U.S. patent application number 12/558681 was filed with the patent office on 2010-02-25 for method and apparatus for continuous flow microwave-assisted chemistry techniques.
Invention is credited to Gary Wilbert Busse, Michael John Collins, JR., Michael John Collins, Wyatt Price Hargett, JR., Edward Earl King.
Application Number | 20100044368 12/558681 |
Document ID | / |
Family ID | 31186019 |
Filed Date | 2010-02-25 |
United States Patent
Application |
20100044368 |
Kind Code |
A1 |
Collins; Michael John ; et
al. |
February 25, 2010 |
Method and Apparatus for Continuous Flow Microwave-Assisted
Chemistry Techniques
Abstract
The invention is a method and associated instrument for
microwave assisted chemistry. The invention includes the steps of
directing a continuous flow of fluid through a microwave cavity
while applying microwave radiation to the cavity and to the
continuous flow of materials therein, monitoring the pressure of
the fluid in the cavity; and cooling the fluid in the cavity when
the pressure exceeds a predetermined setpoint pressure.
Inventors: |
Collins; Michael John;
(Charlotte, NC) ; Collins, JR.; Michael John;
(Charlotte, NC) ; Hargett, JR.; Wyatt Price;
(Matthews, NC) ; King; Edward Earl; (Charlotte,
NC) ; Busse; Gary Wilbert; (Monroe, NC) |
Correspondence
Address: |
SUMMA, ADDITON & ASHE, P.A.
11610 NORTH COMMUNITY HOUSE ROAD, SUITE 200
CHARLOTTE
NC
28277
US
|
Family ID: |
31186019 |
Appl. No.: |
12/558681 |
Filed: |
September 14, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11047348 |
Jan 28, 2005 |
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12558681 |
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10064623 |
Jul 31, 2002 |
6867400 |
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11047348 |
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Current U.S.
Class: |
219/679 ;
219/686; 219/687 |
Current CPC
Class: |
B01J 2219/0009 20130101;
C07C 221/00 20130101; B01J 19/126 20130101; C07C 67/03 20130101;
B01J 2219/1227 20130101; C07C 67/03 20130101; C07C 221/00 20130101;
C07C 223/06 20130101; C07C 69/78 20130101; C07C 57/44 20130101;
C07C 69/76 20130101; C07C 51/38 20130101; C07C 51/38 20130101; C07C
67/08 20130101; H05B 6/806 20130101; B01J 2219/1239 20130101; B01J
2219/00162 20130101; C07C 67/08 20130101 |
Class at
Publication: |
219/679 ;
219/686; 219/687 |
International
Class: |
H05B 6/80 20060101
H05B006/80 |
Claims
1. A method of microwave assisted chemistry comprising: directing a
continuous flow of fluid through a microwave cavity while applying
microwave radiation to the cavity and to the continuous flow of
materials therein; monitoring the pressure of the fluid in the
cavity; and cooling the fluid in the cavity when the pressure
exceeds a predetermined setpoint pressure.
2. A method according to claim 1 wherein the cooling step comprises
moderating the degree of cooling in response to the monitored
pressure.
3. A method according to claim 1 wherein the step of cooling the
fluid in the cavity comprises circulating a coolant in the cavity
in response to the pressure setpoint determination.
4. A method according to claim 3 comprising circulating air as the
coolant in the cavity.
5. A method according to claim 1 comprising directing the
continuous flow of fluid through a single mode microwave
cavity.
6. A method according to claim 1 wherein the step of directing the
fluid comprises directing the fluid in the presence of a
catalyst.
7. A method according to claim 1 wherein the step of directing the
fluid comprises directing the fluid in the presence of a scavenging
composition.
8. A method according to claim 1 wherein the steps of monitoring
and cooling comprise: sending a signal representative of the
pressure from a pressure monitor to a processor; using the
processor to compare the monitored pressure to the setpoint
pressure; and sending a signal from the processor that initiates
and runs a cavity cooling device whenever the monitored pressure
exceeds the setpoint pressure.
9. A method according to claim 1 wherein the steps of directing and
cooling the fluid comprise: directing the fluid through a tube; and
externally cooling the tube.
10. A method according to claim 9 wherein the step of externally
cooling the tube comprises directing a cooling fluid over the
exterior of the tube.
11. A method of microwave assisted chemistry comprising carrying
out a chemical reaction in batch format while irradiating the
reactants with microwave radiation and while concurrently
externally cooling the reaction vessel to thereby identify an
optimum power level for the reaction and without exceeding a
temperature at which the reactants decompose; thereafter directing
a continuous flow of corresponding reactants through a single mode
microwave cavity while applying microwave radiation to the cavity
and to the continuous flow of materials therein at the power level
identified during batch format reaction of the same reactants; and
externally cooling the flowing reactants while applying the
microwave radiation in order to continue at the identified power
level while avoiding an undesired increase in the temperature of
the reaction.
12. A method of microwave assisted chemistry comprising: directing
a continuous flow of fluid that includes reactants through a single
mode microwave cavity while applying microwave radiation to the
cavity and to the continuous flow of materials therein; and
purifying the reaction products with a scavenging composition in a
single-mode microwave cavity.
13. A method according to claim 1 wherein the scavenging step
comprises directing the fluid through a column filled with a solid
support that includes a scavenging functional group selected from
the group consisting of electrophilic scavengers, nucleophilic
scavengers, and combinations thereof.
14. A method according to claim 12 and further comprising:
monitoring the pressure of the fluid in the cavity; and cooling the
fluid in the cavity when the pressure exceeds a predetermined
setpoint.
15. A method according to claim 12 and further comprising:
monitoring the pressure of the fluid in the cavity; and moderating
the applied microwave power when the pressure exceeds a
predetermined setpoint.
16. A method according to claim 12 and further comprising:
monitoring the temperature in the cavity; and cooling the fluid in
the cavity when the temperature exceeds a predetermined
setpoint.
17. A method according to claim 12 and further comprising:
monitoring the temperature in the cavity; and moderating the
applied microwave power when the temperature exceeds a
predetermined setpoint.
18. A method according to claim 12 and further comprising
immediately directing the purified reaction products to a
separation step.
19. A method according to claim 18 wherein the separation step
comprises chromatography.
20. A method according to claim 19 wherein the chromatography step
comprises high pressure liquid chromatography.
Description
RELATED APPLICATIONS
[0001] This invention is a divisional of co-pending application
Ser. No. 11/047,348, filed Jan. 28, 2005, which is a divisional of
co-pending application Ser. No. 10/064,623, filed Jul. 31, 2002,
now U.S. Pat. No. 6,867,400, and is related to commonly assigned
and co-pending application Ser. No. 10/126,838, filed Apr. 19,
2002; and issued U.S. Pat. Nos. 6,744,024, issued Jun. 1, 2004;
6,649,889, issued Nov. 18, 2003; 6,630,652, issued Oct. 7, 2003;
and 6,753,517, issued Jun. 22, 2004. All of these applications and
patents are incorporated entirely herein by reference.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to methods and apparatus for
microwave-assisted chemistry techniques, and in particular to the
use of microwaves in organic synthesis reactions. Most chemical
reactions are generated, initiated, or accelerated by increasing
temperature in accordance with relatively well-understood rate and
thermodynamic principles. Accordingly, because microwaves can
produce heat in certain qualifying substances, microwaves have been
used to generate heat in a wide variety of chemical and chemistry
related processes and techniques. These have typically included
microwave drying for loss-on-drying moisture content analysis, and
digestion of samples as a preparation step prior to other
analytical techniques such as atomic absorption spectroscopy on the
digested residues.
