CA2351336C - Continuous feed parallel reactor - Google Patents

Abstract

A method and apparatus (10) for reacting a plurality of different mixtures in parallel in a semi-batch or continuous mode is provided. Each reaction is contained within a reactor vessel (102), the reactor vessels (102) combined into a reactor block (100). Reactant(s) to be added during the reaction are kept in a header barrel (202), which has a plunger (402) to feed reactant(s) from the header barrel (202) through a transfer line (302) into the reactor vessel (102). The plunger (402) is moved using a drive system (500). The header barrels (202) are optionally combined in a header block (200). The header block (200) is seated to a plate (300) containing the transfer lines (302), which in turn is sealed to the reactor block (100). A latch mechanism (600) is provided for easy sealing of the reactor (100) and header blocks (200) to the plate (300). The entire apparatus (10) may be placed on a rocker or rotating plate for mixture as the reaction is proceeding.

Description

CONTINUOUS FEED PARALLEL REACTOR
BACKGROUND
Technical Field The present invention relates to a method and apparatus for rapidly making, screening, and characterizing an array of materials in which process conditions are controlled and monitored, and in particular where the feed to each reactor vessel is continuously fed.
Discussion Combinatorial materials science generally refers to methods for creating a collection of diverse compounds or materials using a relatively small set of precursors IS and/or methods for rapidly testing or screening the collection of compounds or materials for desirable performance characteristics and properties. As currently practiced, combinatorial materials science permits scientists to systematically explore the influence of structural variations in candidates by dramatically accelerating the rates at which they are created and evaluated. Compared to traditional discovery methods, combinatorial methods sharply reduce the costs associated with preparing and screening each candidate.
Combinatorial chemistry has revolutionized the process of drug discovery. See, for example, 29 Acc. Chem. Res. I-170 (1996); 97 Chem. Rev. 349-509 (1997); S.
Borrnan, Chem. EngrNews 43-62 (Feb. 24, 1997); A. M. Thayer, Chem. Eng News 57-64 (Feb. 12, 1996); N. Tenet, 1 Drug Discovery Taday 402 (1996)). One can view drug discovery as a two-step process: acquiring candidate compounds through laboratory synthesis or through natural product collection, followed by evaluation or screening for efficacy. Pharmaceutical researchers have long used high-throughput screening (HTS) protocols to rapidly evaluate the therapeutic value of natural products and Libraries of compounds synthesized and cataloged over many years. However, compared to HTS
protocols, chemical synthesis has historically been a slow, arduous process.
With the advent of combinatorial methods, scientists can now create large libraries of organic molecules at a pace on par with HTS protocols.

SUBSTITUTE SHEET (RULE 2$J

Recently, combizaatorial approaches have been used for discovery programs unrelated to drugs. For example, some researchers have recognized that canZbinatorial strategies also offer promise for the discovery of inorganic compounds such as high-temperature superconductors, magnetoresistive materials, luminescent materials, and S catalytic materials. See, for example, U.S. Patent 5,776,359, as well as U.S. patent application no. 08/327,513 "The Combinatorial synthesis ofNovel Materials"
(published as WO 96/11878) and co-pending U.S. patent application no. 08/898,71 S
"Combinatorial Synthesis and Analysis of Organometahie Compounds and Catalysts" (published as WU
98/03251).
Because of its success in eliminating the synthesis bottleneck in drug discovery, many researchers have come to narrowly view combinatorial methods as tools far creating structural diversity. Few researchers have emphasized that, during synthesis, variations in temper~.ture, pressure and other process conditions can strongly influence the properties of library members. her instance, reaction conditions are particularly important in formulation chemistry, where one combines a set of components under different reaction conditions or concc;ntrations to determine their influence tin product properties. Moreover, it is often beneficial to mimic industrial processes that are different than in pharmaceutical research so that many workers have failed to realize that processes often can be used to distinguish among library members. Some parallel reactors are known; see .for example WO 98/36826 and U_S. Patents 4,099,923 and x,944,923. However, what is needed is an apparatus for preparing and screening combinatorial libraries in which an industrial process can be followed.
SUMVMARY OF fI-iE INVENTION
The present invention provides a method and apparatus for reacting a plurality of different mixtures in parallel where one or more reactants are con..Stantly fed over a period of time to a plurality of reaction vessels from one or more sources. The present invention provides a method and apparatus for semi-continuous processes, in which one or more reagents is fed into the reactor from a source or header vessel. The present invention also provides a method and apparatus far continuous processes, in which product is simultaneously removed from the reactor as reagents are fed into the reactor. rn addition TOTR~ P.03 WO 00!32308 PCT/US99I28741 to control of the reactants, catalysts, initiators, solvents, etc. chosen for a particular reaction, certain reaction conditions can be controlled including temperature, pressure, mixing, rate of reactant addition and/or rate of product removal.
Broadly, each reaction is contained within a reactor vessel, with a plurality of 5 reactor vessels optionally being combined into a single parallel reactor block. Associated with each reactor vessel is one or more reactant sources (called "header barrels") that provide one or more reactants that are fed into the reactor. A plurality of sources or header barrels can be provided in a header block. The header barrel is connected to the reactor vessels via a transfer line. A transfer system feeds reactant from the header 1o barrel, through the transfer line and into the reactor vessel, optionally while the contents of the reactor are being mixed. The transfer system may comprise a pump or a plunger.
The reactor vessel is typically sealed to the outside except for the connection to the transfer line, and methods of sealing are provided. In same embodiments, the entire system is sized to allow for the reactors, headers, plungers and drive system to fit into an 15 inert atmosphere glove box, appropriate for air and moisture sensitive reactions.
In a much more specific embodiment, a 96-cell semi-continuous parallel reactor block is provided. Ideally, each vessel may be located at standard microtiter plate spacing. A separate header barrel is used for each reactor vessel and 96 header barrels are disposed in a header block. The reactor vessels within the reactor block are 2o disposable glass vials, and the header barrels within the header block are glass syringes.
The blocks and hence the reactor vessels are connected together with an inert orifice, which is the transfer line and also serves to thermally insulate the vessel from the barrel, as well as prevent undesired mixing of the contents of the two vessels. In this specific embodiment, the reactor vessel is constant volume, initially f !led only partially with 25 liquid, leaving a compressible gas headspace in the vessel. The header barrel's volume is decreased throughout the reaction as the contents of the header are injected into the reactor, causing the pressure of the reaction vessel system to gradually increase.
Additional pressure rise is caused as the reactor vessels are heated, potentially above the boiling point of the liquids inside. Filling and assembly of the reactorlheader reaction 3o system may done in two halves, first by filling the reactor vessels to a desired amount and then filling the header barrels to a desired amount. The tops of the reactor vessels and header barrels are held in an array format by a collar, which leaves a portion of the SUBSTI7UfE SHEET (RULE 2~

