Pd PEPPSI-IPr-mediated reactions in metal-coated capillaries under MACOS: The synthesis of indoles by sequential aryl amination/heck coupling

Article abstract of DOI:10.1002/chem.200701588

A method has been devised for the microwave-assisted, continuous-flow preparation of indole alkaloids by a two-step aryl amination/cross-coupling sequence of bromoalkenes and 2-bromoanilines. This process requires both the presence of a metal-lined flow tube (a 1180 micron capillary) and the Pd PEPPSI-IPr catalyst; without either, the catalyst or the film, there is zero turnover of this catalytic process. A silver film has been shown to provide some conversion (48-62%), but optimal results (quantitative) across a variety of bromoalkenes and bromoanilines were achieved by using a highly porous palladium film. Possible roles for the Pd film are considered, as is the interplay of the catalyst and the film.

Full text of DOI:10.1002/chem.200701588

FULL PAPER
DOI: 10.1002/chem.200701588
Pd PEPPSI-IPr-Mediated Reactions in Metal-Coated Capillaries Under
MACOS: The Synthesis of Indoles by Sequential Aryl Amination/
Heck Coupling**
Gjergji Shore, Sylvie Morin, Debasis Mallik, and Michael G. Organ*[a]
Abstract: A method has been devised
for the microwave-assisted, continuous-
flow preparation of indole alkaloids by
Pd PEPPSI-IPr catalyst; without either,
the catalyst or the film, there is zero
turnover of this catalytic process. A
silver film has been shown to provide
some conversion (48–62%), but opti-
mal results (quantitative) across a vari-
ety of bromoalkenes and bromoanilines
were achieved by using a highly porous
palladium film. Possible roles for the
Pd film are considered, as is the inter-
play of the catalyst and the film.
a
two-step aryl amination/cross-cou-
pling sequence of bromoalkenes and 2-
bromoanilines. This process requires
both the presence of a metal-lined flow
tube (a 1180 micron capillary) and the
Keywords:
cycloaddition
cross-coupling
· flow synthesis
·
·
microwaves · palladium · thin films
Introduction
been working on the development of microwave-assisted,
continuous-flow organic synthesis (MACOS) that eliminates
such flasks and minimizes sample handling.[2,3] Synthesis in a
flowed format has the advantage of rapid reaction optimiza-
tion because all that is required is a single drop of product
from the reaction tube to evaluate the progress of the trans-
formation; every subsequent drop will be the same. Further,
once an optimized set of conditions has been reached, the
process is infinitely scaleable.[4,5]
We have demonstrated that complete reaction mixtures
can be flowed through capillary-sized reaction tubes that
traverse the microwave cavity leading to excellent conver-
sions (in minutes or less) over a variety of transformations.[2a]
We have also illustrated that separated reaction components
(e.g., two or more solutions) can be flowed through separate
inlets, mixed at the site of reaction in the microwave, and
also have excellent chemical conversion.[2b] We have also
disclosed the use of thin Pd films in conjunction with
MACOS to promote metal-catalyzed cross-coupling reac-
tions (e.g., Heck and Suzuki–Miyaura coupling) in the ab-
sence of any homogeneous catalyst.[6,7] In this report, we
detail the use of the Pd film to promote a sequential inter-
molecular amination/intramolecular Heck transformation
employing the Pd PEPPSI-IPr (PEPPSI: pyridine, enhanced,
precatalyst, preparation, stabilization, and initiation) cata-
lyst[8] to prepare a collection of indoles by using the
MACOS methodology.