[0003] The carefully controlled conditions required for organic
synthesis, however, generally have been unsuited (or vice versa)
for use in typical earlier-generation microwave laboratory
equipment. Specifically, although microwave devices can produce
relatively large amounts of power, the nature of microwave cavities
and the wavelength of microwaves tend to produce varying levels of
power within the three dimensional space defined by the cavity. For
large samples or samples where of high temperature effects are
required or desired, this aspect of microwave heating does not
matter and indeed permits microwaves to work better than most other
types of heating for such purposes.
[0004] Chemical synthesis, however, and in particular organic
synthesis, requires a more careful and to some extent delicate
application of heat to chemical reactions. In response to the need
for more carefully applied microwave energy for organic synthesis
purposes (by way of example and not limitation), a number of newer
devices have been developed which accomplish this purpose. The
apparatus and instrument set forth in the above co-pending
applications are exemplary of such a device, which has gained rapid
acceptance as a method for carrying out organic synthesis using
microwaves. The instrument is also commercially available under the
DISCOVER.TM. trademark of CEM Corporation, Matthews, N.C., the
assignee of the present invention. The success of the DISCOVER.TM.
instrument has led to an increase in the use of microwave synthesis
techniques, and the corresponding need for additional methods of
carrying out synthetic reactions in this advantageous manner.
[0005] First, in order to scale up reactions from the laboratory
bench top to useful synthesis of larger amounts, it is generally
advantageous to use continuous rather than batch systems. Certain
reactions are also carried out more advantageously in a flowing
condition because of the nature of the catalysts used. As another
issue, microwave penetration of materials tends to be effective,
but spatially limited; i.e., microwaves tend to penetrate part of a
sample, but no further. This spatial limitation can prevent optimum
utilization of microwave power in a batch content. Stated
differently, the lack of penetration depth can prevent microwave
irradiation from affecting an entire batch sample with the result
that interior portions of the sample are merely conductively or
convectionally heated by the exterior portions.
[0006] Accordingly, a flow-through system that allows greater
penetration by exposing a smaller volume to microwaves at any given
time can be advantageous. Yet other reactions (e.g., esterification
to produce polyesters) will move to an equilibrium condition,
unless one of the reaction products is removed. In the case of the
esterification reaction that produces polyester, water is removed
in order to prevent an equilibrium from being established between
the reactives and the products, thus encouraging the production of
the finished esterified polyester, rather than an equilibrium
mixture of reactants and products. Continuous flow reactors can be
advantageous in accomplishing such reactions.
[0007] Continuous flow reactors can also help reduce the total
forces (usually pressure) that can build up in batch reactions
because a proportionally smaller volume is irradiated at any given
time. Additionally, the speed with which microwaves interact with
responsive materials (essentially instantaneously) makes
flow-through techniques at reasonable rates feasible in situations
where conventional heating would be too slow to be effective.
[0008] Microwaves are generally defined as those waves falling in
the portion of the electromagnetic spectrum having frequencies of
from about 300 to 300,000 megahertz (MHz). The corresponding
wavelengths are on the order of between about one centimeter and
one meter. These are of course arbitrary limits and will be
understood as such. Most common instruments that incorporate
microwave radiation use a preferred assigned frequency of 2450
megahertz.
[0009] As understood by those familiar with chemical reactions
exposed to microwaves, the energy of microwave photons is
relatively low compared to the typical energies of chemical bonds
(80-120 Kcal/mole). Accordingly microwaves do not directly affect
molecular structure, but instead tend to generate molecular
rotations, and by the resulting kinetic energy typically generates
heat. Microwave heating does not, however, depend on the thermal
conductivity of the materials being heated, and thus offers an
additional advantage over typical conduction heating methods.
[0010] Because of the speed with which microwaves can heat
materials, the temperature of the sample (reactants, starting
materials, etc.) can quickly increase beyond a desired or
advantageous temperature. Accordingly, another desired aspect of a
chemistry synthesis instrument, including a microwave-assisted
instrument, is the capability of controlling temperature while a
reaction proceeds. Lack of temperature control can produce a number
of undesired consequences. First, the temperature may increase to a
point at which the reactives or the products decompose rather than
react properly. Secondly, if there are volatile products being
generated by the reaction, which is typical in many organic
synthesis reactions, the increased pressure must be contained or
released. Alternatively, the increased pressure can change the
reaction kinetics in an undesired manner. Finally, an increase in
temperature can also produce physical consequences to the reaction
vessels and the instrument itself should pressures and temperatures
and pressures become so high as to create some sort of unintended
mechanical or physical failure.
[0011] Temperature control is available for microwave instruments.
For example, commonly assigned U.S. Pat. No. 6,227,041 illustrates
how measuring the temperature of a sample can be used to moderate
(typically reducing) the applied microwave power, and thus prevent
a sample from overheating and decomposing.
[0012] All chemical reactions are driven by thermodynamic factors,
and most are initiated when energy is added to the reactants. In
many cases, microwave irradiation can apply energy to chemical
reactants faster and more efficiently than conventional heating
steps. Accordingly, when the microwave power is reduced or stopped
in an effort to control temperature, the efficiency of the reaction
can be reduced even as heat is being produced. Thus a reaction
proceeding at an elevated temperature in the absence of microwaves
can still be proceeding less-efficiently than it would if
microwaves were being applied.
[0013] Accordingly, commonly assigned application Ser. No.
10/064,261, filed Jun. 26, 2002, now U.S. Pat. No. 6,744,024,
discloses an instrument for microwave synthesis that incorporates
proactive cooling in a single-mode microwave cavity. By moderating
the heat generated by the applied microwaves or the reaction
itself, the instrument permits a greater amount of microwave power
to be applied to the reaction as may be desired or necessary.
[0014] The instrument described in the '261 application is,
however, a batch-type instrument rather than a continuous-flow
device.
[0015] The general attraction of continuous flow chemistry is
generally well understood in concept, and a number of attempts have
been made to carry it out. For example, in commonly assigned U.S.
Pat. No. 5,215,715, a sample is moved in the form of a slug on a
continuous basis through a microwave heated digesting system. The
same or similar system is used in commonly assigned U.S. Pat. No.
5,420,039. Other recent work includes U.S. Pat. No. 6,242,723 in
which two separate sets of reactants can be moved into a vessel
where they can react while remaining separated by an appropriate
filter while being irradiated with microwaves. U.S. Pat. No.
6,316,759 discloses an apparatus for conducting gas chromatography
while heating the columns using microwaves. U.S. Pat. No. 6,303,005
shows a distillation system that uses microwave heating. U.S. Pat.
No. 5,672,316 shows a semi-flow through technique that has certain
proactive temperature controls, the goal of the technique being to
maintain a pressure equilibrium in high-pressure reactions. U.S.
Pat. No. 5,382,414 shows a reaction vessel that includes a
flow-through passage for use in a conventional microwave
cavity.
[0016] U.S. Pat. No. 5,387,397 shows a flow-through system that
merely incorporates a "microwave enclosure" or a "suitable cavity"
rather than a single mode cavity. The '397 patent also incorporates
a post-irradiation cooling element. The '397 patent thus fails to
recognize the power density issues raised by conventional
multi-mode cavities and likewise fails to recognize that the act of
reducing microwave power to control temperature can correspondingly
reduce the efficient progress (rate and yield) of certain chemical
reactions.
