 psi. A high voltage potential of À2 to À5 kV was applied through
the metal tip of the 500 mL Hamilton syringe. The flow rate of the
syringe pump was 5 to 10 mLminÀ1. After 10 min of reaction mixture
injection, the dry product was collected by carefully rinsing the
polypropylene vessel, glass wool, and silica material with methanol.
For further details see the Supporting Information.
Figure 4. APCI-MS spectra of A) the main product 4 and B) the side
product 9 as well as C) the side product 10 obtained from a preparative
electrospray. The insets show the corresponding structural formulae
and key fragments; rel. I=relative intensity.
Received: August 16, 2012
Revised: September 17, 2012
Published online: October 9, 2012
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Keywords: analytical methods · C C coupling · electrospray ·
mass spectrometry · microscale synthesis
altered but showed minor effects on the product formation
(see Figures S4 to S7 in the Supporting Information).
Remarkably, normal analytical information on the com-
position of the reaction expected from electrospray ionization
is not obtained under the small droplet size (ESSI) spray
conditions used here. Instead the reaction is complete
whether one sprays directly into the instrument or onto
a surface for collection and subsequent analysis.
.
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