Microwave-assisted organic synthesis (MAOS) has been ap-
plied very successfully to both homo- and heterogeneous re-
actions leading to marked reductions in reaction times.[1] Of-
tentimes, the crude products of MAOS reactions are cleaner
(e.g., fewer byproducts) than those obtained from the corre-
sponding conventionally heated transformations, which has
been attributed to the significantly longer times necessary to
achieve the same level of conversion by using, for example,
an oil bath. However, while reaction times are shorter when
using MAOS, the method requires that transformations be
conducted in specialized, sealed high-pressure vials; this re-
quires significant handling of each individual transformation
(e.g., capping and decapping) that significantly slows the
overall synthetic process. To overcome these issues, we have
[a] G. Shore, Prof. S. Morin, Dr. D. Mallik, Prof. Dr. M. G. Organ
Department of Chemistry, York University
4700 Keele Street
Toronto, Ontario, M3J 1P3 (Canada)
E-mail: organ@yorku.ca
[**] PEPPSI: pyridine, enhanced, precatalyst, preparation, stabilization,
and initiation; MACOS: microwave-assisted, continuous-flow organic
synthesis.
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author and contains
methods for the preparation of all thin films used and all MACOS re-
1
action conditions as well as H and/or 13C NMR and LCMS spectra
for all compounds prepared in this study.
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Table 1. MACOS-mediated conversion of 2-bromoalkenes and 2-bromoanilines to indoles by using the Pd PEPPSI-IPr catalyst, both with and without
metal-lined capillaries.
Entry Vinyl
bromide
Mode Conditions[a,b]
Product Conversion [%][c]
(Yield [%])[d]
1
2
3
4
5
1c
flow
flow
flow rate: 15 LminÀ1, 75 psi back pressure, 200 W, T=1008C, clear 1180 mm ID capillary
flow rate: 15 LminÀ1, 75 psi back pressure, 240 W, T=1058C, clear 1180 mm ID capillary
3c
3a
3c
3b
3c
0 (0)
0 (0)
85 (74)
83 (70)
0 (0)
1a
1c
1b
1c
batch 240 W, T=1058C, 20 min
batch 240 W, T=1758C, 22 min
flow
flow
flow
flow
flow
flow rate: 15 LminÀ1, 75 psi back pressure, 22 W, T=2058C, Pd-coated 1180 mm ID capil-
lary[e] (no Pd PEPPSI-IPr catalyst)
6
7
8
9
1a
1a
1a
1a
flow rate: 15 LminÀ1, 75 psi back pressure, 22 W, T=2058C, Ag-mirror coated 1180 mm capil- 3a
lary (i.e., dense Ag film)[e]
48 (32)
62 (47)
95 (81)
57
flow rate: 15 LminÀ1, 75 psi back pressure, 22 W, T=2058C, Ag-coated 1180 mm ID capillary 3a
from colloidal Ag (i.e., porous Ag film)[e]
flow rate: 15 LminÀ1, 75 psi back pressure, 22 W, T=2058C, Pd-coated 1180 mm, ID capil-
3a
lary[e]
flow rate: 15 LminÀ1, 75 psi back pressure, oil bath, T=2008C, Pd-coated 1180 mm ID capil-
3a
lary[e]
[a] The temperature reported for these transformations is the temperature observed by the IR sensor in the irradiation chamber of the Biotage Smith
Creator Microwave Synthesizer. Because the sensor measures only the surface temperature of the capillary, this may, or may not accurately reflect the
temperature of the solution inside of the tube during flow. [b] For the structure of Pd PEPPSI-IPr, see Scheme 1. [c] Percent conversion is determined by
evaluating the ratio of starting material to indole product in the 1H NMR spectrum of the crude effluent taken directly from the reaction capillary.
[d] Percent yield is determined by following purification on silica-gel chromatography of a fixed volume of reaction mixture containing a known amount
of 1 and 2 to begin the transformation. [e] All metal-coated capillaries are prepared to a thickness of 6 microns; of the total length of the capillary
(ꢀ12 cm), approximately 3 cm is actually irradiated in the microwave chamber.
Results and Discussion
tions with the same substrates and discovered that, in fact,
the catalyst was active but the transformation indeed re-
quired 20–22 min to reach >80% conversion (Table 1, en-
tries 3 and 4).
We have been interested for some time in metal-catalyzed,
multistep sequences to rapidly build up significant molecular
structures[9] and recently we have applied multicomponent
reaction methodology to the MACOS format.[10] Indoles are
compounds of considerable biological significance,[11] and as
part of our medicinal chemistry program we were interested
in developing an effective “one-pot” coupling sequence to
prepare them using a flow-synthesis format.