[0017] In the scientific literature, several attempts have been
carried out using a conventional microwave oven (rather than a
specific instrument) in which a fixed bed reactor is placed in the
cavity and exposed to microwaves as the reactants flow there
through. These include Plazl, AIChE Journal Volume 43, Number 3,
March 1997 and Pipus, Chemical Engineering Journal 76 (2000)
239-245. Other flow-through techniques have used conventional
cavities as well including reports by Braun, Microporous and
Mesoporous Materials 23 (1998) 79-81 and Chemat, Journal of
Microwave Power and Electromagnetic Energy, Volume 33, No. 2, 1998,
pages 88-94.
[0018] All of these, however, use the more typical large microwave
cavity that applies large amounts of power, but at a low and
spatially inconsistent power density in the manner discussed above,
thus making successful flow-through techniques less likely and less
reproducible.
[0019] Accordingly, there remains a need for a more elegant
solution to the problem of conducting sensitive organic reactions
at controlled temperatures while maximizing the available use of
microwave energy in a desirable manner.
SUMMARY OF THE INVENTION
[0020] The invention is a method of microwave-assisted chemistry
comprising directing a continuous flow of fluid through a microwave
cavity while applying microwave radiation to the cavity and to the
continuous flow of materials therein. The method includes
monitoring the pressure of the fluid in the cavity and cooling the
fluid in the cavity when the pressure exceeds a predetermined set
pressure. In related aspects, the pressure measurement can be used
to moderate the applied power, or a temperature measurement can be
used to moderate the cooling or the applied power.
[0021] In another aspect, the invention is a method of
microwave-assisted chemistry that includes the steps of carrying
out a chemical reaction in batch format while irradiating the
reactants with microwave radiation and while concurrently
externally cooling the reaction vessel to thereby identify an
optimum power level and reaction time and without exceeding a
temperature at which the reactants decompose or otherwise act
differently than desired. The method thereafter includes the steps
of directing a continuous flow of corresponding reactants through a
single mode microwave cavity while applying microwave radiation to
the cavity and to the continuous flow of materials therein at the
power level and reaction time identified during batch format
reaction of the same corresponding reactants. The method then
comprises and concurrently includes externally cooling the flowing
reactants while applying the microwave radiation in order to
continue at the identified power level while avoiding an undesired
increase in the temperature of the reaction and the reactants.
[0022] In yet another aspect, the method comprises directing a
continuous flow of fluid through a single mode microwave cavity
while applying microwave radiation to the cavity and to the
continuous flow of materials therein and then purifying the
reaction products with a scavenging composition, including
scavenging combined with microwave irradiation.
[0023] In another aspect, the invention includes a method of
microwave-assisted chemistry comprising the steps of directing a
continuous flow of fluid through a single mode microwave cavity
while applying microwave radiation to the cavity and to the
continuous flow of materials therein. In the next step, the
invention comprises directing the fluid from the cavity to a
spectroscopic flow cell and spectroscopically evaluating the fluid,
and then moderating the conditions in the cavity in response to the
spectroscopic evaluation.
[0024] In its apparatus aspects, the invention comprises an
instrument for microwave-assisted chemistry that includes a
microwave cavity, a flow cell in the cavity, a pump for directing
fluid reactants from at least one source to the flow cell, a
pressure meter in fluid communication with the flow cell for
measuring the pressure of fluid in the flow cell and a cooling
system for cooling the flow cell in the cavity.
[0025] In another aspect, the instrument includes a microwave
cavity, a flow cell in the cavity, a pump in fluid communication
with the input side of the flow cell for directing fluids from a
source and into the flow cell in the cavity, a spectroscopy cell
external to the cavity and in fluid communication with the output
side of the flow cell, and a spectrometer with the spectroscopy
cell in the optical path of the spectrometer for analyzing the
characteristics of the fluid flowing from the flow cell and through
the spectroscopy cell.
[0026] In yet another aspect, the apparatus of the invention
comprises a microwave cavity, an attenuator releasably engaged with
the cavity and in microwave communication with the cavity, and a
flow cell releasably engaged with the attenuator in a manner that
fixes the positions of the attenuator and the flow cell with
respect to one another when they are engaged and that
correspondingly fixes the flow cell in the same position with
respect to the cavity when the attenuator is engaged with the
cavity.
[0027] The foregoing and other objects and advantages of the
invention and the manner in which the same are accomplished will
become clearer based on the followed detailed description taken in
conjunction with the accompanying drawings in which:
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1 is a perspective view of an instrument used in
accordance with the present invention.
[0029] FIG. 2 is a perspective view of elements of an instrument
according to the present invention including a magnetron, cavity,
and attenuator.
[0030] FIG. 3 is a cross sectional view of the cavity and
attenuator of FIG. 2.
[0031] FIG. 4 is a partially exploded view of the cavity,
attenuator and flow cell according to the present invention.
[0032] FIG. 5 is an exploded perspective view of portions of the
attenuator and flow cell of the present invention.
[0033] FIG. 6 is a perspective view of the flow cell and attenuator
of the present invention.
[0034] FIG. 7 is a side elevational view of the flow cell and
attenuator of FIG. 6.
[0035] FIG. 8 is a cross sectional view of the attenuator and flow
cell demonstrated in FIGS. 6 and 7.
[0036] FIG. 9 is another cross sectional view of selected elements
of the flow cell and attenuator.
[0037] FIG. 10 is a schematic diagram of one embodiment of the
instrument of the invention.
[0038] FIG. 11 is a schematic diagram illustrating another
embodiment of the present invention.
[0039] FIGS. 12 through 16 are chemical equations for exemplary
reaction schemes for which the present invention has been found
useful.
DETAILED DESCRIPTION
[0040] The invention is a method of microwave-assisted chemistry
comprising directing a continuous flow of fluid through a microwave
cavity while applying microwave radiation to the cavity, and to the
continuous flow of materials therein. In the most preferred
embodiments, the method comprises directing the continuous flow of
fluid through a single-mode microwave cavity. The nature of
microwave radiation and single modes is generally well understood
in this art, and discussions can be found in numerous sources,
including the previously incorporated patents and applications.
[0041] The invention further comprises monitoring the pressure of
the fluid in the cavity. The pressure of the fluid is determined by
several factors, including the pumping and flow rate, but in many
circumstances, particularly organic synthesis, as reaction
temperatures increase, and as reaction products are generated,
potentially including gases, the pressure within a closed system
will increase. Accordingly, monitoring the pressure of the fluid is
one method of monitoring the progress of an ongoing chemical
reaction.
[0042] In response to, or in addition to, the monitoring of the
pressure, the method of the invention comprises cooling the fluid
in the cavity when the pressure exceeds a pre-determined set point
pressure. The cooling step preferably comprises circulating or
directing a coolant into and through the cavity in response to the
pressure set point determination, with air being a satisfactory and
preferred coolant under many circumstances. If desired, however,
the step of cooling the fluid can comprise circulating a different
fluid as may be convenient or necessary. In the most preferred
embodiments, and as will be discussed with respect to the drawings
and the apparatus aspects of the invention, the steps of directing
and cooling the fluid comprise directing the fluid through a tube
and then externally cooling the tube, preferably with a cooling
fluid such as air, nitrogen, including nitrogen generated from
liquid nitrogen, carbon dioxide, or any other appropriate gas that
otherwise does not interfere with the reaction or the
apparatus.