WO 00!32308 FCTlUS99128741 bottom of each reactor vessel exposed. The reactor vessels are filled with different mixtures via a fluid-handling robot or manually. The collar is used to move all reactor vessels from a filling station into the reactor block at once. This allows the filling station to be independent of the reactor block, and also allows automated robotic handling and 5 transfer of the reactors from one station to another. The header barrels are open at the end opposite the plunger rod. This allows the headers to be filled by direct dispensing (manual ar automated), rather than by aspiration from another container. This ensures that the header vessel mixture is not altered in the event that the mixture is non-homogeneous. This open-end design also allows addition of mixing balls into the l0 header, and reduces entrapment of gasses. Once the headers are filled, a plate containing individual orifices at each vessel position seals the entire array at once.
The header barrels may be inverted and attached onto the reactor vessels. The orifices keep the header contents from spilling during the inversion, and are sized to keep the fluid velocity during injection much higher than the diffusion rate, keeping the contents of the 15 header vessel separated from the reactor vessels during a reaction.
Heating of the reactor vessels and/or header barrels may be accomplished in many different ways. In the most specific embodiment, cartridge heaters mounted into the reactor block provide heating. Heat is conducted ko the vessels axially through the block, then radially into the vessel. A temperature sensor is also mounted into the block to 20 provide feedback for a closed-loop temperature controller. The same heating may be used in the header block.
In the preferred embodiment, sealing is accomplished by pressing the lip of the reactor vessel against a seal associated with a plate between the header and reactor blocks. However, a variety of sealing options are presented. Preferably, sealing is 25 accomplished while accounting for a possible variation in the height of the reactor vessels, which may be removable vessels in wells of the reactor block. Thus, preferably both the reactor vessels and the header vessels are independently supported by a preloaded spring. This applies a virtually constant level ofcompression force during axial dimensional changes caused by vial height variations, seal compression set, 30 differential thermal expansion of components, etc. A latch mechanism is also preferably used that translates a single input motion to two counter-rotating drums, which pull the SUBSTlME SHEEP (RULE 2~j WO 00!32308 PCTIUS99I28741 plate carrying the orifices orthogonally onto the vessel lips without tilting.
This mechanism may be actuated either manually, or automatically.
Mixing is optional, but may be accomplished by placing the entire reactor on a rocking platform, which allows mixing balls in each reactor vessel to tumble through the fluids, being pulled by gravity. Uniform stirring of all of the reactions can be obtained, which insures that any differences noted between reactions are not artifacts of the manner in which the samples were mixed: Alternative embodiments include use of stirring bars (either magnetic or mechanical) or mechanical stirring.
A further understanding of the nature and advantages of the present invention 1o may be realized by reference to the remaining portions of the specification and the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
I5 Figure 1 illustrates a parallel reactor system in accordance with the present invention.
Figure 2 illustrates an alternative embodiment parallel reactor system in accordance with the present invention.
Figure 3 shows a detailed cutaway section of the preferred reactor block, plate 2o and header block assembly.
Figure 4 shows a detail of the preferred embodiment for supporting the bottom of the reactor wells.
Figure 5 shows the force vs. deflection curve for a preioaded linear spring used in the preferred embodiment.
25 Figure 6 shows a top and bottom view of the header block, which holds the glass syringes in the preferred embodiment.
Figure 7 illustrates an alternate embodiment of the continuous feed parallel reactor using only 6 wells, header vessels integrated with the header block, a monolithic orifice/insulator plate, and a rubber cushion supporting the bottom of the reactor wells.
3o Figure 8 is a view of the preferred embodiment of a header syringe.
Figure 9 is a view of the preferred embodiment of a syringe plunger SUBSTITUTE SHEET (RULE 28j Figure 10 is a view of the preferred reactor block latch mechanism, with the reactor block and all but one vessel hidden.
Figure 11 is a view of the preferred reactor block latch mechanism.
Figure 12 is a detail of the preferred latch drum.
Figure 13 illustrates an alternate embodiment of reactor vessel seals utilizing an inert "taper seal sheet" which is flared by pressing onto a conical protrusion in the insulator block.
Figure 14 illustrates an alternate embodiment of reactor vessels seals utilizing a composite seal made up of an o-ring fitted onto an inert spool.
1o Figure 15 illustrates an alternate embodiment of individual insulator orifices as seals, which snap into the reactor vessels, and engage the header vessels with a taper fit.
Figure 16 shows a detail of the preferred embodiment of an orifice insert used to separate the reactor vessels from the header vessels, which is pressed into a earner plate.
Figure 17 shows a front view of the preferred embodiment of the drive system 15 with the reactor block and the header block.
Figure 18 shows a back view of the preferred drive system.
Figure 19 shows the preferred embodiment of a mixing system and inert atmosphere enclosure for the continuous feed parallel reactors, in which .two reactors and drive systems are mounted to rotary tables.
20 Figure 20 shows the preferred embodiment of a liquid handling robot used to dispense diverse chemicals into the header and reactor vessels.
Figure 21 shows the preferred method of filling and assembling the header and reactor vessels.
Figure 22 shows an alternate embodiment of the continuous feed parallel reactor 25 in which the reactor vessel volume as well as the header vessel volume is variable.
Figure 23 shows an alternate embodiment of the continuous feed parallel reactor in which a third storage tank is added to the system, allowing materials to be removed from the reactor during or after a reaction.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
SUBSTITUTE SHEET (RULE 2~

The present invention provides an apparatus and method for carrying out multiple reactions in parallel. It is especially useful for synthesizing andlor screening combinatorial libraries. The term "header barrel" is used to describe the container that holds the one or more reactants that are fed into the reactor from the sources in the header. The term "barrel" is not intended to be limiting and a header barrel can take any convenient form including a vessel, tank, barrel, pipe, vial, syringe or other form of container. Also, the phrase "storage tank" is used to describe the container that holds the material that exits the reactor. The term "tank" is not intended to be limiting and a storage tank can take any convenient form including a vessel, tank, barrel, pipe, vial, 1o syringe or other form of container.
Fig. 1 shows a constant volume embodiment of a parallel reactor system 10. The system 10 comprises a reactor block 100 and a header block 200 having sandwiched between them a plate 300 that holds the transfer lines 302 allowing for fluid communication between the reactors 102 in the reactor block 100 and the header barrels 15 202 in the header block 200. There are also two seals associated with the plate 300, a reactor seal 320 and a header seal 340. The system 10 additionally comprises a plunger plate 400 for pressing on plungers 402 that form the top of the header barrels 202 to feed reactants) through the transfer line 302 into the reactor vessels 102. The system additionally comprises a drive system (not shown in Figure 1) for driving the plungers 20 (i.e., the plunger plate).
To perform parallel semi-continuous / semi-batch reactions, reactants, catalysts, initiators, solvents, scavengers, etc. are loaded into the reactor vessels 102 leaving some headspace. Reactant{s) to be added to the reactor vessel 102 during the reaction is loaded into the header barrels 202 at the opposite end from the plungers 402. The vessels 102 25 are placed in the wells 104 of the reactor block i00. The plate 300 comprising the transfer lines 302 and the seals 320 & 340 is then secured to the header block so that a single transfer line 302 communicates with a single header barrel 202 and so that each header barrel is sealed to the outside except for the transfer line. The plate is also secured to the reactor block 100 so that a single transfer line 302 communicates with a 3o single reactor vessel 102 and so that each reactor vessel 102 is sealed to the outside except far the transfer Line. The reaction may begin when all the components are added, but preferably the reaction beginning is controlled, for example by supplying heat to the SUBSTiME SHEE? (RULE 2~

WO 00!32308 PCTIUS99J2874I
reaction vessels via a temperature control system 900 in the reactor block (which is discussed below). The drive system forces the plungers down thereby feeding reactants) into the reaction vessel from the header barrel. This compresses the contents in the reactor vessels. Sufficient headspace in the reactor vessels allows that gas to compress 5 with the pressure increase in the system is withstood by the sealing means.
The reaction components may be mixed by the addition of mixing ball to each reactor vessel and placing the entire system 10 on a rocker platform, which allows the mixing balls to tumble through the contents of the reactor.
The transfer means (described herein - e.g., pumps, plungers, etc.), for 1o transferring the liquid reactants) from the header barrels) to the reactor vessels, can be controlled so that a desired rate of reactant feed into the reactor vessels is met. In some embodiments, the motor is controlled so that the drive system drives the plungers down feeding at a desired volume per unit time. In other embodiments, the reactants are fed into the reactor so that the time required for substantially complete feeding of the 15 reactant{s) into the reactor from the header is on the time fi~ame of typical industrial processes. This time is in the range of from about 0.5 hours to about 24 hours, preferably in the range of from 1-12 hours. Overall, the kinetics of the chemistry is used to select the desired feed rate, with fast chemistry allowing for faster feed rates and vice versa.
Thus, the feed time may be in the range of from about 1 minute to about 48 hours.
2o An alternative embodiment is shown in Fig. 2, where the reactor system i0 comprises a reactor block 100 having a plurality of reactor wells 104. A
transfer Iine 302 allows for fluid communication between a pump 20 and each well 104. The pump 20 has a feed line 22 for obtaining reactant from the header barrel 202. In this embodiment, the reactor vessels are individually sealable (e.g., with a screw cap or other sealing means) to 25 allow for a constant volume reaction. A check valve may be added to avoid back diffusion into the transfer Line. In this embodiment the method of feeding the reactant{s) into the reactor is a pump. There may be more than one pump, e.g., 2, 3 or more pumps, up to the number of reactors, or in some embodiments, more than the number of reactors.
Suitable pumps include syringe pumps and gear pumps. Alternatively, a plate (not 3o shown) can connect the transfer lines 302 to each reactor vessel as well as seal each reactor vessel. A plate 300 such as discussed below could be used for this purpose.
Another alternative is to provide valves in the transfer lines 302, to prevent reverse flow SUBSTIME SHEET (RULE 2~