We were interested in ascertaining the kinetics of this re-
action in batch mode to determine if there was necessarily a
lag phase, such as would be the case if catalyst activation
under these particular conditions was slow. This might ac-
count for the prolonged reaction times necessary to drive
the reactions to completion under MAOS, which for most
cross coupling reactions occurs much more quickly.[1] We de-
termined that this reaction mixture under batch conditions
takes approximately 2.5 min to reach the desired tempera-
ture (i.e., ꢀ2008C); assuming for now that the top end tem-
perature is necessary to initiate the catalytic cycle, we began
taking readings at that time (Figure 1). Interestingly, there
appears to be no lag phase and conversion followed almost
linear kinetics, albeit slowly. This was concerning for it im-
plied that the sequence might not be suitable for MACOS
as continuously flowed reactions must proceed as far as pos-
sible within ꢀ120 seconds to avoid the need for stop flow,
or passing the sample back through the microwave cavity
multiple times,[14] which compromises some of the advantag-
es of working in a flowed format.
The amination/Heck MACOS sequence,[12] utilizing our
active Pd PEPPSI-IPr catalyst,[8,13] employing a simple glass
capillary as the flow tube showed no conversion (Table 1,
entries 1and 2; residence time in the irradiation zone of the
microwave instrument during flow is approximately 120 s).
The catalyst is fully soluble and was premixed with the sub-
strates at 2.5 mol% and the whole solution was flowed
down the capillary setup. This negative result left us with a
number of questions. We have demonstrated that metal-cat-
alyzed reactions, such as Suzuki–Miyaura coupling and ring-
closing metathesis, can be driven to completion by MACOS
in the brief time that the sample resides in the irradiation
chamber of the microwave;[2a] perhaps it is possible that the
Pd PEPPSI-IPr catalyst is simply ineffective for this particu-
lar sequence. Alternatively, the catalyst may be active but
simply requires longer than 120 s (in continuous flow) to
show appreciable catalytic activity in this particular se-
quence. To probe these queries, we performed batch irradia-
The poor MACOS results when using Pd PEPPSI-IPr sug-
gested the use of metal-coated capillaries for this coupling
sequence due to success of these capillaries in related cou-
pling reactions.[6] In those cases, no additional (homogene-
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Synthesis of Indoles
FULL PAPER
homogeneous catalyst) point to a catalytic role, at least with
Pd, but metal films are also known to couple very effectively
with microwave irradiation to generate a current that gener-
ates significant heat.[15] In light of this, we considered flow-
ing the Pd PEPPSI-IPr-containing solution through a metal-
coated capillary to see if the superior heating might help
promote this transformation. We have found that silver
films absorb microwave irradiation suitably, thus we first
tried such a capillary (Table 1, entry 6). For the first time
with MACOS, we began to see appreciable conversion
(48%) that proceeded straight through to the indole, that is,
we saw no intermediate coupling products and starting ma-
terials which could account for the balance of the reaction
mixture. We tried the same transformation by using a Pd-
coated capillary (Table 1, entry 8) and noticed another sig-
nificant improvement in conversion (essentially quantita-
tive) relative to the Ag-mirror-coated capillary. With this ob-
servation in hand, we subjected a variety of coupling part-
ners to the MACOS procedure employing the Pd-coated ca-
pillary and it worked very smoothly (Scheme 1); the reac-
tions were very clean with minimal, if any, byproducts.
Figure 1. Percent conversion of 1-bromo-1-phenylethylene (1c) and 2-
bromoaniline (2a) to 2-phenylindole (3c) by Pd PEPPSI-IPr under batch
reaction conditions as a function of time by using the conditions listed in
Table 1, entry 3.
ous) Pd catalyst was required as a Pd film by itself promoted
Suzuki–Miyaura and Heck reactions.[6] While successful in
those applications, there was no conversion in the present
sequence with just the Pd-coated capillary and no Pd
PEPPSI-IPr catalyst (Table 1, entry 5).
