CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to and the benefit of the filing date of
Provisional Application Serial No. 60/133,061, filed May 7, 1999, entitled
"INCREMENTAL FLOW REACTOR AND METHOD FOR PARALLEL
SCREENING".
BACKGROUND
1. Field of the Invention
The present invention is directed to a method for rapid screening of reactants,
catalysts, and associated process conditions and, more specifically, to a method of
producing a chemical reaction that emulates those carried out in production-scale,
continuous flow or continuous stirred tank reactors.
2. Discussion of Related Art
Since its introduction in 1970, combinatorial chemistry has become a popular
research tool among scientists in many fields. High throughput and combinatorial
screening for biological activity have been prevalent in the pharmaceutical industry
for nearly twenty years, and more recently, high throughput and combinatorial
screening for improved catalysts for the bulk chemical industries have enjoyed
increasing popularity.
A substantial reason for the lag in the development of high throughput and
combinatorial screening for production scale reactions is the difficulty in emulating
the production-scale reactions at the micro-scale necessary for high throughput or
combinatorial work. In particular, special problems can arise for reactions that are
significantly dependent on flow rate or configuration.
Most combinatorial work to date has focused on "solid phase" reactions. It is
known that a wide variety of organic reactions can be carried out on substrates
immobilized on resins. However, a substantial number of production scale reactions

are "liquid phase" or "mixed phase" and, as noted, are carried out in continuous flow
reactor systems.
Early efforts in high throughput screening of solutions have focused on
catalyst screening. Before the application of the high throughput and combinatorial
approaches, catalyst testing was traditionally accomplished in bench scale or larger
pilot plants in which the feed to a continuous flow reactor was contacted with a
catalyst under near steady state reaction conditions. However, rapid and combinatorial
screening of reactants, catalysts, and associated process conditions require that a large
number of reactions or catalytic systems be tested simultaneously. In certain
applications, screening-level data can be generated by using miniaturized batch
reactors in conjunction with liquid-handling robots that aliquot the appropriate
catalysts and reactants to each vial or reaction well. In other applications, however,
batch reactions do not behave in the same fashion as continuous flow reactions and
could provide misleading results if the goal of screening is to identify reactants or
catalyst systems that will be implemented in production-scale continuous flow
reactors.
As the demand for bulk chemicals has continued to grow, new and improved
methods of producing more product with existing resources are needed to supply the
market. Unfortunately, the identities of additional effective reactants and catalyst
systems for these processes continue to elude the industry. What are needed are new
and improved methods and devices for rapid screening of potential reactants,
catalysts, and associated process conditions.
SUMMARY OF THE INVENTION
Accordingly, the present invention is directed to a method for producing a
chemical reaction in a manner useful for rapid screening of reactants, catalysts, and
associated process conditions.
In one embodiment, the method includes the steps of providing a reaction
vessel and reactants; placing at least one of the reactants in the reaction vessel; and