of reagents from the reactor to the header, or to direct flow from the header barrel in a rapid serial fashion to each of the reactor vessels, using a single flow meter or pump.
A preferred reactor block 100 is shown in a cutaway view in detail in Figure 3. The reactor block 100 includes removable vessels 102 for receiving reactants, catalysts, initiators, solvents, etc. Wells 104 formed into a reactor block 100 contain the vessels 102.
The wells 104 can serve as reactor vessels, in one embodiment, with the wells being disposed in the reactor block. In a preferred embodiment, removable vessels 102 are used inside the wells because of several advantages. For example, following reaction and preliminary testing (e.g., screening), one can remove a subset of vessels 102 from the reactor 1o block 100 for further in-depth characterization. When using removable vessels 102, one can also select vessels 102 made of material appropriate fox a given set of reactants, products, and reaction conditions. Unlike the reactor block 106, which represents a significant investment, the vessels 102 can be discarded if damaged after use. Finally, one can lower system 10 costs and ensure compatibility with standardized sample preparation and testing equipment by designing the reactor block 100 to accommodate commercially available vessels. The removable reactor vessels 104 can be made of any appropriate material that is inert to the reaction being conducted, including plastic, glass, etc.
Preferably, the reactor vessels are glass because glass vessels of varying size and shape are commercially available and amenable to various sealing methods. The vessels 104 are shown as cylindrical in 2o shape, but any convenient shape can be employed, including square, rectangular, etc.
As shown in Fig. 3, each of the removable vessels 102 preferably contacts the bottom of the well 104. In a preferred embodiment, the bottom of the well 104 is the top of a spring pre-tensioner 106 that is surrounded by a spring 108 and bolted to the bottom 110 of the reactor block 100 with a nut 112. A detail of this reactor spring 1 OS
assembly is zs shown in Figure 4. The spring 108 is preloaded with a desired amount of compression.
There are two related functions this assembly performs: (1) allowing for consistent sealing of a plurality of reactor vessels and (2) accounting for variances in the height of the reactor vessels. As shown in Figure 3, the bottom of the reactor vessels 102 contact the top of the spring pre-tensioners 106. The top of the reactor vessels 102 contacts a reactor seal 320 3o associated with the plate 300, which is discussed in detail below. As the plate 300 is secured to the reactor block 100 the spring 106 provides the force to seal the reactor to the reactor seal 320. The amount of compression in the spring and the stiffness of the spring determine the amount of force pressing the top of the reactor vessel into the reactor seal. Figure 5 is a graph showing a preferred method in which a particular spring at a particular preload changes the sealing force very little over a limited deflection, 5 accounting for variations in reactor vessel height, and accounting for differential thermal expansion. Therefore, different spring tensions allow for different pressures.
The pressure in the reactor vessel can thus be adjusted for a particular reaction.
The reaction pressure can vary from atmospheric to about 1000 psi. It is possible to have a negative pressure in the system, for example by loading heated starting materials or reactants) to followed by sealing the system and then cooling or for example by removing contents from the reactor without adding reactants from the header (in the continuous embodiment discussed below).
Also, the reactor spring assembly 1 OS allows for a variation in height in the reactor vessels with maintaining the same amount of pressure in each reactor.
Because 15 commercially available replacement reactor vessels have some height variation, this system accounts for that variation. Although this preferred embodiment employs a single spring for each well, in other embodiments, a single spring can be used for a plurality of reactor wells and vessels. A possible disadvantage is that sealing may not be sufficient;
however, the number of wells, the uniformity of the vessels as well as the reaction being 20 studied {e.g., a low-pressure reaction) may allow for a single spring system to sufficiently seal the reactors.
The reactor block contains any desired number of wells. The embodiment shown in Figure 1 has 96 wells. This embodiment is shown more clearly in Figure 6, where the top of the reactor block 100 is shown in Figure 6A having a plurality of wells 104. The 25 bottom of the reactor block 100 is shown in Figure 6B, showing the reactor bottom 110 having a plurality of holes 114 for receiving the spring pre-tensioners 106 (see Figure 4 for the detail). Another embodiment is shown in Figure 7, where three reactor vessels 102 are shown, without the reactor spring system just discussed. In the embodiment in Figure 7, sealing and variation in reactor vessel height is accounted for by tightening the 3o plate 300 to the reactor block 100 with bolts, clips, clamps or other fastening mechanisms known to those of skill in the art. The overall size of the reactor block and the volume of the reactor vessels influence the number of wells. Thus, if a larger volume SUBS11TUT~ SHEET (RULE 2~

reaction is desired, typically a fewer number of wells are in the reactor block. Preferably, there are at least 6 wells, more preferably at least 15 wells and even more preferably at least 48 wells. In the most preferred embodiment there are at least 96 wells.
In general, the number of wells is preferably 96*N, where N is an integer ranging from about 1 to about 100, and preferably from about 1 to about 10. A 96 well reactor block (or a 9b*N
well reactor block) may correspond to a standard microtiter plate format (or a extended version thereof), namely an 8 by 12 array of wells on 9 mm spacing and is preferred due to its high throughput capacity and standardization of equipment. The spatial density of the reactor wells or reaction vessels in the reactor block is, for the rnicrotiter plate format, to about 1.25 reactors per cm2. In general, the spatial density of the reactor wells or reaction vessels in the reactor block is preferably at least about 1 reactor per cmz, and can vary from about 1 reactor per cm2 to about 10 reactors per cmZ, or higher, if micromachining and microelectromechanical technologies such as are known in connection with the semiconductor industry are employed. The reactor block also 15 contains a temperature control system as described below.
Turning now to the header block 200, Figure 3 shows a cutaway, detailed view of the bottomi portion of the preferred header block. The header block 200 includes removable barrels 202 for receiving reactants} that are to be fed into the reactor during the reaction: As shown in Figure 1, header wells 204 formed into a header block 200 2o contain the barrels 202. Although the header wells 204 can serve as barrels, removable barrels 202 provide several advantages. For example, they prevent fouling or contamination of the header block, requiring less cleanup following a reaction. When using removable barrels 202, one can also select barrels 202 made of a material appropriate for a given set of reactants and reaction conditions. The barrels can be 25 obtained with very high dimensional precision, improving the seal between barrel 202 and plunger 402. If necessary, the barrels 202 can be discarded after use.
This can lower system costs and ensure compatibility with standardized sample preparation and testing equipment by designing the header block 200 to accommodate commercially available vesseis/barrels. In the preferred embodiment, the header block contains the same number 30 of wells as the reactor block, in a matching configuration. The barrels 202 can be made of any material that is inert to the reaction, solvents, reactants, etc., including glass, SUBS~TnJTE SHEEN (RULE 2~

WO 00/32308 PCTIUS99128~41 plastic, etc. Preferably, the barrels are made of glass, for the same reasons that the reactor vessels are preferably made of glass.
The removable barrels 202 are shown in detail in Figure 8. The barrel 202 may include a collar 206 on the outside of the barrel and near one end of the barrel. This 5 collar keeps the spring compressed, performing the same function as the spring pre-tensioners and nut in the reactor block. The end of the barrel opposite the collar is flared to match the diameter of a header spring 210, shown in Figure I. As shown in Figure 1, the header spring assembly 208 contains a spring 210 that forces the barrel 202 into the header seal 340. The header barrel is sized to match the diameter of the header spring l0 210. The header spring is preloaded in compression, similarly to the reactor spring 108 and for the same reasons. In this case, the preloaded compression force on the spring comes from appropriate sizing of the length of the header barrel and the spring, as well as a header block top plate 212 that compresses the spring to the appropriate preloaded force. As also shown in Figure 1, the header block top plate 212 may fit into a broader 15 section of the top of the header block or may be the top of the header block (not shown).
There are two related functions the header spring assembly performs: ( 1 ) allowing fox consistent sealing of a plurality of header barrels and (2) accounting for variances in the height of the header barrels, differential thermal expansion. As shown in Figure I, the top of the header barrels 202 contact the bottom of the header spring 2 i 0.
The bottom of 20 the header barrel 202 contacts a header seal 340 associated with the plate 300, which is discussed in detail below. As the plate 300 is secured to the header block 200 the header spring 210 provides the force to seal the barrel to the header seal 340. The amount of compression in the spring and the stiffness of the spring determine the amount of force pressing the bottom of the header barrel into the header seal. Therefore, different spring 25 tensions allow for different pressures. The pressure in the header barrel can thus be adjusted for a particular reaction.
Also, the header spring assembly 208 allows for a variation in height in the header barrels with maintaining the same amount of pressure in each barrel.
Because commercially available replacement header barrels have some height variation, this 30 system accounts for that variation. Although this preferred embodiment employs a single header spring for each header well, in other embodiments, a single spring can be used far a plurality of header wells and barrels. A possible disadvantage is that sealing may not SUBSTITUTE SHEET (RULE 2~j be sufficient; however, the number of wells, the uniformity of the barrels as well as the reaction being studied (e.g., a low-pressure reaction) may allow for a single spring system to sufficiently seal the barrels.
A plunger 402 runs through the center of the header spring assembly 208 to inject reactants) from the header into the reactor. Here, the plunger is the transfer method.
The top of the plunger 402 is attached to a plunger plate 400, which in turn is associated with the drive system for driving the plungers forward to inject reactants) into the reactor from the header. A detail of the plunger is shown in Figure 9. The top of the plunger 404 comprises a head that attaches to the plunger plate. Attachment can be by 1o any method known to those of skill in the art. A preferred method of attaching the plunger top 404 to the plunger plate 400 is via a detachable method, such as by screwing the top of the plunger into the plunger plate. Clamping, bolting or other methods can also be used. A detachable attachment is preferred because it allows for plungers to be removed from the plunger plate for replacement or cleaning. Another preferred feature 15 of the plunger is a swivel joint 406 between the plunger rod 408 and the plunger top 404.
The swivel joint allows for some flexibility in the connection between the plunger and plunger plate while the plunger plate 400 is being pressed by the drive system. The plunger can be made of any suitably rigid material, such as metal.
The bottom portion of the plunger 402 has a plunger tip 410, shown in Figure 9 in 2o detail and shown in context in Figure 1. The plunger tip 410 contacts the reactants) and forces them into the reactor from the header as the plunger moves forward. The plunger tip is fitted over the end of the plunger rod 408 with sufficient adhesion so that the tip does not come off of the rod when the plunger is moved backward. Those of skill in the art can decide on methods for fitting the tip over the end of the plunger rod.
For 25 example, the tip may be made of plastic that is heat shrunk onto the end of the plunger rod or it may seal against o-rings between the rod shaft and the plunger tip, when pressed into barrel 202. The plunger tip 410 contains one large raised portion 411 and one or more small raised portions 412 (shown in Figure 9) for sealing the contents of the header barrel. As the plunger is moved forward, the raised portions 411,412 contact the inside 30 of the header barrel 202 forming a seal. The size and number of raised portions will depend on the pressure in the system, but preferably there are from 2-10 smaller raised portions on the plunger tip. The plunger tip 410 is made of a material that is inert to the SUBST~ME SHEET (RULE 2~

