M. Legrand and A. Foucard Centre de Recherches Roussel Uclaf 93230 Romainville. France
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Automation on the Laboratory Bench
In designing an automation kit we attempted to give chemists a system which is versatile and easy to apply in taking over the boring and difficult task of controlling parameters manually.
Automation is already well-known to chemists hut so far it has mainly been applied a t the production stage in the factory. The principal improvements which it has brought about are 1)Increased security 2) Increased efficiency of operations 3) Less boring work
On the other hand, the use of automation in chemical research is much less freauent. the svstems available commercially usually being designed for onk specific purpose and only useful for repetitive work. For this reason, we have been developing for several years in our Research Centre a system in the form of a kit which the chemist can set up rapidly, with a minimum of material, to cover his needs.
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Description Automation involves the use of different sensors to evaluate the state of the system, actuators which modify the adjustable parameters (heating, cooling, speed of addition of reagents etc.), and an organ of decision which uses the information from the sensors to decide what action to take in order that the operations may continue according to the pre-arranged program. In a laboratory, the needs are usually simple and, in most cases, a regulation hy switching control will suffice.In this case it is possible to physically separate the sensor and the actuator parts and to obtain all the desired combinations. The most frequently used sensors measure the following parameters: temperature, pressure, levels of liquids, volume, weight, pH, and redox potential. The actuators which are linked to these sensors are capable of directing the following chemical onerations: heatine. coolina. and the introduction of solid, liquid, or gas reagents. someof these actuators are peculiar to our system, for instance the "thermovalet" (Fig. I),a pneumatic jack which can lift a heating or a cooling bath to regulate the temperature in the reaction vessel, the minipump (Fig. 2) used for transferring liquid reagents of a corrosive nature-bromine, ammonia, fuming nitric acid-and a system for introducing powders (Fig. 3). All these actuators are equipped with interfaces to link them to the rest of the system. They include a logical input
Figure 1. Thermovaiet
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Figure 2. Minipump and its electronic control device.
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Figure 3. Powder distributor and its electronic control device.
Volume 55,Number 1 2 December 1978 1 767
Figure 5. pH cantrol kit-pH meter. its threshold comparator, and minipump of introduction. Figure 4. Logical correlator.
command activated by external switches. For the sensors, some, such as contact thermometers, for instance, already have the decision organ and can therefore be linked directly to the actuator. Others of a more sophisticated nature need a specialized interface; such is the case for analogic sensors of temperature, pH, pressure, and flow. For these, the measured value is compared to a threshold value by an interface in which a switch position is decided according to the results of the comparison. For simple regulation loops containing only one sensor and one actuator, a direct link is made between the sensor, interface, and actuator. In more complex cases, where information from several sensors is combined and controls several actuators, a supplementary element, called a "correlator" (Fig. 4), is inserted between the sensors and actuators. By these means, using a group of logical functions AND, OR, and INVERSION, complex combinations may be carried out following the rules of Boole algebra. As described above, the system is suitable for the regulation of a given step in a chemical preparation. With the addition of a chronometer, a series of consecutive operations may be carried out, thus extending the possibilities of the system. Applications Among many applications which have been carried out with our kits, we have selected four of them illustrating several possibilities of the system. Time Saving In peptide synthesis, amino groups of amino acids (I) must always be blocked. Schnabel's method1 using t-Bu azido formate (11) is often used. This reaction is easy to carry out, a t
Figure 6. A simple pH control loop.
T h e assembly is straightforward and is illustrated in Figure 6. The threshold is adjusted a t the optimal value a t the comparator and as soon as the pH falls below this value, the pump introduces the necessary quantity of NaOH. The quality of the regulation can he verified by linking a recorder to the comparator. In this particular case, the saving is about twothirds of the time necessary when the reaction is carried out manually (namely the ratio of the work-time of the chemist over 24 hr). All reactions which are slow and demand the adjustment of a parameter by the introduction of a reagent can be treated in the same way. Optimization The preparation of di(bxrhethoxyethy1)-benzylamine(VI) from ethyl-P-bromopropionate (V) and henzylamine (IV) following general procedure2 (i.e. contact in presence of Ag20)
least theoreticklly, hut it is very sensitive to pH. A too high pH severely decreases the yield, a too low one slows down the reaction. It is necessary to adjust the pH manually but, as for certain aminoacids. such as L-leucine for instance, the reaction lasts more than 70 hr; it has to he stopped during the night. This not only considerably incr~asesthe time o f t h r reaction hut the freq;ent start-stips do not improve the yield. For solving this problem, the chemist has a t his disposal, apart from a conventional pH probe and a pH meter, a threshold comparator and a pump with its interface (Fig. 5). 768 / Journal of Chemical Eduoltion
'Schnabel, E., Liebigs Ann. Chem., 702,188 (1967). 2Tha~er,J. R., McElvain, S. M., J. Am. Chem. Soe., 49, 2862 (1921).