[0043] The proactive cooling step of the invention permits
continued high energy transfer using the microwave irradiation,
while minimizing or eliminating potentially undesired
temperature-driven effects. Using the invention, very high
temperatures can be reached in a "point" or "instantaneous" sense
that help drive the reaction more efficiently, but are rarely
reflected in the bulk temperature of the reactants.
[0044] It will also be understood that the cooling step is not
limited to a simple on-or-off context. In addition, the cooling
step can include increasing or decreasing the rate of cooling at
any given time in response to the measured parameters.
[0045] In preferred embodiments, the steps of monitoring and
cooling the fluid comprise sending a signal representative of the
pressure from a pressure monitor or detector, to a processor; i.e.,
a semiconductor device with both memory and logic functions. The
method then includes using the processor to compare the monitored
pressure to the set point pressure, and then sending a signal from
the processor that initiates and runs a cavity cooling device
whenever the monitored pressure exceeds the set point pressure.
[0046] In another aspect, the step of directing the fluid can
comprise directing the fluid in the presence of another
non-reacting material, the most common of which are catalysts.
Because the catalyst is being used in the presence of microwave
radiation, it (and its support in some cases) can be selected to
couple with microwaves (if desired) or to be transparent to
microwaves (again, if so desired).
[0047] In another aspect, the invention is a method of microwave
assisted chemistry comprising carrying out a chemical reaction in
batch format while irradiating the reactants with microwave
radiation and while concurrently externally cooling the reaction
vessel to thereby identify an optimum power level for the reaction
and without exceeding a temperature at which the reactants
decompose or otherwise suffer heat-related consequences different
from those desired or intended. The term "reactants" is used herein
in its generally understood sense to refer to those compounds or
elements which react in a chemical reaction to form different
compounds and elements. Nevertheless, it will be understood by
those of skill in the art that the reaction can also be carried out
in the presence of other materials such as reagents or catalysts
while still operating within the scope of the invention.
[0048] In the present invention, once the optimum power is
identified that can be applied in the presence of the available
cooling, the method comprises directing a continuous flow of
corresponding reactants; --i.e., not the same samples, but the same
chemical compositions--through a single mode microwave cavity while
applying microwave radiation to the cavity and to the continuous
flow of materials therein at the power level identified during the
batch format reaction of the same reactants. The method includes
the step of cooling the flowing reactants, preferably by externally
cooling the tubing through which the fluid flows in the cavity
while applying the microwave radiation in order to continue at the
identified and selected power level while avoiding an undesired
increase in the temperature of the reaction or an undesired effect
upon the reactants.
[0049] In another aspect, the invention is a method of
microwave-assisted chemistry that comprises directing a continuous
flow of fluid through a single-mode microwave cavity while applying
microwave radiation to the cavity and to the continuous flow of
materials therein, and then purifying the reaction products with a
scavenging composition. In preferred embodiments, the scavenging
step comprises directing the fluid through a column (or any
equivalent or other satisfactory device) filled with a solid
support that includes a scavenging functional group selected from
the group consisting of electrophilic scavengers, nucleophilic
scavengers, and combinations thereof. These terms are well
understood in the art and appropriate scavengers are commercially
available from a number of suppliers. In many cases, the scavenger
is a microporous resin or a silica gel that supports a desired
functional group. For example, a macroporous aminomethylpolystyrene
resin or equivalent silica gel is suitable for a scavenger of acids
or acid chlorides. In another example, a benzaldehyde-based
scavenger is useful for scavenging primary amines or hydrazines and
hydroxylamines. As a third example (and the selection is almost
endless), macroporous resin that includes a polymer-bound
ethylenediamine is useful for scavenging acids, acid chlorides,
anhydrides and other electrophilic compounds. A similar set of
scavenging compounds can be selected for nucleophilic scavenging,
and combinations can be used where appropriate. By way of example
and not limitation, such macroporous scavenger resins are available
from Polymer Laboratories (Amherst, Mass.) under the StratoSpheres
trademark, and scavengers based in silica gel (which are presently
preferred to date) are available from SiliCycle Inc. of Quebec
City, Canada. Other exemplary scavengers are available from
Calbiochem-Novabiochem Corporation of San Diego, Calif., or from
Sigma-Aldrich Corporation, St. Louis, Mo.
[0050] The scavenging step can remove unwanted byproducts from the
reaction leading to a purified product, which, in turn, can be
immediately directed to a separation step, preferably a
chromatography separation step and most preferably a high pressure
liquid chromatography separation step. High pressure liquid
chromatography is well understood in the art and will not be
otherwise discussed herein and those of ordinary skill in this art
will be able to couple HPLC to the method steps in this manner
without undue experimentation.
[0051] As in the previous embodiments, the method can also comprise
monitoring the pressure of the fluid in the cavity and cooling the
fluid when the pressure exceeds a predetermined setpoint. The
temperature can also be monitored, for example, of the fluid, the
ambient air in the cavity, or the external temperature of the
tubing, whatever is desired or necessary, in the cavity and then
the cavity can be cooled by a cooling system when the temperature
exceeds a pre-determined setpoint.
[0052] In another aspect, the invention is a method of
microwave-assisted chemistry that comprises directing a continuous
flow of fluid through a single-mode microwave cavity while applying
microwave radiation to the cavity and to the continuous flow of
materials therein, and then directing the fluid from the cavity to
a spectroscopic flow cell and spectroscopically evaluating the
fluid, and then moderating the conditions in the cavity in response
to the spectroscopic evaluation. The step of directing the fluid to
a spectroscopic flow cell preferably comprises directing it to an
in-line cell, but can also comprise directing the fluid to a sample
line separate from a main line and then evaluating the fluid in the
sample line.
[0053] In preferred embodiments, the spectroscopy step is selected
from the group consisting of ultraviolet, infrared, and Raman
spectroscopy. Although it will be understood that the invention is
not limited to these types of spectroscopy, these are quite
exemplary for identification of particular molecules and compounds.
As is well understood by those of ordinary skill in this art, a
typical spectrometer includes a source and detector. The source
directs electromagnetic radiation within a particular frequency
range through the sample and then to the detector. The difference
between the light emitted by the source and that collected by the
detector is known as the absorbance, and the absorbance at
particular frequencies identifies particular characteristics of
elements and compounds. In particular, ultraviolet spectroscopy
identifies electronic transitions within molecules and identifies
them on that basis. Infrared spectroscopy measures asymmetric
vibrational movements in molecules and identifies them
correspondently, while Raman spectroscopy identifies compounds by
their symmetric vibrational modes. Each of these techniques is well
understood in the relevant art and need not be discussed in detail
herein, and can be used in conjunction with the other elements of
the invention by those of ordinary skill in this art and without
undue experimentation. Furthermore, because in most circumstances
the identity and nature of the reactants, the desired products, and
the potential byproducts are well understood, each of these
spectroscopy techniques can be extremely useful in quickly
identifying such products and byproducts and potentially unreactive
starting materials.
[0054] The immediate spectroscopic evaluation of the products from
the continuous flow provides an excellent in-line monitoring
capability because the conditions in the cavity can be quickly
monitored based on the evaluations of the spectrometer. As in the
previous embodiments, the preferred moderating step is to cool the
cavity in response to an undesired rise in temperature which is or
may be reflected by the spectroscopic results. Alternatively, the
moderation can comprise adjusting the fluid flow rate through the
cavity, or moderating the microwave power applied in the
cavity.
[0055] In any of the embodiments of the invention, when a
moderation of the microwave power is desired or necessary, a
preferred technique is that set forth in commonly assigned U.S.