reaction, solvents, reactants, etc:, including plastic, etc. Preferably, the tip is made of plastic, such as PTFE.
Referring again to Figure 1, a plate 300 resides between the reactor black 100 and header block 200. The plate 300 is secured to both blocks and includes the transfer lines 5 302, the reactor seal 320 and the header seal 340. The plate can also function as either a heat conductor or insulator. As discussed below, heat may play an important roll in the reactions that can be run in this reactor system. In some circumstances, the heat that is applied to the reactors will be conducted to the reactants) that reside in the header. In other cases, the heat applied to the reactors is not to be conducted to the header barrels.
1o Thus, the plate can be designed to either conduct heat ar not. For most reactions, heat should be applied only to the reactor and not to the reactant{s) waiting in the header barrels for injection into the reactors. Thus typically, the plate will have thermal insulating properties and be made from a material that is a poor conductor of heat, such as stainless steel, ceramic, or plastic.
15 The plate 300 is attached to each o~the reactor block 100 and header block via a method of attachment that seals each to the plate with sufficient force to withstand the pressure of the reaction occurring in the reaction vessels. The method of attachment can be by bolting, clamping, clipping or other removable fasteners. Far example, in the embodiment shown in Figure 7, the plate 300 is bolted between the reactor block 100 and 2o the header block 200.
A preferred method for attaching the plate 300 to the reactor block and header block is via a latch mechanism 600, shown in Figure 10. The latch mechanism provides several advantages for combinatorial research. The latch mechanism translates a single input motion to two counter-rotating drums 604, which pull the plate 25 carrying the transfer lines 302 orthogonally onto the reactor vessel 102 and header barrel 202 lips without tilting the vessels or barrels, assuring little or no spillage from the reactor vessels or header barrels, and assuring uniform application of sealing farce.
Sealing of each reactor vessel and header barrel is simultaneous with the latch mechanism 600.
30 As shown in Figure 10, the latch mechanism 600 includes one or more, preferably a plurality of, latch pins 602 that are fixed to the plate 300. The latch pins 602 engage a latch drum 604, which rotates pulling the latch pins 602 down thereby securing the plate SUBSTfiUTE SHEEP (RULE 2~

to the reactor block and header block. The plate in most instances is locked to the block.
In one embodiment, the latch mechanism 600 which has been fabricated for sealing an array of vessels supported by the reactor spring assembly 105 in the reactor block with each latch pin 602 having a hemispherical ball-tip 603 on the end of the latch pin 602.
Shown in detail in Figure 12, the latch drum 604 has a hemispherical socket 605 cut into its perimeter which mates with the ball-tip 603. The shape of the socket and pin is not critical. A relief 607 is provided in the latch drum 604 so that when the drum is in open position, the bail tip 603 can be inserted into the reactor black past the latch drum 604.
The latch drum 604 is then rotated to its closed position (approximately one-quarter turn}
to so that the socket 605 mates with the ball tip 603 and pulling the latch pin 602 down.
Each end 60b of the latch drum 504 extends outward and beyond the edge of the end row of reactor vessels or header barrels to a latch arm 608, shown in Figure 11. The latch drum arm 608 is pivotally attached to an over-center link 610, which in turn is attached to a latch gear 612 that is rotated by an input shaft 614 and pinion 616. The 15 input shaft is rotated either manually or automatically. When the input shaft 614 is rotated, the pinion 61b engages the first latch gear 612a, which engages the second latch gear 612b thereby simultaneously moving the over-center links b 10. The over-center links 610 rotate the latch arms 608, which rotate the latch drums b04, securing the latch pins 602 and thus securing the plate 300 to the reactor block 100.
20 There are preferably at least two latch drums 604 in each of the reactor block and header block, on opposite sides of the block. The latch gears 612a, 612b allow the two symmetrical latch drums 604 to counter-rotate fully sealing both the vessels and barrels.
As shown in Figures 10 and 11, the latch mechanism completes a four-bar mechanism with the gears 612a, 612b, drum arm 608, and reactor block. This four-bar mechanism is 25 optimized to be quick-acting, with a rapidly increasing mechanical advantage as the mechanism is actuated to a closed position, and a corresponding decrease in drum rotation for input gear rotation. For a constant velocity input to the driving gear, this quick-acting movement opens or closes the drums 604 rapidly, slowing down for the final portion of the stroke when the preloaded springs 108 become engaged, best seen in 3o Figure 10. Once the latch drums 604 have pulled the latch pins 602 far enough to adequately press the reactor seal against the vessels 102, the over-center link 610 goes over-center by a few degrees. This provides a locked position requiring no input force to SUBST1M~ SHEET (RULE 28j hold the mechanism closed. To release, the input shaft 614 is simply rotated in the reverse direction past this over-center position, and the springs 108 push the mechanism open.
Although the latching mechanism 600 is shown for the reactor block, the same s mechanism is in the header block 200 for attaching the plate 300 to the header block 200.
The Iatch mechanism 600 operates in the header block in the same fashion as in the reactor block. Other embodiments of this latch mechanism could be accomplished via eccentric cams, worm gears or other simple mechanisms.
In the constant volume embodiment of this invention, the reactor vessels are to sealed to the outside except for the transfer line and the header barrels are sealed to the outside also except for the transfer line. These are pressure tight seals that withstand pressures up to 1000 psi, depending on the sealing material and method chosen.
The preferred embodiment of this closed system has three seals, but could have more seals in other embodiments. For example, the system in Figure 2 has four seals, two seals where 15 the feed line joins the barrel 202 to the pump 20 and two seals where the transfer line 302 joins the pump to the wells 104. In the preferred embodiment, the three seals are at the plunger tip 410 sealed to the inside of the header barrel 202, the header barrel 202 lip sealed to the plate 300 and the reactor vessel 102 lip sealed to the plate 300. The first of these seals is discussed above.
zo In this preferred embodiment, the header seal 340 is the seal between a lip of the header barrel 202 lip and the plate 300. Similarly, the reactor seal 320 is the seal between a lip of the reactor vessel 102 and the plate 300. Basically, the preferred sealing method has a lip of the reactor vessel or header barrel forced into a material that receives the lip. This sealing method has several embodiments.
25 The most preferred sealing method is shown in Figure 3. Looking first at the reactor seal 320, there is a gasket 322 that fits over one end of the transfer line 302, with the gasket 322 fitting snuggly to the outer diameter of the transfer line 302 and extending beyond the diameter of the reactor vessel I02. The gasket 322 is associated with the plate 300 in that the gasket is attached to the plate without allowing substantial leakage 30 between the gasket and the plate. Although some leakage may occur, it is kept to a minimum by tightening the attachment means, which attaches the reactor block 100 to the plate 300. When the reactor vessel 102 lip is tightened up against the gasket 322, the SUBSTITUTE SHEEP (RULE 2~