second controls the introduction of TEA as a function of pH. Several measurements are necessary: internal temperature of the reaction vessel, pH, and weight of TEA consumed. All this information is recorded. As the svstem has to be onerated a t night. - . without sunervision, a control of water supply for the condenser has been added and its logical information (one if the water is running, zero if not) is combined with the logical signal from the contact thermometer in the logical unit. This unit allows the heating only if the hath temperature is below the given threshold and the condenser is operating. As a matter of fact, from the first run a quantitative yield was reached and the optimization essentially concerned the choice of the DH for the shortest reaction time compatible with quantitative yield. Figure 8 gives the consumption of TEA versus time a t pH 6.5, as measured with the recording scale (Extension-gauge sensor). From this measurement, the time needed to reach the end of the reaction is easv to determine. Fieure 9 shows the relationship between time of reaction and ;H. In this exam~le.both control and recordine are imnortant. Control allows'so~eof the parameters to hekept constant; measurement and recording of the variable parameters give the information necessary for optimization.
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Figure 7. pH control with recording of different parameters.
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Nitration of 3-methoxv-4-acetoxv henzaldehvde (VII) with , highly concentrated nitric acid is very exothermic and dangerous to carry out on a fairly large quantity of reagenk3 T o NO1 cw30 CH3CO0
Figure 8. Consumption of TEA versus time at pH 6.5.
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Figure 9. Relationship between reaction time and pH.
leads to a mixture of nrimarv and secondarv amine and the yield is not very high. 'After &me trials, chemists reached the conclusion that a base such a s triethvlamine (TEA) should be used but it must be introduced under pH control. As a matter of fact, as in the preceding case too high a pH destroys the hromiuated reagent, too low a pH increases the reaction time. Figure 7 shows the combination used. Here, two loops are used: one controls the temperature of the reaction hath, the
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minimize the hazard of such a reaction running out of control, chemical apparatus is set up inside a hood. With conventional design, the protection is frequently illusory because the chemist has to manipulate inside the hood to control the introduction of HNOs and the temperature of the reaction mixture. Our kit gives a good solution to this problem (Figs. 10 and 11.)First of all. a cooline bath of eood size containine Drv Ice in a chlorinated solveniis put o n i h e thermovalet, t i e aEtion of which is controlled by the temperature inside the reaction vessel. When the temperature goes above the threshold, the cooling hath is automatically brought into contact with the vessel. As the reaction is carried out a t about 0°C and the cooling hath is a t -80°C, the coolina Dower is high and can prevent any bursting of the reaction.'~oreover, tKe response is short, much less than 1s, after the rise of temperature over the threshold has been detected. With this procedure the temperature control is only approximate, hut this is unimportant as nitrations are fairly insensitive to the temperature as far as yield is concerned. Secondlv. " . HNO.\ is automaticallv introduced under the control of the temperature of the reaction mixture and conseauentlv the chemist no loneer - needs to manioulate inside the hood. Thirdly, . only . sensors and actuators are inside the hood with the chemical apparatus. Interfaces and measurement devices are outside, particularly the temperature control system. Thus, the system can easily he supervised from outside, the more so as the size of the figures on the thermometer interface are enlarged. Three interesting features of our kit can he emphasized here 1)
Wiring and logic inputs being standard, two actuators, namely the valet and the pump, can be connected to the same sensor, here the thermometer and its interface.
:'Dub&J., private communication. Volume 55, Number 12. December 1978 1 769
Figwe 10.A
nitration in the hwd
Figure 12. System for controlled reduction by N
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is variable when this reaction is manuallv controlled. On the average, 85% can be experred. With automarion, quanritatiw vicld is r e r ~ ~ l a robtained. lv Firun* 12 shows tlw setrinr ur, uf the apparatus with our kit. ~ 6 controls e can be brokendown in the following ways if if if
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Figure 11. Control of an exothermic reaction.