Pat. No. 6,084,226, which explains a preferred technique for
applying and adjusting continuous power in a microwave context. As
set forth therein and elsewhere, the word "continuous" refers to
the application of microwave power in short duty cycles so that the
most efficient power level can be applied using the shortest duty
cycle possible.
[0056] There are a number of method aspects of the invention and
these are best understood with respect to the accompanying
drawings.
[0057] FIG. 1 is a perspective view of an instrument according to
the present invention and broadly designated at 20. A first portion
of the instrument broadly designated at 21 is a single mode focused
microwave device essentially identical to the devices described and
claimed in commonly assigned and co-pending application Ser. Nos.
10/064,261 filed Jun. 26, 2002; 10/063,914 filed May 23, 2002;
10/063,628 filed May 3, 2002; 10/136,838 filed Apr. 19, 2002, and
09/773,846 filed Jan. 31, 2001. The single mode cavity device 21
incorporates and integrates a modular pumping system broadly
designated at 22. The nature of the modular system is such that any
number of pumps can be included, and thus any number of different
reactants can be included in a given reaction scheme. In normal
circumstances, between one and four pumps will be incorporated, but
in each case they will be identical in concept and operation to
those discussed with respect to these particular illustrations. The
pumps can be any standard pump suitable for handling the reactants
(and solvents or reagents) and producing the desired flow rates
(e.g., 1-5 ml/min). Pumps suitable for high-pressure liquid
chromatography (HPLC) are suitable for the present invention, with
pumps from Scientific Systems, Inc. (State College, Pa.), being
incorporated in the presently preferred embodiments.
[0058] The instrument 20 includes a microwave cavity in the
interior portions of the instrument, and thus not entirely visible
in FIG. 1, but has its location designated at 23 in FIG. 1. A flow
cell (FIGS. 3-8), is present in the cavity 23. The pumps are
similarly not visible in the perspective view of FIG. 1, but are
carried within the pump housings 24, which, as noted above, are
modular in structure and execution.
[0059] FIG. 1 does, however, illustrate the pump heads at 25 into
which liquid flows from any appropriate source vessel. These can be
customized vessels, or beakers, or Erlenmeyer flasks, or any other
appropriate piece of laboratory glassware, or can comprise the flow
from the output of another reactor or instrument. The pump outlets
are illustrated at 26 and are likewise conventional in that they
typically need to match to appropriate chemically inert tubing for
the reactants. Each pump preferably also includes a priming and
purging valve 27.
[0060] The tubing used to carry the reactants into the cavity 23 is
omitted for the sake of clarity from FIG. 1, but are generally
directed into an appropriate opening illustrated at 30 in FIG. 1.
FIG. 1 also shows the attenuator portion 31 of the instrument 20,
which, in a manner well understood in this art, prevents microwaves
in the cavity from propagating outside of the instrument.
[0061] The various reactants exiting from the pump outlets are
initially mixed at the T-fitting 32 which preferably also includes
an appropriate filter and a relatively tortuous flow path in order
to encourage the reactants to blend prior to their entry into the
cavity.
[0062] Other details illustrated in FIG. 1 include a nut 33 that
helps fix a portion of the attenuator 31 and flow cell together in
a manner best understood with respect to the remainder of the
drawings. A respective control panel 34 acts as the input/output
device for each pump and includes appropriate data entry keys as
well as a variety of indicators, both light emitting diodes (LEDs)
and liquid crystal displays (LCDs) that display the status or
operation of the instrument 20. A similar display 35 forms a
portion of the single mode cavity portion 21 of the instrument
20.
[0063] FIG. 2 is a perspective view of portions of the instrument
20 in the absence of the housing illustrated in FIG. 1. Several of
the elements are common with FIG. 1, including the cavity 23, which
can now be seen as circular in shape, the attenuator 31, the inlet
and outlet opening 30 for the reactant fluid tubes (not shown), and
the nut 33 on the attenuator 31. Additionally, FIG. 2 illustrates
that the instrument includes a microwave source 37, which in most
circumstances is a magnetron, but can also comprise a klystron, or
a solid-state device, such as a Gunn diode. The magnetron 37 is in
microwave communication with the cavity 23, typically and
preferably through the wave-guide 40. The interior of the cavity is
preferably the single mode design incorporating a plurality of
openings from the wave-guide, as set forth in the previously
incorporated applications.
[0064] The attenuator 31 is releasably engageable with and from the
cavity 23 for removing and replacing the vessel (in this case the
flow cell) from the cavity 23. Typically, the attenuator engages
with a 1/4-turn design, best illustrated in other drawings, and
FIG. 2 illustrates the handles 41 that help facilitate this
task.
[0065] In preferred embodiments, the cooling system of the
invention is provided by a flow of air into the cavity, it having
been found convenient, appropriate, and satisfactory to use air in
most circumstances. As noted earlier, however, other gases (noble
gases, CO.sub.2, N.sub.2) including gases that have been cooled,
can be used as well. Accordingly, FIG. 2 shows the airflow inlet 42
and an airflow solenoid valve 43. Because the valve 43 is a
standard on and off device, the instrument typically, additionally
includes an airflow regulator 44 that can variably control the flow
of air to the cavity. FIG. 2 illustrates a section of tubing 45 for
the airflow between the solenoid and the regulator, and also from
the regulator to the cavity 23.
[0066] In preferred embodiments, the instrument includes a
processor (104 in FIGS. 10 and 11) in communication with a pressure
sensor 108 (FIG. 10) and the cooling system represented by the air
regulator 44 and tubing 45 for moderating the cooling of the flow
cell (not visible in FIG. 2) in the cavity 23, in response to the
pressure measured by the pressure sensor 108. As in the case of the
pumps, the pressure sensor can be the same as or similar to those
conventionally used in HPLC, and such pressure sensors are
available from many of the same manufacturers that provide the HPLC
pumps and related equipment and components.
[0067] Although the processor is not shown in FIG. 2, an
appropriate set of plugs 46 are illustrated, and show the relative
position of the processor and its accompanying board in this
particular embodiment. Additionally, FIG. 2 illustrates the cabling
47 that provides the signal communication between and among the
processor, the air flow regulator 44, any appropriate temperature
measuring device and the power supply for the magnetron 37, all of
which can be used to moderate the conditions in the cavity. With
the processor in communication with the source (a magnetron 37 in
this embodiment), the application of microwaves from the source can
be moderated in response to the pressure detected by the pressure
sensor 108, or can be moderated by the cooling system in response
to the temperature measured by the temperature detector 103 (FIGS.
10-11).
[0068] FIG. 2 also shows some additional details of the illustrated
instrument. These include a stirrer motor 50 and its corresponding
belt 51 which can be used if desired to operate a magnetic stirrer
bar (not shown) inside the cavity 23. FIG. 2 also shows a plurality
of brackets 52 that help mount the cavity within the device, along
with the posts 53 that are used to mount the magnetron 37 to the
waveguide 40. These are basic structural features and although
included in FIG. 2 for the sake of completeness, do not limit the
scope of the invention or the claims. An additional bracket and
screw are indicated together at 54. FIG. 2 also shows an additional
set of cables 55 and plugs 56 for providing communication between
the solenoid 43 and the processor. In a similar manner, the post 57
is included in this particular embodiment to provide a place where
the housing of the instrument can be fixed to the portions
illustrated in FIG. 2.