Metal films possibly have a dual role in these coupling
procedures.[6] Clearly, cross-coupling reactions performed
with just a Pd-coated reaction capillary (i.e., no additional
According to our mechanistic understanding of this partic-
ular coupling sequence, it is not likely that the Ag film is ca-
pable of serving in any role other than as an effective heat
source, that is, it is not actively catalyzing any of the chemis-
try. Given that the Pd film on its own did not yield any
Scheme 1.
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1353

M. G. Organ et al.
product, it is not immediately clear why the Pd film provid-
ed considerably better results than its Ag-mirror film coun-
terpart when the Pd PEPPSI-IPr catalyst was employed.
The Pd film[16] is made of nanoparticles and it is highly
porous in contrast to the Ag-mirror film; the Ag-mirror film
is compact with only small voids between the grains (Fig-
ure 2b and d). This latter morphology gives the Ag film its
mirror-like appearance, while the porous nature of the Pd
the Pd PEPPSI-IPr catalyst in those regions. This might be
considered analogous to flash vacuum thermolysis transfor-
mations in which gas-phase reactants under high vacuum
are flowed through a quartz tube that is generally heated to
ꢀ5008C; contact with the super-heated walls results in very
fast and remarkably clean conversions (e.g., retro-Diels–
Alder reactions). With this in mind, we re-examined the
morphology of the Ag film and tried to create a microstruc-
ture that was more similar to
the porous Pd film. This was
achieved by depositing Ag2O
colloids from ethylene glycol
onto the glass surface; the re-
sulting films were dull gray and
semitransparent.
SEM
(Figure 3) and EDX analysis
confirmed that the films have a
larger surface area than the cor-
responding silver-mirror films
(see Figure 2b to compare
images at the same magnifica-
tion) and that they contained
mostly Ag0, respectively. How-
ever, the surface area is still
much lower than for the Pd
films (see Figure 2a to compare
images obtained at the same
magnification). The resultant
porous Ag film did result in sig-
nificantly better conversion
when compared to the silver
Figure 2. SEM images depicting the morphology of the Pd and Ag films lining the capillaries that are used in
the MACOS process to generate indoles by an amination/Heck coupling sequence. Panels a) and b) show a
section of the Pd- and Ag-thin film removed from the capillary at ”30000 magnification, respectively. Pan-
els c) and d) show images obtained for the same region of Pd- and Ag-thin films at ”100000 magnification, re-
spectively.
mirror
(Table 1,
entry 7
film (Figure 2a and c) leads to a
dark grey, partially transparent
film, despite the fact that both
films were prepared such that
they contained the same quanti-
ty of metal by weight. The more
porous Pd film is not likely to
heat up any more effectively en
masse than the Ag-mirror film
Figure 3. SEM images depicting the morphology of the Ag film prepared by using Ag2O colloids. Panels a)
and b) are taken at ”10000 and ”30000 magnifications, respectively.
at the macroscopic level. This is
supported by the IR sensor
temperature readings in the mi-
crowave cavity (see Table 1, entry 6 and Scheme 1) indicat-
ing that the same temperature was reached in both sys-
tems.[17] That said, perhaps the Pd film, possessing more ir-
regularities, could potentially have hotter sites at the micro-
scopic level; steps and corners on the surface of metal films
have been suggested to enhance microwave absorption that
could lead to localized “hot spots” in the film.[6] So, while
the bulk temperature recorded by the IR sensor is 2008C,
microscopic regions in the film could be 300 or 4008C (or
higher) and this could lead to a much higher reactivity of
versus 6); the filmꢁs morphology clearly plays an important
role in this chemistry.