gasket 322 conforms to the lip of the vessel 102 while the end of the transfer line 302 extends into the vessel. The gasket 322 is preferably a continuous sheet that fits over each transfer line for each reactor vessel 102 in the array of wells and vessels that comprise the reactor block. A continuous sheet has the advantage of ensuring that the diameter of the reactor vessels 102 does not extend beyond the edge of the gasket 322, and can be replaced for all vessels simultaneously. The properties of the gasket can be selected to account for different sealing pressures, with the seal withstanding a pressure in the reactor vessel of up to about 1000 psi without leaking. Also, the gasket material should be inert to the reaction conditions and chemicals in the reaction. In this embodiment, the gasket can be made of to perfluoroelastomer, such as KalrezTM or some other chemically resistent elastomer. Most preferably the gasket is made from PTFE (Teflon) encapsulated silicone rubber.
Similarly shown in Figure 3, in the most preferred embodiment of the header seal 340 there is a header gasket 342 that fits over the other end of the transfer line 302, with the header gasket 342 fitting snuggly to the outer diameter of the transfer line 302 and extending beyond the diameter of the header barrel 202. When the header barrel 202 lip is tightened up against the header gasket 342, the gasket 342 gives to accept the lip of the barrel 202 while the end of the transfer line 302 extends into the header barrel. The header gasket 342 is preferably a continuous sheet that fits over each transfer line for each header barrel 202 in the array of wells and barrels that comprise the header block. A continuous sheet has the 2o advantage of ensuring that the diameter of the header barrels 202 do not extend beyond the edge of the header gasket 342. The properties of the gasket can be selected to account for different sealing pressures, with the seal withstanding a pressure in the header barrel of up to about 1000 psi without leaking. Also, the gasket material should be inert to the reaction conditions and chemicals in the reaction (e.g., the reactant(s)). In this embodiment, the 2s gasket can be made of a perfluoroelastomer such as Kalrez~ or some other chemically resistant elastomer. Most preferably the gasket is made from PTFE (Teflon) encapsulated silicone rubber.
Another sealing embodiment is shown in Figure 13. As shown in Figures 13A & B, the reactor seal 320 includes a rubber reactor gasket spring 322 that fits into a channel 304 3o that is cut into the plate 300. A feature of the channel 304 is a tapered portion 306 for receiving the lip of the reactor vessel 102. Optionally, a second inert gasket 324 is in between the reactor gasket spring 322 and the reactor vessel 102 to provide additional inert properties with respect to the reaction conditions and chemicals in the reaction being studied. Although not shown in Figure 13, this same seal could be used for the header seal. The properties of the gasket and second gasket can be selected to account for different sealing pressures, with the seal withstanding a pressure in the reactor of up to about 1000 psi without leaking. Also, the gasket material should be inert to the reaction conditions and chemicals in the reaction (e.g., the reactant(s)). In this embodiment, the gasket can be made of silicone rubber. Most preferably the gasket is made from either Kalrez or some other chemically resistant elastomer. The second ZO gasket can be made of PTFE (Teflon}.
Yet another sealing embodiment is shown in Figure 14. An o-ring 326 rests inside a spool 328, which is placed at the end of the reactor vessel 102. The transfer line 302 feeds reactant through the center of the spool. When the vessel 102 lip is tightened against the reactor seal 320 a seal is formed. As shown in Figure 7, the spool 328 rests inside a channel 304 cut into plate 300 that is designed to accommodate the shape of the spool 328. Preferably, the spool is made of plastic and more preferably PTFE
(Teflon) .
The o-ring may be made of a standard material such as silicone rubber. This seal has particularly good thermal insulating properties. Figure 14 also shows a mixing ball 370 in the barrel 202.
2o Still another sealing embodiment is shown in Figure I5. in this embodiment, the reactor seal 320 comprises a channel 304 cut into the plate 300 for receiving the reactor vessel 102 Iip. In this embodiment, the plate 300 is an individual piece for each vessel, and preferably a plastic material so as not to damage the reactor vessels. To seal, the inner surface of the reactor vessel snaps into the tapered portion 306 of the channel 304 via a raised portion 308. For the header seal 340 embodiment shown in Figure 15, the collar 206 of the header barrel 202 extends over a tapered tip 310, which fits over the tapered portion 306 of the channel 304 on the header side of the plate 300.
This system also snaps the header barrel to the plate to form the seal. Preferably the wetted portions of this seal embodiment are inert to the reacrion conditions and chemicals in the reaction.
Figure 15 also shows mixing balls 370 in the reactor vessel 102 and header barrel 202.
The transfer lines function to transfer reactants) from the header into the reactor.
They are preferably inert to the reactants being studied. Also preferably, the transfer SUBSTTCUTE SHEEP (RULE 2~}

lines are sized {either in length or diameter) so that the injection velocity into the reactor from the barrel is higher than the back diffusion velocity from the reactor into the barrel.
Preferably, the plurality of transfer Iines are sized to substantially limit the amount of back diffusion of reaction components from the reactor to the header. For example if a s sufficiently small diameter is chosen for the transfer line, chemicals that are reacting or are needed in the reaction (such as solvent, scavengers, etc.) will remain in the reactor and not diffuse to the header. The transfer lines 302 can be tubing or conduit as shown in Figure 2. The dimensions of the transfer lines are not narrowly critical, and can include both macro-sized conduits and micro-sized conduits such as capillaries. The transfer lines 302 can be channels in plate 300 as shown in Figures 13, 14 and 15. In the preferred embodiment shown in Figure 1, the transfer Iines 302 are inert inserts that fit into a hole in the plate 300. A detail of the preferred transfer line 302 is shown in Figure i 6, where the transfer line includes a line 312 running the length of the insert that allows the communication of fluids from the header to the reactor. At one end of the insert is a 15 flange 314 that holds the insert in place and prevents it from moving. This flange is preferably placed at the reactor side of the plate 300 (as shown in detail in Figure 3).
Continuing with Figure 3, the line 312 is shown as larger in diameter at the header side than at the reactor side, which is preferred to limit diffusion of chemicals from the reactor to the header. Another feature of the inserts is a channel 316 (also shown in Figure 16), 2o transverse to the axis of the transfer line 3 I2, in each end of the insert to allow for the flow of reactant in the presence of a mixing ball so that the mixing ball cannot block the line 312.
The preferred drive system is shown in Figures 17 and 18. Looking first at Figure 17, the reactor block i 00 is shown with a plurality of reactor vessels 102 that are sealed zs to the plate 300, which in turn is sealed to the reactor block 200. A
plurality of plungers 402 is shown extending into the header block 200 from the plunger plate 400.
The entire system, from bottom of the reactor block 100 to the top of the plunger plate 400 is associated with the drive system 500, which functions to force the plunger plate down so that the plungers feed reactant{s) from the header barrels to the reactor vessels.
3o Conceptually, the drive system 500 could simply be a weight of sufficient mass that drives the plunger plate down due to gravity. However, such a system could not function SUBSTITUTE SHEET (RULE 26j in alternative embodiments where the entire system is placed on a rocking plate far mixing.
Thus, the preferred drive system comprises a frame 502 having a center support 504 with a movable carriage 506 extending therefrom at about a right angle at one end s and a fixed arm 508 extending therefrom also at about a right angle at the other end. The center support 504 is shown as a plate, however, other designs will be evident to those of skill in the art, including a series of two or more rails. The carriage 506 freely moves along the length of the center support 504 on one or more rails 510, which may be fi~cedly attached to the center support 504 and attached to the carriage via a clamp and bearings to (not shown) to allow smooth movement. .Alternatively the rails may be attached to the back of the carriage, with the clamp and bearings being fixedly attached to the center support. It is preferable to reduce fiiction in the movement of the carnage 506 with respect to the center support 504. The method of attachment is not critical to the invention and those of skill in the art may use other reduced friction types of attachments:
15 The carriage 506 comprises a flat plate 512 extending approximately perpendicularly from the rails 510 with the bottom of the flat plate 512 contacting the plunger plate 400. The carriage 506 could comprise this plate alone, however for higher pressures in the reaction system (e.g., reactor vessels, header barrels and transfer lines), it is preferred that the carriage be able to withstand high forces and the embodiment shown 2o in Figure 17 exemplifies such a carnage 506. The carriage 506 in Figure 17 comprises a flat plate 5i2 connected at each side to carriage support plates 514. The carriage flat plate S 12 and carriage support plates 514 are attached to a carnage back plate 516, which in tum is connected to the clamp and bearings for movement along the rails 510. This preferred carriage S06 design is capable of driving 96 plungers forward without 25 deformation. The carriage design is not critical to the invention and other carriage designs will be apparent to those of skill in the art.
The back of the preferred drive system 500 is shown in Figure 18. The back of the carriage 506 extends through the center support 504 and is attached to a lead screw 518. The Lead screw 5I 8 is attached by supports S20 to the center support 504, such that 30 the lead screw 518 may rotate within supports 520. The lead screw 518 is threaded with matching threads on the back of the carriage 506 so that when the lead screw rotates, the carriage 506 moves up and down along the rails S 14. A toothed belt 522 joins one end of SUBSTtME SHEEP (RULE 2~