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hut if 2) The temperature control system accommodates two thresholds in such a way that two logical outputs are available. In the last example described, the threshold for temperature regulation is set at O"C, hut the one far HN03 introduction at P C . This procedure takes advantage of the high cooling power of the bath and appreciably shortens the reaction time. 3) In case of power failure,the valet has a pneumatic memory, and goes to a preselected position (up in our case). This very simple setting allows the processing of several hundred grams of substance practically without supervision. More Sophisticated Combinations The reduction of the dihydroisoquinolines (1x1 by sodium borohydride is not an easy reaction to carry ouL4 NaBH4 has
pH b pH Q 7.5 Q T> T>
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7.5 pH 6 8 18°C 20°C
if foamsdevelop
introduction of NaBH4 is stopped introduction of HCI is stopped both reagents are introduced cooling of the system introduction of both reagents is stopped on any conditions of pH introduction of both reagents is stopped whatever the pH may be (foamsare easily detected as they are of low electrical resistivity)
As several sensors are combined for controlling several octuarurs. rhc wirinr!is nor srrairhtforuard. Simnlitled Hoolenn algebra is very useful in such a case but its application cannot he detailed here. Let us give the result
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The comparators and contacts in our example are set in such a way as
to he diluted in NaOH solution hut the starting material is sensitive to alkaline conditions which lead to ring opening. The mixture therefore has to he neutralized by the introduction of acid. Below pH 7, however, NaBH4 is decomposed. The reaction is exothermic moreover and foams are frequently developed. It is therefore not surprising that the yield obtained 770 1 Journal of Chemical Education
T pH pH' F pH
= 1 = 1 = 1 = 1
if temperature higher than 20°C if the pH of the medium 5.7.5 if the pH of the medium b8 if foams are present means inverse of pH, pH = 1when pH 67.5
ATeitcl, S., and Brossi, A., J. Heterocycl. Chem., 5,825 (1968).
C o n s e q u e n t l ~ i n t r ~ d u c t i oofn HC1 in the medium is stoppedwhen PUMP = 1 (i.e. PUMP = O), which implies T = 1or pH = 1or F = 1(i.e. T 3 20°C, pH < 7.5, and presence of foam). I n s i m i l a r way, the introduction of NaBH4 is stopped (PUMP = 1)if T = 1or pH' = 1or F = 1(i.e. T 3 20°C, pH 3 8, and presence of foam). For facilitating interconnection, use is made of the correlator (see Fig. 41, which materializes the Boolean operations AND, OR, and INVERSE. The lower part of Figure 12 shows the wiring which corresponds to the Boolean expression. This wiring is very easily carried out by chemists by plugging in wires in the right plugs of the correlator. Conclusions
The principal aim in the designing of our kit for automation has been to give chemists a system which is versatile and easy to apply for taking over the boring and difficult task of controlling parameters manually. As borne out by the examples cited, this aim has been fulfilled thanks to solid-state electronics which allow reliable devices capable of standing up to the drastic conditions met a t the chemical bench. A less predictable effect, however, has been observed on the behavior of the chemist. Except for a few exceptions not mentioned in this paper, our system is chiefly a more or less sophisticated combination of control loops. This implies the choice of the right parameters: T, pH, redox potential, optical density, etc. for controlling the actuators. Consequently, a
chemist having the means of action a t his disposal, is led to study more thoroughly the mechanism of the reaction in order to select the right parameters and, as a corollary, to measure them. Considering the medium in which the measurements are carried out, it is certain that the data obtained have little thermodynamical significance; but from the point of view of automation, they are in many cases sufficiently reproducible for allowing the control of the reaction. In the past, temperature was practically the only measurement at the bench, at least in organic chemistry and, time, the main controlling parameter. Now it is characteristic to see several small recorders around the chemical apparatus, as well as different probes immersed in the reaction vessel; and in the procedure reports, sentences of the type "the reagent is introduced over two hours" are often replaced by sentences such as "the reagent is introduced in such a way that pH remains hetween 7.5 and 8" for instance, with frequently an increase in yield and a shorter reaction time. To lead to a better understanding of the reactions is certainly not a negligible merit of automation on the bench. Acknowledgment
The authors thank M. Dupuy, P. Meunier, E. Godbille, and E. Scohy for their help in the design and the realization of the different parts of the kit as well as J. Prost-Marechal and J. Dub6 who performed the experiments described in this paper and contributed by their suggestions to the improvements of our automation system.
Volume 55. Number 12, December 1978 / 771