While an improvement in conversion was observed when
the Ag filmꢁs surface area was enhanced, it still fell noticea-
bly short of the quantitative conversion obtained when the
structurally-analogous Pd film was used. It is possible that
the Pd film is doing more than just providing heat. Perhaps
Pd PEPPSI-IPr catalyzes one of the steps quite efficiently
when a metal film is present, but it catalyzes the other step
less effectively. The Ag film can provide high temperatures,
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Synthesis of Indoles
FULL PAPER
but no catalytic role, whereas the Pd film is capable of pro-
viding both heat and catalytic activity and this leads to the
high conversion in the Pd case that is absent with Ag. This
might be supported by the fact that Pd PEPPSI-IPr has
been demonstrated to be highly efficient in sp3–sp3 couplings
with little or no competing b-hydride elimination, which, of
course, is a requisite for the Heck reaction in this se-
quence.[13] Perhaps it is the Heck component of the se-
quence that is responsible for the prolonged reaction times
in batch mode employing Pd PEPPSI-IPr in which full con-
version to product requires >20 min., whereas the flowed
reactions through Pd-coated capillaries are complete in
<120 s!
There is perhaps some concern over the thermal stability
of the Pd PEPPSI-IPr catalyst during prolonged irradiation,
and this might account for the sluggish reactivity in the
batch runs; that is, some of the catalyst may be decompos-
ing. To probe this possibility, we performed two control ex-
periments; both involved stressing the catalyst. In one case,
we flowed Pd PEPPSI-IPr through a Pd-coated capillary
while irradiating at 2058C and in another case we simply
heated Pd–PEPPSI-IPr at 2058C in a batch setting for
20 min. Both stressed catalysts were used (separately) for
the batch reaction shown in Table 1, entry 3; both yielded
complete conversion to the indole product, thus catalyst sta-
bility does not appear to be an issue in this chemistry.
To further probe the reliance of Pd PEPPSI-IPr on the
Pd-coated capillary for this process (and vice versa), we ran
several additional control experiments. We have already
published that MACOS with Pd films smoothly performs
the Heck reaction of 4 with 5 in 99% conversion by using
DMA (DMA=dimethylacetamide) solvent (Scheme 2).[6]
Under the optimized conditions developed for the two-step
coupling sequence in this manuscript with toluene as the sol-
vent, but otherwise identical conditions to our previous
Heck results, there was no conversion at all to 6. Not sur-
prisingly, based on our alkyl–alkyl coupling results when
using Pd PEPPSI-IPr,[13] we also saw no Heck coupling
when it was used in the MACOS reactor with no Pd film.
Similarly, we tried independent amination reactions of 4
with 7 (Scheme 2), which we know to work with Pd
PEPPSI-IPr from other studies in our laboratories which
use DME (DME=dimethoxyethane) solvent in batch. Once
again, there is a high solvent dependence as the reaction
completely failed when using MACOS, as it did with just
the Pd-coated capillary. Thus, under the optimized reaction
conditions for the two-step process to generate indoles in
this report, none of the independent reactions proceeded
under MACOS in the absence of either the homogeneous
catalyst or the Pd film. We believe that the codependence of
a homogeneous catalyst with a metal surface demonstrated
in this study is without precedent.
A question often asked with MAOS-related methodology
relates to the existence of a “microwave effect” that pro-
motes reactions beyond simple effective heating. It is
common to run the analogous MAOS reaction by using con-
ventional heating methods and see if there is a significant
difference in the results. The reaction outlined in Table 1,
entry 8 was repeated in every aspect with the exception that
the transformation was conducted in an oil bath set to deliv-
er the identical temperature recorded by the IR sensor in
the Biotage Smith Creator Synthesizer (entry 9). A signifi-
cant reduction in conversion was observed when using con-
ventional heating (57 versus 95% with microwave irradia-
tion). This result also is suggestive that heating of the film,
at least in microscopic regions, may be generating tempera-
tures significantly in excess of the value recorded outside of
the metal-coated capillary.[17] This does not necessarily point
to a special microwave effect per se, but may none-the-less
point to a special relationship between metal films and mi-
crowave irradiation that leads to vastly superior heating.