[0069] FIG. 3 is a cross-sectional view taken along the axis of the
attenuator 31 and the cavity 23. A number of common elements from
FIG. 2 are illustrated including the attenuator 31, the nut 33, the
handles 41, and the cavity 23. In particular, FIG. 3 helps
illustrate the advantages of the instrument in using the attenuator
31 to position the flow cell, now broadly designated at 60, at a
consistent position within the cavity 23 as the attenuator 31 is
releasably removed and re-engaged. FIG. 3 illustrates that the flow
cell 60 includes a number of structural elements with one of the
posts for this purpose being designated at 61 in FIG. 3. In
preferred embodiments, (FIG. 5), the structure of the cell includes
several of the posts 61, a bottom plate 62, and a top plate 63. The
top plate 63 is illustrated somewhat more clearly in FIG. 4 and
includes a plurality of openings 64 between the posts 61.
[0070] In order to handle the fluid reactants, the flow cell 60
includes an extended length of tubing 65. The tubing 65 is
illustrated in a "woven" pattern in FIGS. 3, 6, 7 and 8, or
alternatively, in FIG. 3 in a more contiguous wrapping pattern as
shown on the left hand side of the cross-sectional view of FIG. 3.
Although the particular pattern is not crucial to the present
invention, it will be understood that a consistent pattern for the
tubing is similarly expected to give the most consistent results
with respect to the operation of the cavity and thus, to the
running of particular reactions. The tubing 65 can be made of any
material that avoids interfering with the microwave field in the
cavity and that is compatible with the starting materials,
solvents, reagents, and expected products or byproducts. In
preferred embodiments, the tubing is formed of a fluorocarbon
polymer such as one of the various TEFLON.TM. polymers, and is
wrapped in a covering (wound, woven, or braided) of fibers formed
from an engineering polymer such as one of the KEVLAR.RTM.
polyimides.
[0071] In order to provide the consistent positioning, the
attenuator 31 is releasably engaged with the cavity 23, and the
flow cell 60 and its tubing 65 are releasably engaged with the
attenuator 31 in a manner that fixes the positions of the
attenuator 31 and the flow cell 60 with respect to one another when
they are engaged and that correspondingly fixes the flow cell 60 in
the same position with respect to the cavity 23 when the attenuator
31 is engaged with the cavity 23. Stated differently, the
instrument permits the flow cell 60 to be placed in a desired fixed
position in the cavity 23.
[0072] In the illustrated embodiment, the positioning is
accomplished with the use of a two-part (66, 67). The lower portion
of the post 66 is threadedly engaged with the top plate 63 of the
flow cell 60 to define a standard position, while the top portion
of the post 67 is likewise threaded into the top plate 63 of the
flow cell and maintained in place in the attenuator by the nut 33,
previously described positioned on the top exterior surface of the
attenuator 31. In the illustrated embodiment, the post portions 66
and 67 serve an axillary function in that they include respective
coaxial openings (70 in post portion 66 and 71 in post portion 67).
These coaxially aligned shafts 70 and 71 provide a thermal well
into which an appropriate temperature measuring device can be
positioned in order to measure temperature inside the cavity. The
incorporation of the thermal well is not, however, necessary for
the other structural aspects of the post portions 66 and 67 and the
thermal well can be positioned elsewhere or the temperature
measuring device can be positioned elsewhere as may be desirable or
necessary.
[0073] The temperature measuring device is preferably selected to
be as minimally intrusive as possible. Suitable temperature
measuring devices include fiberoptic temperature sensors and
transducers based on the thermal expansion of glass materials, of
which representative commercial devices are available from FISO
Technologies, Inc. of Quebec, Canada. Such devices offer particular
advantages because they avoid interfering with, and are not
affected by, microwave or radio frequency radiation. Alternatively,
fiberoptic based infrared detecting thermometers such as those
commercially available from LUXTRON of Santa Clara, Calif. are
similarly useful. These devices direct infrared frequencies emitted
by a warm sample to an appropriate photodetector via optical
fibers, with the photodetector converting the measured wavelengths
into a useful temperature reading.
[0074] It will also be understood that the posts 66 and 67 can be
used to adjust or change the position of the tubing 65 with respect
to the attenuator 31 and thus with respect to the cavity 23. It
will also be understood that the illustrated structure of the flow
cell 60 and the pattern of the tubing 65 are exemplary, rather than
limiting, of the present invention.
[0075] Other details illustrated in FIG. 3 and the embodiment it
represents includes the air inlet 72 which is incorporated with the
drain pipe 73. During normal operation, air from the source,
solenoid and regulator described earlier, are directed into the
cavity 23 through the air inlet 72 and the drain pipe 73. The drain
pipe 73 serves an additional purpose, however, in that if fluid
spills or leaks in the cavity 23, the drain pipe provides an
available path to an appropriate spill tray. The elbow 74
illustrated in cross-section in FIG. 3 is another portion of this
draining system with the drain pan not being illustrated in FIG. 3.
A bracket 75 holds several of these elements in place as desired or
necessary. Several of these features are also discussed in detail
in the corresponding incorporated applications.
[0076] FIG. 3 also illustrates the presence of a dielectric insert
76 (e.g., formed of PTFE) which helps protect the interior of the
cavity 23 and provides are additional cooling path as set forth in
the incorporated applications. The remaining portions illustrated
in FIG. 3, particularly the engagement between the cavity 23 and
the attenuator 31 are best understood with respect to other
figures.
[0077] FIGS. 4 and 5 illustrate more aspects and details of the
attenuator and flow cell and their relationship to the cavity 23.
FIG. 4 is a partially exploded view illustrating the attenuator 31
and portions of the flow cell 60 exploded from the cavity 23. For
the sake of clarity, several of the posts 61 are eliminated from
FIG. 4. In order to provide a physically and microwave secure
engagement when the cavity and attenuator are engaged, the
attenuator 31 is centered in a collar 80 that includes at least two
radially extending locking tabs 81 (only one of which is visible in
FIG. 4). The tabs 81 fit into corresponding receiving openings 83
in upper portions of the cavity 23. In order to engage the
attenuator 31 and its collar 80 with the cavity, the tabs 81 are
positioned in the tab receiving openings 83. Then to further secure
the attenuator in place, the attenuator can be rotated
approximately 1/4 turn with the tabs 81 sliding in a locking
channel 84 adjacent and co-planar with the lower portions of the
tab receiving openings 83. As stated earlier, the handles 41 on the
attenuator 31 assist in turning the attenuator 31 to either engage
it or disengage it with the cavity 23. In preferred embodiments,
the assembly includes the mesh ring illustrated at 85 in FIG. 4
which helps with both the mechanical and microwave sealing
characteristics.
[0078] FIG. 4 also shows a few additional details such as several
mounting screws or rivets 86. Because the magnetron 37 is not
illustrated in FIG. 4, FIG. 4 also illustrates the opening 87 in
the waveguide 40 into which the magnetron antenna (not shown) can
extend to propagate the microwaves into the waveguide 40 and then
into the cavity 23.
[0079] FIG. 4 also illustrates an upper cover 90 for the attenuator
31 along with an upper collar 91. The cover or cap 90 covers the
entire top opening of the attenuator, with the exception of the use
of the post 67, and helps prevent heat loss through the attenuator
31.
[0080] FIG. 5 shows the attenuator 31 and cell 30 in exploded
fashion apart from the cavity 23. All of the elements illustrated
in FIG. 5 have already been described and carry the same reference
numerals as in the previous drawings and description.
[0081] FIGS. 6 and 7 are perspective and side elevational views of
the attenuator 31 and flow cell 60 engaged with one another. All of
the elements illustrated in FIGS. 6 and 7 have already been
described previously and carry the same reference numerals as with
respect to the other figures. Accordingly, FIGS. 6 and 7 provide an
additional view and understanding of this aspect of the
invention.