allowing the reaction to proceed for a time interval. A volume increment of at least
one of the reactants is added to the reaction vessel, and a volume increment of at least
one of the reactants is withdrawn from the reaction vessel. The volume increment
addition/withdrawal is repeated after successive time intervals until the reaction
reaches a substantially steady state. In alternative embodiments, the volume
increment withdrawal can take place before, after, or contemporaneously with the
volume increment addition.
BRIEF DESCRIPTION OF THE DRAWINGS
Various features, aspects, and advantages of the present invention will become
more apparent with reference to the following description, claims, and appended
drawings, wherein FIG. 1 is a graphical representation of concentration gradients of
various reactions;
FIG. 2 is a schematic view of a device capable of performing an aspect of an
embodiment of the present invention;
FIG. 3 is a graphical representation of the relationship among various reaction
conditions; and
FIG. 4 is a graphical representation of a reaction kinetics model comparing a
continuous stirred tank reactor with an incremental flow reactor.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The present invention is directed to a method for producing a chemical
reaction. Generally, it is contemplated that the method can be useful for high
throughput screening of reactants, catalysts, and associated reaction conditions. More
specifically, it is contemplated that the present method can be useful for parallel high-
throughput screening of chemical reactants, catalysts, and processes in which
continuous flow of reactor influents and effluents is desired. The method allows
researchers to mimic continuous flow in order to obtain useful information that may
be dependent on flow rate or configuration (e.g., reaction yield; selectivity; and other
reaction characteristics or process variables). It is believed that the method can be
particularly useful for studying the formation of bisphenol A from phenol and
acetone.
As noted, a significant number of production scale chemical processes cannot
be accurately emulated in a batch reactor. The present method overcomes the
limitations of traditional batch screening while advantageously allowing the use of
convenient, miniaturized reactor vessels, such as vial arrays, multi-welled microtitre
plates, and the like.
In the practice of one embodiment of the invention, the method includes the
steps of providing a reaction vessel and reactants; placing at least one of the reactants
in the reaction vessel; and allowing the reaction to proceed for a time interval. A
volume increment of at least one of the reactants is added to the reaction vessel, and a
volume increment of at least one of the reactants is withdrawn from the reaction
vessel. The volume increment addition/withdrawal is repeated after successive time
intervals until the reaction reaches a substantially steady state. As used herein, the
term "substantially steady state" refers to a point where the reaction effectively
emulates a reaction of interest, such as those carried out in production-scale,
continuous flow or continuous stirred tank reactors. As noted, certain reaction data are
dependent on flow rate, residence time, or similar parameters. Utilizing the present
method, these parameters can be manipulated in order to obtain useful data at a micro
scale.
In various alternative embodiments, the volume increment withdrawal can
take place before, after, or contemporaneously with the volume increment addition.
The preferred order will depend on the discrete circumstances of a given application.
For example, when working with micro amounts, it may be preferable to add a
volume increment before withdrawal in order to maintain favorable reaction
conditions within the reaction vessel. In a preferred embodiment, the time increments
are selected such that withdrawals are made before the reactants present in the
reaction vessel have had a chance to completely react, thereby ensuring substantially
continuous reactivity within the reaction vessel.
Each volume increment added contains at least one of the reactants. In the
present context, the term "reactant" means any substance that affects the reaction in
any capacity, including catalysts, promoters, and the like. The relative amounts of
each reactant in the volume increments can be determined based on the differential
depletion, exhaustion, or inactivation of each species during the course of the
reaction. It is also contemplated that multiple additions of various reactants and
reactant combinations can be made. In a preferred embodiment, the total volume of
the multiple additions is equivalent to the volume increment withdrawn.
Withdrawn volume increments can be dealt with in a number of ways. For
example, each volume increment withdrawn from the reaction vessel can be analyzed
individually for properties of interest. Selected volume increments can be analyzed,
while the non-analyzed volume increments are discarded. Alternatively, withdrawn
volume increments can be pooled to provide cumulative data for the entire course of
the reaction or for selected time periods of interest.
In further alternative embodiments, automated robotic equipment can be used
to deliver and remove the volume increments. Desired space velocity and reactor
residence times can be obtained by controlling the size of the volume increments
withdrawn/added and the size of the time intervals between volume increment
additions. Unless otherwise noted, time intervals denote the period of time between
successive volume additions.
The effective liquid residence time in the reactor can be defined by the
following relationship:
wherein ?t = time interval;
?V = volume increment;
RT = residence time; and
Vtot = total liquid volume in the reaction vessel.
Likewise, the effective liquid flow rate (Q) can be defined by the following
relationship:

It is evident that the behavior of the present incremental flow method
approaches that of a continuous stirred tank reactor as the time interval and volume
increments approach zero:

Conversely, as the volume increment approaches the total liquid volume in the
reaction vessel, the behavior of the incremental flow method approaches that of a
sequential series of batch reactions:

The selection of optimal At and AV values will depend on several factors,
including reaction kinetics and the capabilities of the liquid-handling equipment. As
shown in FIG. 1, a faster reaction will generally exhibit larger concentration gradients
within a given time interval than a slower reaction. Preferably, for a given reaction
system, the At and AV values should be chosen to minimize the within-increment
concentration gradients without placing excessive demands on liquid handling
equipment.