Conclusions
A highly effective process has been developed for a two-
step amination/Heck coupling sequence to make indoles by
flowed synthesis catalyzed by both Pd PEPPSI-IPr and a
thin Pd metal film on the surface of the flow tube while
being heated by microwave irradiation. The flowed process
yields zero product when either the Pd PEPPSI-IPr or the
Pd-metal film is omitted. Substitution of the Pd film for an
Ag-mirror, which presumably generates that same bulk
heating, leads to a significant reduction in conversion, sug-
gesting that both the Pd PEPPSI-IPr and the Pd film are in-
volved in the catalysis. Conversely, irregularities in the struc-
ture of the Pd film, which are absent in the Ag-mirror film,
could lead to localized “hot spots” of intense temperature in
the presence of microwave irradiation[6] that drives the Pd
PEPPSI-IPr catalyst more effectively to conduct not only
the amination reaction, but the high-energy b-hydride elimi-
nation step that is required for the Heck step in this process.
The Ag film possesses much lower electrical resistance
Scheme 2.
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1355

M. G. Organ et al.
(1.617”10À8 W) relative to Pd (10.73”10À8 W) (values for
298 K) and, therefore, should generate more heat while
being irradiated, and yet conversion with Ag is consistently
lower than with Pd.[18] Temperatures of microscopic regions
in the films cannot be assessed, but it seems to support the
morphology argument. This notion might be supported by
the observed increase in conversion when the dense Ag-
mirror morphology is substituted with a rougher Ag film.
Indeed in attempted Heck reactions conducted in our labo-
ratories utilizing Pd PEPPSI-IPr, the Heck product was only
observed after prolonged batch heating at 1208C in an oil
bath. Product formation always happened concomitantly
with significant darkening of the solution that may well have
been the result of the catalyst blacking-out; there is a strong
possibility that the conversions in these Heck reactions were
catalyzed by Pd black, and not by Pd PEPPSI-IPr. In an
analogous manner then, it is also possible that the deposited
Pd colloids in the film are promoting the second step. In this
case, the Pd film would be incapable of performing the ami-
nation (vide supra), hence the need for both the catalyst
and the Pd film.
Saaby, K. R. Knudsen, M. Ladlow, S. V. Ley, Chem. Commun. 2005,
2909.
[5] For reports dealing with the use of flow microwave approaches for
preparative or semi-preparative scale organic synthesis see: a) M. C.
Bagley, R. L. Jenkins, M. C. Lubinu, C. Mason, R. Wood, J. Org.
Chem. 2005, 70, 7003; b) S. Saaby, I. R. Baxendale, S. V. Ley, Org.
Biomol. Chem. 2005, 3, 3365; c) M. Fagrell (PCT Int. Appl., 20
pp.CODEN), PIXXD2 WO 2003041856, 2003; M. Fagrell (PCT Int.
Appl., 20 pp.CODEN), A120030522, 2003; M. Fagrell (PCT Int.
Appl., 20 pp.CODEN), CAN 138:403615; M. Fagrell (PCT Int.
Appl., 20 pp.CODEN), AN 396771, 2003; d) T. Cablewski, A. F.
Faux, C. R. Strauss, J. Org. Chem. 1994, 59, 3408.
[6] G. Shore, S. Morin, M. G. Organ, Angew. Chem. 2006, 118, 2827;
Angew. Chem. Int. Ed. 2006, 45, 2761.
[7] For two seminal reports using Pd-metal films to promote batch cou-
pling reactions see: a) J. Li, A. W.-H. Ma, C. R. Strauss, Chem.
Commun. 1997, 1275; b) A. Stadler, C. O. Kappe, Org. Lett. 2002, 4,
3541.
[8] C. J. OꢁBrien, E. A. B. Kantchev, N. Hadei, C. Valente, G. A. Chass,
J. C. Nasielski, A. Lough, A. C. Hopkinson, M. G. Organ, Chem.
Eur. J. 2006, 12, 4743.
[9] M. G. Organ, J. T. Cooper, L. R. Rogers, F. Soleymanzadeh, T. Paul,
J. Org. Chem. 2000, 65, 7959.
[10] S. Bremner, M. G. Organ, J. Comb. Chem. 2007, 9, 1 4.