[0082] In the same manner, FIGS. 8 and 9 are cross-sectional views,
taken perpendicularly to one another, of the assembled attenuator
31 and flow cell 60. FIG. 8 illustrates the nature in which the
tubing 65 can be placed around and between the posts 61 to define a
flow path for fluids through the flow cell 60.
[0083] FIG. 9 illustrates a number of the same elements, but with
the upper post 67 removed, and with the figure being in an
orientation 90 degrees from that of FIG. 8. FIG. 9 perhaps most
clearly shows the overall shape of the attenuator 31 in a proposed
preferred embodiment, including the u-shaped bottom portions 93.
FIG. 9 also shows that the top plate 63 of the flow cell 60 defines
a plurality of shafts 94 which permit the movement of air between
the attenuator and the flow cell 60. The remaining elements of FIG.
9 have similarly been described with respect to previous drawings
and carry the same reference numerals.
[0084] FIGS. 10 and 11 help illustrate some of the functional
relationships of the elements of the instrument and the method
steps of the invention. FIGS. 9 and 10 are schematic diagrams, but
wherever possible, common reference numerals have been used with
the other drawings.
[0085] Accordingly, FIG. 10 shows a source or vessel for reactants
97 which are drawn by the pumping system 22, then preferably
through a pressure transducer 115, and delivered into the flow cell
60 in the cavity 23. From the flow cell 60 and the cavity 23, the
reaction products, which will be understood to include desired
products, byproducts, and in some cases unreacted starting
materials, flow to and through the pressure regulator 108 following
which they are scavenged in the scavenger 100. As set forth with
respect to the method aspects of the claim, the scavenged products
can then be immediately forwarded to a further step which in FIG.
10 is illustrated as the high-pressure liquid chromatography,
101.
[0086] The pressure regulator 108 helps maintain a constant or
near-constant pressure (250 psi is typical) in the fluid so that
pressure fluctuations detected by the transducer 115 can be used by
the processor 104 to help moderate conditions in the cavity. The
pressure regulator ("backpressure regulator") is a standard
commercial device, with those available from Upchurch Scientific
(Oak Harbor, Wash.) being exemplary. The backpressure regulator
offers several advantages, including moderating the pressure
fluctuations that can occur when gas bubbles form in the flowing
fluid, and serving as a pump preload for low pressure
applications.
[0087] FIG. 10 also schematically illustrates another microwave
cavity 109 (dotted lines). In this regard, the scavenging step is
preferably carried out under microwave irradiation either in the
original cavity 23 or in a separate cavity as indicated at 109. In
both cases, the use of microwaves greatly accelerates the rate of
scavenging, and two specific comparative examples are included
later herein.
[0088] In FIGS. 10 and 11, the cooling system is designated at 102,
the temperature detector at 103, and the processor at 104. In FIG.
10 the processor is in signal communication with the cooling system
102 through the cable 105. It will be understood that a cable or
wire is a presently preferred embodiment of the invention, but that
any appropriate signal communication between the processor and the
cooling system can be incorporated. These could include infrared
communication as is common with certain computers and their
peripheral devices, or communication over some other assigned
frequency within the electromagnetic spectrum, or an optical
cabling system as the case may be. The processor is also in signal
communication with the temperature detector 103 through the cable
106 and with the pressure detector (transducer) 115 through the
cable 107, and with the source 37 through the cable 116.
[0089] FIG. 11 shows a number of the same elements as FIG. 10, but
in particular illustrates the spectroscopy cell 110 which is
positioned external to the cavity 23 and in fluid communication
with the output side of the flow cell 60. A spectrometer
represented by the source 111 and detector 112 has the spectroscopy
cell 110 in its optical path for analyzing the characteristics of
the fluid flowing from the flow cell 60 and through the
spectroscopy cell 110. The general principles and operation of
spectroscopy and spectrometers are well understand in this and many
related arts and will not be discussed in detail herein. The term
"optical path" refers, of course, to the path defined between the
source 111 and the detector 112 and does not necessarily refer to
the passage of light within the visible spectrum. Indeed, as noted
above, in addition to potentially using visible light spectroscopy,
the invention more preferably incorporates ultraviolet
spectroscopy, infrared spectroscopy, Raman spectroscopy, each which
operates in frequencies and wavelengths that are outside of the
visible spectrum. As in the case of FIG. 10, the processor 104 is
in signal communication with the cooling system 102 through the
cable 105. The processor 104 is in signal communication with the
source 37 through the cable 116, with the temperature detector 103
through the cable 106, and in signal communication with the
spectrometer and its detector 112 through the cable 113.
[0090] The spectroscopic evaluating step preferably comprises at
least portions of the infrared spectrum of the fluid, or at least
portions of the ultraviolet spectrum of the cooling fluid, or at
least portions of the Raman spectrum of the flowing fluid. In each
case, it will be understood that when certain reactions are being
carried out, certain portions of their spectrum are well understood
and can be predictably identified as present or absent.
Accordingly, the spectroscopic evaluation can, but does not
require, a full selection of wavelengths. It can be limited as
desired or necessary to a relatively smaller range or set of ranges
from which the expected products, byproducts and remaining starting
materials can be identified.
[0091] With the processor and the signal communication in place,
FIG. 10 illustrates how the conditions in the cavity, particularly
including the operation of the microwave source 37 and the cooling
system 102 can be moderated in response to the pressure detector
115 or the temperature detector 103.
[0092] The term "processor" is used herein in its generally
accepted sense, and such devices are also typically referred to as
microprocessors, coprocessors, or CPUs (central processing unit).
Downing, Dictionary of Computer and Internet Terms, Sixth Ed.
(1998), Barron's Educational Series, Inc., e.g., at pages 110, 293,
and 370. As set forth therein, the processor carries out arithmetic
and logical operations, and decodes and executes instructions.
Processors useful for the operations described herein are
commercially available, and in many cases correspond to the
processors incorporated in personal computers. Such processors can
also be programmed to carry out the operations described herein by
those of ordinary skill in the relevant arts and without undue
experimentation.
[0093] In an analogous manner, FIG. 11 illustrates how the
processor 104 and its relationships can moderate the conditions in
the cavity 23 by moderating the microwave power from the source 37
or the operation of the cooling system 102 and in particular in
response to the temperature 103 or most preferably in response to
the spectrometer and particularly the detector 112.
Experimental
[0094] Tables 1-7 show some of the results of various experiments
carried out using the method and apparatus of the invention, and
with comparisons to prior techniques in some cases.
[0095] Tables 1 and 2 are examples of scavenging carried out under
the application of microwave radiation. In the experiments carried
out in Tables 1 and 2, acetonitrile was used as the solvent for the
five listed compounds. These compounds were selected as having
those functional groups that amine-type scavengers are designed to
remove. Accordingly, Table 1 represents a scavenging reaction
carried out using a silica-based amine-3 scavenger from SiliCycle
Inc. (Quebec City, Canada). As the results in Table 1 show, under
the influence of microwaves for four minutes, almost all of the
compounds were entirely scavenged. By way of comparison, under room
temperature stirring conditions--i.e., a conventional scavenging
technique--only three of the compounds were removed.