Accordingly, it may be useful to determine the sub-interval concentration
gradients at various points throughout the course of the reaction. Not only can this
information be useful in verifying that appropriate At and AV values have been
chosen, it could also provide valuable insight regarding reaction kinetics. Such
information can be obtained by establishing a reaction as described above. That is,
allowing the reaction to proceed for a time interval, followed by controlled addition
and withdrawal of nominal volume increments until the reaction reaches a point of
interest. When concentration gradient information is desired, a sample volume
increment is added that is larger (e.g., two to three times larger) than the nominal AV.
Volume sub-increments are then withdrawn at appropriate subintervals within the
time interval, such that the sum of the volume sub-increments is equivalent to the
sample volume increment. Analysis of the withdrawn sub-increments provides
desired concentration gradient data. The reaction is allowed to continue until sub-
interval concentration gradient information is again desired, at which point the steps
for obtaining such information can be repeated.
In a further alternative embodiment, volume increment withdrawals are
effected by inserting a probe to a predetermined level in the reaction vessel and
withdrawing reactor fluid until no further fluid can be withdrawn by the probe at that
predetermined level. In this manner the probe acts as a liquid level controller, thereby
ensuring that the liquid level in the reaction vessel will be the same at the end of each
time interval. When using a robotic probe, the efficacy of this approach depends, inter
alia, on how accurately and reproducibly the probe can be positioned at the desired
liquid level.
This embodiment reduces or eliminates the possibility of cumulative volume
error related to the accuracy of incremental volume withdrawals and also
compensates for error related to the accuracy of incremental volume additions. For
example, if a slightly larger than desired volume increment is added at the beginning
of a time interval, a similarly larger volume increment will be withdrawn at the end of
that time interval since the volume increment removal is based on a liquid level
control mechanism. Conversely, a smaller than desired volume increment addition
would be compensated for by a smaller volume increment removal.
EXAMPLE
The following prophetic example utilizes a mathematical reaction kinetic
model to compare incremental flow reactor behavior with continuous stirred tank
reactor behavior. The example is included to provide additional guidance to those
skilled in the art in practicing the claimed invention and is merely representative of
the teaching of the present application. Accordingly, this example is not intended to
limit the invention in any manner.
The dihydric phenol 2,2bis(p-hydroxyphenyl) propane (commonly referred to
as "bisphenol-A", "BPA" or "pp-BPA") is commercially prepared by condensing 2
moles of phenol with a mole of acetone in the presence of an acid catalyst. The
phenol is typically provided in molar excess of the stoichiometric requirement.
Optional reaction promoters, such as free mercaptans, can be added to aid the
reaction. Common acid catalysts for the production of BPA include acidic ion
exchange resins, such as sulfonic acid substituted polystyrene and the like. Current
industry research efforts are focused on improving the effectiveness of these ion
exchange catalysts and identifying additional promoters.
In this context, assume that the ion exchange resin-catalyzed formation of
BPA from phenol and acetone is conducted in continuous-flow reactors at a space
velocity of 2.33 g liquid feed/g resin/hr. For a small vial containing 150 mg resin
and 1000 |iL liquid volume, the corresponding liquid flow rate for a true
continuous flow reactor would be 338 uL/hr (assuming a liquid feed specific
gravity of 1.018 g/mL). To mimic continuous flow in the small vial example
using the incremental flow method, the following sequence would be followed:
With reference to FIG. 2, each vial or reaction well is loaded with the
appropriate mixture of phenol:acetone feed 12. The feed can contain optional
promoter(s) and catalyst(s). Each vial is provided with resin beads 16 and an optional
stir bar 18. It will often be beneficial to allow the initial feed to sit for an extended
period in contact with the resin to allow the resin to swell.
The reaction is allowed to proceed in batch mode for one time interval, At.
Near the end of this time interval, a probe (not shown) withdraws one liquid volume
increment, ?V, of reaction mixture 14 from the vial (reactor effluent). The withdrawn
volume increment is replaced with an equal volume increment, AV, of fresh feed 12.
Cycle time, At, is defined as the time period between successive volume increment
additions. The incremental withdrawal and addition of reactants is continued until the
reaction reaches a substantially steady state, and screening data are collected.
The values of the time intervals and volume increments (At and AV) can be
selected to obtain a desired space velocity. The relationship between the time
intervals and volume increments is as follows:

The relationship between At and AV is plotted in FIG. 3 for the present
example (Vtot = 1000 µL; resin amount = 150 mg/L; space velocity = 2.33 g liquid
flow/g resin/hr), along with results for a range of other space velocities.
FIG. 4 shows a comparison between the incremental flow method and a
traditional continuous stirred tank reactor (CSTR). These plots were generated using
mathematical reaction kinetics models with the following parameters:
It is clear that the incremental flow method closely emulates the CSTR under
these conditions.
It will be understood that each of the elements described above, or two or
more together, may also find utility in applications differing from the types described
herein. While the invention has been illustrated and described as embodied in a
method for high throughput chemical screening, it is not intended to be limited to the
details shown, since various modifications and substitutions can be made without
departing in any way from the spirit of the present invention. For example, various
detection techniques may be incorporated into the method to provide data at
accelerated rates. As such, further modifications and equivalents of the embodiments
herein disclosed may occur to persons skilled in the art using no more than routine
experimentation, and all such modifications and equivalents are believed to be within
the spirit and scope of the invention as defined by the following claims.
We claim:
1. A method of producing bisphenol A by a chemical
reaction) the method comprising the steps oft
a) providing a reaction vessel and reactants;
b) placing at least one of the reactants comprising
phenol and acetone in the reaction vessel;
c) allowing the reaction to proceed for a time
interval 5
d) withdrawing a volume increment of at least one of
the reactants from the reaction vessel;
e) adding a volume increment of at least one of the
reactants to the reaction vessel; and
f) repeating steps c>» d), and e) until the reaction
reaches a substantially steady state.
2. The method of claim 1, wherein the volume increment
comprises phenol.
3. The method of claim 1, wherein the volume increment
comprises acetone.
4. The method of claim 1, wherein the reaction vessel
further contains an ion exchange resin as herein described.
5. The method of claim 1, wherein the volume increment
further comprises a reaction promoter as herein described.
6. The method of claim 1, further comprising the step of
selecting the reactor residence time of at least one of the
reactants by controlling the time interval between additions.
7. The method of claim 1, further comprising the step of
selecting the reactor residence time of at least one of the
reactants by controlling the size of the volume increments added
and withdrawn from the reactor.
8. The method of claim 4, wherein the time intervals and
the volume increments are selected to obtain a desired space
velocity according to the following relationships!