[11] a) Indoles (Ed.: R. J. Sundberg), Academic Press, San Diego, 1996;
b) J. A. Joule, Indole and its derivatives, Science of Synthesis,
George Thieme, 2001, 10, 361–652.
[12] A similar Pd-mediated process has been reported recently: J. Bar-
luenga, M. A. Fernandez, F. Aznar, C. Valdes, Chem. Eur. J. 2005,
11, 2276.
We have discovered a variety of other transformations,
both metal-catalyzed and non-metal-catalyzed, that similarly
only proceed in the presence of a metal film. This will allow
the exploration of a wealth of new chemistries that can be
run under the highly efficient MACOS methodology. We
will be reporting on these observations in due course.
[13] a) M. G. Organ, M. Abdel-Hadi, S. Avola, N. Hadei, J. Nasielski,
C. J. OꢁBrien, C. Valente, Chem. Eur. J. 2007, 13, 150; b) M. G.
Organ, S. Avola, I. Dubovyk, N. Hadei, E. A. B. Kantchev, C. J.
OꢁBrien, C. Valente, Chem. Eur. J. 2006, 12, 4749.
[14] N. S. Wilson, R. C. Sarko, G. P. Roth, Org. Process Res. Dev. 2004, 8,
535.
Acknowledgements
[15] A. G. Whittaker, D. M. P. Mingos, J. Chem. Soc. Trans. 1995, 2073.
[16] Questions have been raised about the actual surface of the Pd film,
that is, is it Pd0 or PdIIO. EDX analysis indicates very little oxygen is
present (0.3%) and when we flowed hydrogen gas down the inside
of the capillary, significant sparking ensued confirming that a signifi-
cant portion of the filmꢁs surface is metallic Pd.
[17] We recognize that the IR sensor measurement is not likely to deliv-
er an accurate measure of the temperature inside of the capillary.
However, we have not yet been successful in getting more accurate
measurements, for example, employing a miniature thermocouple as
such devices also couple with microwave irradiation leading to cur-
rent and heating itself; this would lead to erroneous results. What
we can say is that the temperature is likely higher than 2008C, as
read by the IR sensor, but less than 6008C, which is the melting
temperature of borosilicate glass.
This work was funded by the Ontario Research and Development Chal-
lenge Fund (ORDCF), the Canada Foundation for Innovation (CFI), the
Ontario innovation trust (OIT), the NSERC, and York University. The
authors are grateful to Biotage Inc. for the donation of a Smith Creator
Synthesizer to develop this new methodology. We acknowledge R. Da-
vidson at Surface Science Western, University of Western Ontario,
London, ON for the SEM and EDX measurements.
[1] a) P. J. Tierney, P. Lidstrom Microwave Assisted Organic Synthesis,
Blackwell Publishing, Oxford, 2005; b) C. O. Kappe, Angew. Chem.
2004, 116, 6408; Angew. Chem. Int. Ed. 2004, 43, 6250.
[2] a) E. Comer, M. G. Organ, J. Am. Chem. Soc. 2005, 127, 8160;
b) M. G. Organ, E. Comer, Chem. Eur. J. 2005, 11, 7223.
[3] For another approach to MACOS see: P. Watts, S. J. Haswell, Chem.
Eng. Technol. 2005, 28, 290.
[4] For discussion of flow synthesis on a non-microscale, see: a) R. A.
Kautz, W. K. Goetzinger, B. L. Karger, J. Comb. Chem. 2005, 7, 1 4;
b) D. M. Ratner, E. R. Murphy, M. Jhunjhunwala, D. A. Snyder,
K. F. Jensen, P. H. Seeberger, Chem. Commun. 2005, 578; c) S.
[18] a) CRC Handbook of Chemistry and Physics, 88th ed., p. 12, 2007,
CRC Press/Taylor and Francis, Boca Raton, Fl; b) CRC Handbook
of Chemistry and Physics, 88th ed., p. 12, 2008, CRC Press/Taylor
and Francis, Boca Raton, Fl.
Received: October 8, 2007
Published online: December 13, 2007
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