the lead screw 518 to a gear head 524. The belt 522 need not be toothed, but slippage is preferably avoided with such a belt. The method of rotating the lead screw is not critical to the invention and other methods of transmitting motion will be evident to those of skill in the art. A motor 526 rotates the gear head 524. The motor 526 may be either AC or DC driven and is preferably a commercially available gear motor, such as Industrial Devices model G23PI-S23-0100 or equivalents. Other features of the preferred drive system shown in Figure 18 include the belt tensioner 532 for maintaining the tension on belt 522 to further avoid slippage. Also shown in Figure 18 is a motor amplifier 528 for converting commands to appropriate electrical signals for the motor, such as Applied to Motion Products model PD2035 or equivalents.
This preferred drive system 500 operates by the motor 526 turning gear head and gear 530, which move the belt 522 and which in turn rotates the lead screw 518, leading to movement of the carriage. This system is preferred because it is strong, compact and can operate either vertically or horizontally or at other angles.
Given these features, the drive system with reactor system in place can be placed on a rocking platform or other oscillating mechanism for mixing the reaction and reactants) with a mixing ball. Obviously, in the stationary vertical position, mixing balls would be ineffective and another mixing method would be employed, such as magnet stir bars.
Because reaction products can be influenced by mixing intensity, a uniform mixing rate 2o ensures that any differences in products does not result from mixing variations. Thus, mixing balls are preferred with this invention.
Depending on the nature of the starting materials, types of reactions and method used to characterize reaction products and rates of reaction, it may be desirable to enclose either the entire system or reactor block 100 in a chamber 700, as shown in Figure 19.
The chamber 700 may be evacuated or filled with a suitable gas, such as an inert gas like nitrogen or argon. This chamber is most usefully a glove box (or dry box), such as those sold commercially by Vacuum Atmospheres, Inc. In some cases, the chamber 700 may 3o be used only during the loading of starting materials into the vessels 102 and/or barrels 202 to minimize contamination during sample preparation, for example, to prevent poisoning of oxygen sensitive catalysts. In other cases, the chamber 700 may be used during the reaction process or the characterization phase, providing a convenient method of removing one or mare fluids from all of the vessels 102 simultaneously. In this way, a gaseous reactant could be added to all of the vessels 102 at one time.
Another feature of Figure 19 that should be noted is the rotating plate 710 pivotally mounted on a support platform 720 and driven by a motor (not shown).
This is an alternative embodiment to the rocking plate that has been discussed throughout this specification. The embodiment shown in Figure 19 shows the rotating plate 710 with the entire reactor system and drive system attached. The rotating plate turns at a to predetermined rate to allow the mixing balls in the reactor vessels and/or header barrels to mix the contents thereof.
Typically, the reactants are liquids {but they may be one or more gases). When one or more of the contents of the reaction (such as the solvent, catalyst, monomer, scavenger, initiator, ete.) is a liquid, an automated liquid handling system may be 15 employed to handle the liquid. As illustrated in Figure 20, a robotic liquid handling system 800 is may be used to load vessels and barrels with starting materials.
The robotic system 800 includes a probe 801 that dispenses measured amounts of liquids into each of the vessels and/or barrels. The robotic system 800 manipulates the probe 801 using a 3-axis translation system 802. The probe 80I is connected to one or more 2o sources 803 of liquid reagents through flexible tubing 804. Pumps 805, which are located along the flexible tubing 804, are used to transfer liquid reagents from the sources 803 to the probe 801. Suitable pumps 805 include peristaltic pumps and syringe pumps. A mufti-port valve 806 located downstream of the pumps 805 selects which liquid reagent from the sources 803 is sent to the probe 801 for dispensing in the vessels 25 and/or barrels. Figure 20 shows a reactor block 100 in place for loading, but a series of vessels or barrels or a header block could also have been shown.
The rabotic liquid handling system 800 is controlled by a processor 807. in the embodiment shown in Figure 20, the user first supplies the processor 807 with operating parameters using a software interface. Typical operating parameters include the 3o coordinates of the vessels and the initial compositions of the reaction mixtures in individual vessels. The initial compositions can be specified as lists of liquid reagents from each of the sources 803, or as incremental additions of various liquid reagents SUBSTIME SHEEP (RULE 2~

relative to particular vessels. Similarly, the robotic handling system may dispense reactant into the header barrels. See U.S. Patent 5,104,621 and WO 98/40159 for robotic workstations.
The robotic handling system may be used in a methodology shown in Figure 21.
Looking first at Figure 21A, liquid reactants are added to both the reactor vessel 102 and the header barrel 202 (shown with the plunger tip 410). Figure 21 B is next where the plate 300 having transfer lines 302 with orifices 312 is attached to the header barrels 202 forming the header seal and the plunger 402 is optionally moved forward to expel gas to from the header barrel 202. Turning to figure 21 C, the header barrels 202 are inverted to connect the plate to the reactor vessels 102 forming the reactor seal. The reactants) in the header do not spill out because of surface tension given the size of the orifice 312.
This reactor system is then put into the drive system and then entire assembly is put onto a rocker platform 30, shown in Figure 21 D, that rocks back and forth over a pivot point 32.
Figure 22 shows another embodiment of this invention, which will build less pressure due to compression of the headspace during reaction. Shown there is a single reactor vessel 102 sealed to a plate 300 that contains the transfer line 302.
The header barrel 202 is also sealed to the plate 300. The header barrel 202 has a plunger 402 that 2o controls the volume of the header barrel 202 by moving forward and backward as controlled by a drive system 500. This is similar to that discussed above. In this embodiment, the reactor vessel 102 is a variable-volume reactor vessel, and can include a plunger 402' that controls the volume of the reactor vessel 102 by moving froward and backward as controlled by a reactor drive system 500'. The reactor drive system 500' for 2s the controllable, variable volume reaction vessels is similar to or identical to the header drive system 500, which has been discussed in detail. With both parts, one end of the plungers 402, 402' is attached to a plunger plate (not shown) that may be part of or separate from a carriage 506, 506'. The carriage 506, 506' is moved forward and back by a lead screw 518, 518', which is rotated by a motor 526, 526'. The header barrels 202 and 3o reactor vessels 102 are sealed at the plunger 402, 402' end by contact of the plunger tip 410, 410' to the inside of the bagel or vessel, respectively. The entire system is built on a support 550, including a support for the plate 300. With the reactor plungers 402', each plunger runs through a reactor vessel and has a tip 410' that forms a seal with the inside of the reactor vessel, such that when the reactor plunger 410' is moved backward the 5 volume of the reactor vessel is increased. When the reactor plunger is moved forward, the reactor vessel volume is decreased. The reactor plungers each have a top attached to another plunger plate that moves the plurality of reactor plungers simultaneously, as described above for the header plungers.
To operate the system in Figure 22, the liquids and gasses are added to the vessels t0 102 and barrels 202 along with mixing balls or other mixing parts (discussed above) either manually or in an automated fashion. The vessels and barrels are then sealed to the plate 300 and connected to the drive system 500, 500'. The entire system may then be placed on rocking plate or a rotating plate (such as shown in Figure 19) for mixing during reaction. The sum of reactor and header volume may be kept constant by moving the 15 reactor plunger 402' backward at the same speed that the header plunger 402 is moved forward. In an alternative methodology, this embodiment allows operation at constant available reactor volume by moving only the header plunger 402, as discussed above.
Although only a single reactor system is shown in Figure 22, there can be any number of matched vessels and headers such as discussed above for the constant volume 2o embodiment discussed above. There may be 6, 20, 48 or 96 or more reactor systems in reactor and header blocks, or modular as discussed above.
Another embodiment of this invention is shown in Figure 23, which shows the embodiment of a continuous reactor system. As shown in Figure 23, one side of the reactor vessel 102 is connected to the header barrel 202 via a transfer line 302. The 25 reactor vessel 102 is sealed to plate 300. This part of this embodiment works as described in detail above. In addition, a holding tank 150 (also called a storage tank) is connected to other end of the reactor vessel 102 via a second transfer line 152 that is contained in a second plate I 54. The various embodiments for the second transfer line and second plate can be any of those discussed above for the plate and transfer line(s).
30 Here, the reactor vessel is constant available volume, while both the header barrel 202 and the holding tank 150 are variable volume, with plungers 402, 402" driven by independent carriages 506, 506". The numbered parts are the same as discussed above SUBSTITUTE SNEEi' (RULE 2~

WO 00!32308 PCT/US99/28741 for similarly numbered parts. In operation, the contents of the header barrel 202 are pushed into the reactor vessel 102. Once a desired reaction time or other criteria has been met, some of the contents are pulled into the holding tank, which may be filled, with chemicals that quench the reaction. Thus, the residence time in the reaction vessel may be varied to suit a particular type of reaction. The sum of reactor, holding tank and header volume may be kept constant by moving the holding tank plunger 402"
backward at the same speed that the header barrel plunger 402 is moved forward. For a parallel system {not shown) a plurality of second transfer lines corresponding and seated to the plurality of reactor vessels is also corresponding and sealed to a plurality of holding 1o tanks. A second transfer means is provided associated the plurality of holding tanks and the second transfer means is adapted to remove at least some of the contents of the plurality of reactor vessels through the second transfer lines into the holding tanks. The second transfer means may be a pump and the second transfer lines may be tubing.
Preferably, the second transfer means comprises a plurality of plungers 402", with each plunger running through a holding tank and with each of plunger having a tip 410" that forms a seal with the inside of the holding tank, such that when the plunger is moved backward contents are removed from the reactor vessel through the second transfer line and into the holding tank. As with the header plungers, preferably each plunger has a tap that is attached to a second plunger plate, such that all plungers in the plurality move zo simultaneously when the plunger plate is moved. The second plunger plate is moved by the second drive system 500".
in other alternative embodiments, the reactor and header blocks may be split up into modules, each containing a certain number of wells and vessels for a given number of reactions. The use of modules offers several advantages over a monolithic block. For example, the size of the block can be easily adjusted depending an the number of reactants or the size of the combinatorial library. Also, relatively small modules are easier to handle, transport, and fabricate than a single, large block. A
damaged module can be quickly replaced by a spare module, which minimizes repair costs and downtime.
Finally, the use of modules improves control over reaction parameters. For instance, the 3o plunger plate of different modules may be driven forward at different rates or the temperature or pressure of each of the vessels can be varied between modules.
Multiple SUBS'~iNfE SHEET (RULE 2~