wherein At is the time interval (min),
?V is the volume increment,
p is density of the volume increment added,
SV is the space velocity (g liquid feed/g
resin/hr), and
R is the quantity of ion exchange resin.
9. The method of claim 1, further comprising the steps of:
adding a sample volume increment, the volume increment
being larger than the volume increment added in step d);
withdrawing volume sub-increments at appropriate
subintervals within the time interval, such that the sum of the
volume sub-increments is equivalent to the sample volume
increment? and
analysing the volume sub-increments to provide data
regarding the concentration gradient during a time interval.
10. The method of claim 1, wherein the size of the volume
increments are chosen to minimize concentration gradients between
time intervals.
11. The method of claim 1, wherein the volume increments
withdrawn from the reaction vessel are analyzed for properties of
interest.
12. The method of claim 1, wherein the volume increments
withdrawn from the reaction vessel are subsequently analyzed to
provide cumulative data.
13. The method of claim 1, wherein the volume increments
are withdrawn from the reaction vessel by positioning a probe at
a predetermined level within the reaction vessel and withdrawing
a reactor fluid until no further fluid can be withdrawn by the
probe at the predetermined level.
14. The method of claim 1, wherein after the reaction is
allowed to proceed for a time interval the volume increments are
withdrawn and added simultaneously.
15. The method of claim 1, wherein after the reaction is
allowed to proceed for a time interval the volume increments are
added before being withdrawn.
16. A method of producing a chemical reaction according to
claim 1, wherein the vessel also contains an ion exchange resin
and the time intervals and the volume increments are selected to
obtain a desired space velocity.
17. The method of claim 16, wherein the volume increment
comprises phenol.
18. The method of claim 16, wherein the volume increment
comprises acetone.
19. The method of claim 16, wherein the reaction vessel
further contains an ion exchange resin.
20. The method of claim 16, wherein the volume increment
further comprises a reaction promoter.
21. The method of claim 16, further comprising the step of
selecting the reactor residence time of at least one of the
reactants by controlling the time interval between additions.
22. The method of claim 16, further comprising the step of
selecting the reactor residence time of at least one of the
reactants by controlling the size of the volume increments added
and withdrawn from the reactor.
23. The method of claim 16, wherein the desired space
velocity is obtained by selecting the time intervals and the
volume increments in accordance with the following relationship:

wherein ?t is the time interval (min),
?V is the volume increment,
P is density of the volume increment added,
SV is the space velocity (g liquid feed/g
resin/hr), and
R is the quantity of ion exchange resin.
24. The method of claim 16, further comprising the steps
of :
adding a sample volume increment, the volume increment
being larger than the volume increment added in step d);
withdrawing volume sub-increments at appropriate
subintervals within the time intervals, such that the sum of the
volume sub-increments is equivalent to the sample volume
increment; and
analysing the volume sub-increments to provide data
regarding the concentration gradient during a time interval.
25. The method of claim 16, wherein the size of the volume
increments are chosen to minimise concentration gradients between
time intervals.
26. The method of claim 16, wherein the volume increments
withdrawn from the reaction vessel are analayzed far properties
of interest.
27. The method of claim 16, wherein the volume increments
withdrawn from the reaction vessel are pooled and subsequently
analysed to provide cumulative data.
28. The method of claim 16, wherein the volume increments
are withdrawn from the reaction vessel by positioning a probe at
a predetermined level within the reaction vessel and withdrawing
reactor fluid until no further fluid can be withdrawn by the
probe at the predetermined level.
29. The method of claim 16, wherein after the reaction is
allowed to proceed for a time interval the volume increments are
withdrawn and added simultaneously.
30. The method of claim 16, wherein after the reaction is
allowed to proceed for a time interval volume increments are
added before being withdrawn.

A method of producing a chemical reaction is provided. In the
practice of one embodiment of the invention, the method includes
the steps of providing a reaction vessel and reactants; placing
at least one of the reactants in the reaction vessel; and
allowing the reaction to proceed for a time interval. A volume
increment of at least one of the reactants is withdrawn from the
reaction vessel, and a volume increment of at least one of the
reactants is added to the reaction vessel. The volume increment
withdrawal/addition is repeated after successive time intervals
until the reaction reaches a substantially steady state. In
various alternative embodiments, the volume increment withdrawal
can take place before, after, or contemporaneously with the
volume increment addition.