[0096] For the scavenging of benzoyl chloride with amine-3
scavenger, 400 mg of benzoyl chloride were used in 1 ml of solvent
(acetonitrile) to form a 0.14M solution. Therefore 0.57 mmol of
amine functional group constitutes 1 equivalent of scavenger. Four
(4) equivalents would be 2.3 mmol of scavenger, which is 158 mg for
a loading capacity of 3.6 mmol/g. The benzoyl chloride, scavenger,
and solvent are added together in a 10 ml pressurized vessel and
either put into the microwave system or stirred at room temperature
The percent scavenged is determined by GC/MS.
TABLE-US-00001 TABLE 1 % scavenged % scavenged Using acetonitrile
microwave room temp Benzoyl chloride 100 100 Acetic Anhydride 99 99
tert-butylphenyl- 100 isocyanate 1,1,3,3-tetramethyl- 100
butylisocyanate benzaldehyde 97 97 Amine-3 Amine-3 4 EQ's, MW
conditions 4 EQ's, rt conditions 4 min, 150 C., 300 W stirred 1
hr
[0097] Table 2 represents the same experiment carried out with the
same compounds, but using a triamine-3 silica based scavenger, and
again comparing a microwave technique versus a conventional
technique. As Table 2 indicates, microwave technique demonstrated
equivalent or superior scavenging results in all cases, and was
carried out in four minutes rather than one hour.
TABLE-US-00002 TABLE 2 % scavenged % scavenged Using acetonitrile
microwave room temp Benzoyl chloride 100 100 Acetic Anhydride 97 99
tert-butylphenyl- 95 62 isocyanate 1,1,3,3-tetramethyl- 89 62
butylisocyanate benzaldehyde 80 59 Triamine-3 Triamine-3 4 EQ's, MW
conditions 4 EQ's, rt conditions 4 min, 150 C., 300 W Stirred 1
hr
[0098] Tables 3-7 are exemplary organic synthesis reactions carried
out using the flow through techniques and apparatus of the present
invention. In some cases the results are shown in comparison to the
identical reaction carried out in batch fashion in a manner
consistent with applicant's co-pending 261 application. Unless
indicated otherwise, the comparative batch reactions were carried
out in a DISCOVER.TM. instrument from CEM Corporation, Matthews,
N.C.
TABLE-US-00003 TABLE 3 Knoevenagel Invention DISCOVER .TM.
Instrument 25 g malonic acid 0.098 g malonic acid 25 mL
benzaldehyde 0.096 ml benzaldehyde 35 mL pyridine 0.069 ml pyridine
15 mL ethanol 0.5 ml EtOH FR = 1 ml/min 5 ml coil resonance time =
5 min 6 min ramp, 5 min hold Temp = 160 C. T = 175 C. P = 250 psi P
= 250 psi Power = 300 W Pwr = 300 W Cooling = 1-2 psi Cooling = On
Yield = 20% comparable result (U.S. Pat. No. 5,387,397): 18%
yield
[0099] Table 3 shows the results of a Knoevenagel reaction (FIG.
12) using the indicated starting materials. In particular, a
flow-through reaction was carried out at a flow rate of 1
milliliter per minute in a 5-milliliter coil in an instrument
according to the present invention, thus defining a residence time
of 5 minutes. This was compared to a batch reaction among the same
compositions similarly carried out under microwave irradiation for
five minutes. As Table 3 indicates, the temperature and powers used
were equivalent and in the case of the invention, produced a yield
of 20%, which is comparable to the results demonstrated in the
prior art; e.g. U.S. patent No.
TABLE-US-00004 TABLE 4 Esterification Invention 9.1 g benzoic acid
30 mL MeOH 0.5 mL H2SO4 FR = 1.5 ml/min 5 ml coil residence time =
3:20 Temp = 80 C. P = 250 psi Power = 75 W Cooling = 15 psi Yield =
100% comparable result: 92% yield (U.S. Pat. No. 5,387,397)
[0100] Table 4 shows the results of an esterification reaction
(FIG. 13) between benzoic acid and butanol in the presence of
sulfuric acid. The flow rate was set for 1.5 milliliter per minute
in the 5-milliliter coil for a residence time of 3 minutes and 20
seconds. Using the cooling of the present invention, the
temperature could be maintained at 80.degree. centigrade while the
power was maintained at 75 watts to give a yield of 100%. A
comparable result from the prior art showed a 92% yield; e.g. U.S.
patent No.
TABLE-US-00005 TABLE 5 Transesterification Invention DISCOVER .TM.
Instrument 30 mL BuOH 0.4 mL H2SO4 FR = 2 ml/min 5 ml coil Temp =
80 C. P = 250 psi Power = 100 W Cooling = 1-2 psi Yield = 89%
comparable results (U.S. Pat. No. 5,387,397) 40% - 1st pass 48% -
2nd pass
[0101] Table 5 shows the results for a transesterification reaction
(FIG. 14) between methyl-4-chlorodenzoate and butanol also in the
presence of sulfuric acid. The flow rate was 2 milliliter per
minute in a 5-milliliter core for a residence time of 21/2 minutes.
Once again, the cooling step of the present invention enabled the
temperature to be maintained at 80.degree. C. while the power was
applied at 100 watts. This produced an 89% yield of product
comparable to yields of 40 and 48% in the prior art.
TABLE-US-00006 TABLE 6 Nucleophilic Aromatic Substitution Invention
DISCOVER .TM. Instrument 6 g 4-chlorobenzaldehyde 0.1 g
4-chlorobenzaldehyde 4.4 mL isopropyl amine 0.073 mL isopropyl
amine 30 mL acetonitrile neat FR = 1.5 ml/min 5 ml coil residence
time = 3:20 5 min ramp, 10 min hold Temp = 90 C. Temp = 175 C. P =
250 psi P = 250 psi Power = 300 W Power = 100 W to 300 W Cooling =
10-13 psi Cooling = On Yield = 100% Yield = 100%
[0102] Table 6 shows a nucleophilic aromatic substitution reaction
(FIG. 15). Table 6 demonstrates the comparison between the flow
through technique of the present invention and the batch technique
of the '261 application using the DISCOVER.TM. instrument. In Table
6, the reaction times differed slightly in that the method of the
invention was carried out at a 1.5-milliliter flow rate in a
5-milliliter coil to produce a residence time of 3 minutes and 20
seconds, while in the batch reaction the reaction was allowed to
run for 10 minutes. In each case, proactive cooling was applied so
that the power level could be maintained between 100 and 300 watts.
In each case, the yield was 100%.
TABLE-US-00007 TABLE 7 Diels-Alder Invention DISCOVER .TM.
Instrument 6.8 mL furan .107 mL furan 15 mL diethylacetylene .24 mL
diethylacetylene dicarboxylate dicarboxylate neat Neat FR = 0.5
ml/min 5 ml coil residence time = 10:00 10 min hold Temp = 100 C.
Temp = 100 C. P = 250 psi P = 200 psi Power = 300 W Power = 300 W
Cooling 6-8 psi Cooling = On Yield = 92% Yield = 85%
[0103] Table 7 shows the results of a Diels-Alder reaction (FIG.
16) and again comparing the flow through method of the present
invention with the batch technique of the 261 application. In each
case, the residence time was 10 minutes, with cooling applied to
keep the temperature at 100.degree. C., thus allowing power of 300
watts to be applied. The flow through technique of the invention
showed a slightly greater yield of 92% as compared to the batch
yield of 85%.
[0104] In the drawings and specification there has been set forth a
preferred embodiment of the invention, and although specific terms
have been employed, they are used in a generic and descriptive
sense only and not for purposes of limitation, the scope of the
invention being defined in the claims.
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