WD 00/32308 PCTlUS99/28741 header vessels may feed into each reactor vessel, and multiple holding vessels may remove contents from each reactor vessel.
The wells, reactor vessels, header barrels, storage tanks, etc. of this invention can be arranged and/or operated in a combinatorial fashion, that is, in rapid serial andlor 5 parallel fashion, e.g., in a library or array format. In a combinatorial array, each of the plurality of materials in the array of reactor vessels, header barrels, storage tanks, plungers, ete. can be the same or different in some manner from the others in the array.
Such differences in materials can be compositional (such as having a composition that is different) or quantitative (differences in amount of material) or can involve a processing l0 parameter (such as temperature, pressure, atmosphere composition, etc.) or other differences that those of skill in the art will recognize from a review of this specification.
Also, each member in the array is in a different reactor such that each reaction is isolated from the others.
The array or library format typically comprises at least 6 different reactions, e.g., 15 6 different compositions being reacted or 6 different processing conditions (such as temperature or pressure). In other embodiments, there are at least 25 reactions; in still other embodiments, there are at least 48 or 96 or 124 or more different reactions.
Because of the manner of forming combinatorial arrays, it may be that each compound, material or composition is not pure. Similarly, reaction conditions, processes, reactants, 2o catalysts or solvents can be varied in a known manner using one or more arrays of the present invention.
The ability to monitor and control the temperature of individual reactor vessels and/or individual header barrels an important aspect of the present invention.
During chemical reactions, temperature can have a profound effect on structure and properties of 25 reaction products. For example, in free radical emulsion polymerization, polymer structure and properties-molecular weight, particle size, glass transition--can be influenced by reaction temperature. During screening or characterization of combinatorial libraries, temperature control and monitoring of library members is often essential to making meaningful comparisons among members. Finally, temperature can 3o be used as a screening criteria or can be used to calculate useful process and product variables. For instance, catalysts of exothermic reactions can be ranked based on peak SUBSTIME SHEET' (RULE 2~

reaction temperature, and temperature measurements can be used to compute rates of reaction and conversion.
One embodiment of a temperature monitoring and control system, which includes temperature sensors that are in thermal contact with individual vessels 102.
Suitable 5 temperature sensors include jacketed or non-jacketed thermocouples (TC), resistance thermometric devices (RTD), and thermistors. The temperature sensors communicate with a temperature monitor, which converts signals received from the temperature sensors to a standard temperature scale. An oprional processor receives temperature data from the temperature monitor. The processor performs calculations on the data, which may include wall corrections and simple comparisons between different vessels 102, as well as controlling heaters in closed loop fashion. In the preferred embodiment, a dedicated temperature controller is provided, which communicates to an external computer. Thus, control functions and calculations may be performed in either place.
Depending on the application, each of the vessels and/or barrels can be 15 maintained at the same temperature or at different temperatures during an experiment.
For example, one may screen compounds for catalytic activity by first combining, in separate vessels, each of the compounds with common starting materials, and then reacting the mixtures at a uniform temperature. One may then further characterize a promising catalyst by combining it in numerous vessels with the same starting materials 2o used in the screening step. The mixtures are then reacted at different temperatures to gauge the influence of temperature on catalyst performance (speed, selectivity). In many instances, it may be necessary to change the temperature of the vessels during processing.
For example, one may decrease the temperature of a mixture undergoing a reversible exothermic reaction to maximize conversion. Or, during a characterization step, one may 25 ramp the temperature of a reaction product to detect phase transitions (melting range, glass transition temperature). Finally, one may maintain the reactor block at a constant temperature, while monitoring temperature changes in the vessels during reaction to obtain calorimetric data.
For clarity, we describe the temperature monitoring and control system with 3o reference to the monolithic reactor block i00 of Figure 1, but this disclosure applies equally well to the modular reactor block described previously. The temperature monitoring can be done at a convenient location in the reactor block and/or header block SUBS~1ME SHEET (RULE 2~

the temperature of both the reaction and the reactants) is important to both monitor and control. For example, each of the vessels 102 of the reactor block 100 shown in Figures 1 or 3 are equipped with a heating element (such as cartridge heater) that fits into a channel 120 in the reactor block 100. A similar channel 220 is in the header block 200.
In other embodiments, each vessel has its own heating element between the vessel 102 and the top of the spring pre-tensioners 106. In still other embodiments, a channel can run through the reactor block and/or header block that carries a heating fluid or cooling fluid, thereby heating or cooling the entire block to a desired temperature.
Use of the heating or cooling fluid embodiment with an individual heater for each vessel and/or 1o barrel provides complete control of temperature. Therefore the temperature of each reaction can range from about -100°C to about 300°C.
To complete the closed loop, temperature monitors are included to monitor the temperature of each vessel and/or barrel, so that the temperature of the vessels 102 or 1 s barrels 202 can be controlled independently. Other embodiments include placing the heating element and temperature sensor within the vessel or barrel, which results in more accurate temperature monitoring and control of the contents, and combining the temperature sensor and heating element in a single package. An example of a combined temperature sensor and heater is a thermistor, which can be used for both temperature 2o monitoring and control because its resistance depends on temperature.
Mixing variables such as the addition of mixing balls of various size with respect to the size of the reactor vessels and/or header barrels as well as the rate at which a rocker plate is rocked or a rotating plate is rotated or the composition or density of the 25 mixing balls may influence the course of a reaction and therefore affect the properties of the reaction products. For example, in connection with stirring bars, stirring blade torque, rotation rate, and geometry, may affect the reaction.
Many different types of reactions can be studied in parallel using the apparatus 3o and methods of this invention, including carbonylation, hydroformylation, WO 00!32308 PCT/US99/2$741 hydroxycarbonylation, hydrocarbonylation, hydroesterification, hydrogenation, transfer hydrogenation, hydrosilylation, hydroboration, hydroamination, epoxidation, aziridination, reductive amination, C-H activation, insertion, C-H activation-insertion, C-H activation-substitution, C-halogen activation, C-halogen activation-substitution, C-s halogen activation-insertion, cyclopropanation, alkene metathesis, alkyne metathesis and polymerization reactions of all sort, including alkene oligomerization, alkene polymerization, alkyne oligomerization, alkyne polymerization, co-polymerization, CO-alkene co-oligomerization, CO-alkene ca-polymerization, CO-alkyne co-oligomerization and CO-alkyne co-polymerization. One preferred reaction for study is polymerization, to including coordination polymerizations, cationic polymerizations and free radical polymerizations. Polymerization is a preferred reaction for study in this mechanism and apparatus because of the variety of methods by which a polymerization reaction can be carried out.
As evidenced by the variety of industrially important reactions that may be 15 performed the apparatus and method of this invention, using semi-continuous or continuous processes, where one or more reagents is metered into the process reactor at a controlled rate is important. Other processes are conducted in a continuous manner, where reagents are metered into the process reactor at a controlled rate, while products are simultaneously removed from the reactor. It is frequently important to screen 2o candidate catalysts, materials, and processes under realistic process conditions. Many catalytic reactions proceed most favorably when one or more reagents is maintained at a low concentration during the course of the reaction. Semi-continuous and continuous processes allow such conditions to be established, if the rate of reagent is consumed in the reactor at a rate comparable or faster than the rate at which it is introduced. Semi-25 continuous and continuous processes also allow for efficient use of industrial reactor capacity, since the final concentration of products can be much higher than the instantaneous concentration of starting materials during the course of the reaction. Also, semi-continuous and continuous processes are readily controlled, because the rate of heat release is limited by the rate of reagent addition to the reactor. Semi-continuous and 30 continuous processes can add the reagents more slowly than the rate of reaction, so that the instantaneous concentration of reagents is low throughout the process, but so that the concentration of product from the reactor is high. Reactions that benefit from this mode SUBSTITUTE SHEEF {RULE 2~j include cyclization reactions to form medium- and large-sized rings; reactions where one or more of the reagents is prone to unwanted self reaction or polymerization, and catalytic processes where one or more reagents acts as an inhibitor to the catalyst.
Furthermore, semi-continuous or continuous processes may allow for the production of more chemically uniform copolymers because the process can occur with a low concentration of monomer.
Emulsion polymerization processes produce polymer dispersions or colloids, typically of small polymer particles in water stabilized by surfactant. Such colloids are frequently unstable in the presence of organic solvents or molecules, such as monomers.
Semi-continuous and continuous process can produce emulsions with the slow addition of monomer, because the monomer concentration is maintained very low during the process. Also, semi-continuous and continuous processes allow unstable, highly reactive reagents, such as thermal initiators, to be metered throughout the course of the process, so that useful concentrations of the reagent is maintained until the reaction is complete.
15 The above description is intended to be illustrative and not restrictive.
Many embodiments as well as many applications will be apparent to those of skill in the art upon reading the above description. The scope of the invention should therefore be determined, not with reference to the above description, but should instead be determined with reference to the appended claims, along with the full scope of equivalents to which 20 such claims are entitled. The disclosures of all articles and references, including patent applications and publications, are incorporated by reference for all purposes.

SUBSTITUTE SHEET (RULE 2~

Claims (38)

WHAT IS CLAIMED IS:

1. A parallel semi-continuous or continuous reactor, comprising:
a reactor block (100) comprising a plurality of semi-continuous or continuous reactor vessels (102), at least two of the plurality of reactor vessels (102) containing a plurality of starting materials;
multiple header barrels (202), each of the multiple header barrels being in fluid communication with each of the plurality of reactor vessels during a reaction, the header barrels each containing one or more liquid reactants;
a plurality of transfer lines (302) providing fluid communication between each of the plurality of reactor vessels (102) and the multiple header barrels (202) associated therewith; and a transfer system for feeding the one or more reactants from the multiple header barrels (202) through the plurality of transfer lines (302) and into the plurality of reactor vessels (102) during the reaction.

2. The parallel reactor of claim 1 wherein the plurality of reaction vessels are arranged in a format with at least about 1 reactor per cm2.

3. The parallel reactor of claim 1 further comprising a header block comprising the multiple header barrels, a transfer plate between the reactor block and the header block, the transfer plate comprising the plurality of transfer lines, a reactor seal between the reactor block and the transfer plate for sealing the plurality of reactors, and a header seal between the header block and the transfer plate for sealing the multiple header barrels.

4. The parallel reactor of claim 1 wherein the transfer system comprises a plurality of plungers corresponding to the multiple header barrels, each of the plurality of plungers running through the corresponding header barrel and having a tip that forms a seal with the inside of the header barrel, such that forward movement of the plunger feeds reactant from the header barrel through the corresponding transfer line and into the corresponding reactor vessel.

5. The parallel reactor of claim 1 wherein each of the plurality of reactor vessels has a variable volume.

6. The parallel reactor of claim 1 wherein the volume of each of the plurality of reactor vessels is controllable.

7. The parallel reactor of claim 1, wherein the reactor vessels are removable reactor vessels, the reactor block further comprising a plurality of wells corresponding to the plurality of reactor vessels for receiving the removable reactor vessels.

8. The parallel reactor of claim 7 wherein each of the plurality of wells comprise a spring loaded bottom such that the plurality of removable reactor vessels contact the spring-loaded bottoms.

9. The parallel reactor of claim 1 wherein the transfer system comprises, for each of the multiple header barrels, a pump, a feed line providing fluid communication between the header barrel and the pump, and a transfer line providing selective fluid communication between the pump and each of the plurality of reactor vessels, the transfer line including a valve for serially directing flow into each of the plurality of reactor vessels during a reaction.

10. The parallel reactor of any one of claims 1 through 9 wherein said plurality of reactor vessels comprises at least 6 reactor vessels.

11. The parallel reactor of claim 1 wherein the plurality of reactor vessels comprises 96 reactor vessels arranged in a microtiter plate format.

12. The parallel reactor of claim 1 wherein the plurality of reactor vessels are different from each other with respect to the composition of the starting materials or the process parameters.

13. The parallel reactor of claim 8 further comprising a plate secured to the reactor block such that the plurality of removable reactor vessels are sealed, and a plurality of spring pre-tensioners corresponding to spring-loaded bottoms of the plurality of wells, each of the plurality of spring pre-tensioners being attached to a respective well bottom and moveably attached to the reactor block by a spring such that when the plurality of reactor vessels are sealed inside the wells by the plate, the reactor vessels are forced upward against the plate.

14. A method for effecting multiple continuous-feed reactions in parallel, the method comprising providing a parallel semi-continuous or continuous reactor, the reactor comprising (i) a reactor block (100) having a plurality of semi-continuous or continuous reactor vessels (102), and (ii) at least one header barrel (202) for containing one or more liquid reactants, and (iii) a plurality of transfer lines (302) providing fluid communication between each of the plurality of reactor vessels and the at least one header barrel (202), filling at least a portion of the plurality of reactor vessels (102) with starting materials, filling at least a portion of the at least one header barrel (202) with one or more liquid reactants, initiating a reaction in each of the plurality of reactor vessels (102), and feeding the plurality of reactor vessels (102) with one or more liquid reactants under reaction conditions.

15. The method of claim 14 wherein the one or more reactants are simultaneously fed into each of the plurality of reactor vessels.

16. The method of claim 14 wherein the one or more reactants are serially fed into each of the plurality of reactor vessels.

17. The method of any one of claims 14 through 16 further comprising mixing the contents of each of the plurality of reactor vessels during the feeding step.

18. The method of claim 17 wherein the mixing step comprises stirring the contents of each of the plurality of reactor vessels.

19. The method of any one of claims 14 through 18 further comprising varying the reaction conditions between at least two of the plurality of reactor vessels.

20. The method of claim 19 further comprising varying the temperature or pressure between at least two of the plurality of reactor vessels.

21. The method of claim 17 further comprising varying the mixing of the contents between at least two of the plurality of reactor vessels.

22. The method of any one of claims 14 through 18 further comprising varying the feed composition of one or more reactants between at least two of the plurality of reactor vessels.

23. The method of any one of claims 14 through 18 further comprising varying the feed rate of one or more reactants between each of the plurality of reactor vessels.

24. The method of any one of claims 14 through 18 wherein the reaction initiated in each of the plurality of reaction vessels is a polymerization reaction.

25. The method of claim 24 wherein the polymerization reaction is a free radical polymerization reaction, a cationic polymerization reaction or an emulsion polymerization reaction.

26. The method of claim 24 wherein the starting materials are selected from the group consisting of solvents, catalysts, monomers, comonomers, co-catalysts, initiators, co-initiators, scavengers and combinations thereof.

27. The method of claim 24 wherein the one or more liquid reactants are selected from the group consisting of solvents, monomers, comonomers, scavengers and combinations thereof.

28. The method of any one of claims 14 through 18 wherein the starting materials comprise one or more catalysts, co-catalysts or combinations thereof.

29. The method of claim 14 wherein the parallel reactor comprises a header block having a plurality of header barrels corresponding to said plurality of reactor vessels.

30. The method of claim 14 wherein the plurality of reactor vessels have a variable volume.

31. The method of claim 14 wherein the reactor vessels are removable reactor vessels, and the reactor block further comprises a plurality of wells sized to receive the removable reactor vessels.

32. The method of claim 14 wherein the reactor comprises at least six reactor vessels.

33. The method of claim 14 wherein the plurality of reactor vessels are a plurality of semi-continuos reactor vessels.

34. The method of claim 14 wherein the plurality of reactor vessels are a plurality of continuos reactor vessels, the method further comprising removing reaction product from the reactor vessels as feed components are fed to the reactors.

35. The method of claim 14 wherein the parallel reactor is the parallel reactor as set forth in any one of claims 1-13.

36. The method of claim 14, further comprising a method for effecting multiple continuos-feed reactions in parallel, the method comprising providing a parallel semi-continuos or continuous reactor, wherein the reactor further comprises (i) multiple header barrels for containing one or more liquid reactants, and (ii) a transfer system for feeding the one or more reactants from each of the multiple header barrels to each of the plurality of reactor vessels, the transfer system comprising, for each of the multiple header barrels:
a pump, a feed line providing fluid communication between the header barrel and the pump, and a transfer line providing selective fluid communication between the pump and each of the plurality of reactor vessels, the transfer line including a valve for serially directing flow into to each of the plurality of reactor vessels, filling at least a portion of each of the multiple header barrels with one or more liquid reactants, and feeding the one or more reactants from the multiple header barrels into the plurality of reactor vessels under reaction conditions, the reactants being fed from each header barrels through its associated feed line, pump, valve and transfer line.

37. The method of claim 14 further comprising providing a parallel semi-continuous or continuous reactor, the reactor comprising six or more semi-continuous or continuous reactor vessels, and at least one header barrel for containing one or more liquid reactants, the at least one header barrel being in fluid communication with each of the six or more reactor vessels, filling at least a portion of the six or more reactor vessels with starting materials, filling at least a portion of the at least one header barrel with one or more liquid reactants, initiating a reaction in each of the six or more reactor vessels to effect six or more parallel reactions, feeding the one or more reactants into each of the six or more reactor vessels under reaction conditions, and varying the reaction mixture compositions or reaction conditions between each of the six or more reactor vessels.

38. The parallel reactor of any one of claims 1 through 12, wherein the reactor vessels are sealed.