Arthur A. Sunier
Judson College Elgin, Illinois 60120
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The Phenomenon of Synergism in the Field of Chemistry
The word synergism is derived from the Greek: syn = with, together, and ergo = work. It has been used in classical Greek as early as 415 B.C. Over the centuries it has been used in theological discussions, in materia medica and pharmacology, but apparently it has not been used in the realm of chemistry until about fifteen years ago. It will be the object of this paper to show that the phenomenon of synergism has been known and used in t,he field of chemistry for centuries (hut that it has not been recognized thus) and that it is a very common phenomenon and will probably be recognized and so treated much more frequently in the future. The more usual definition of the word runs somewhat as follolr-s: t,he phenomenon of synergism is displayed when two (or more) agents a h e n used together produce an effect greater than the algebraic sum of the effects when the agents are used singly. I n the early classical Greclc literat,ure the word xvas also used if the effect produced \!-as bad or evil, so for present purposes it seems appropriate to speak of a posit,ive synergistic effect and a negative synergistic effcct corresponding to these two cases and also to speak of no synergistic effectif the algebraic sum of t,he effect.^ when the agents \yere used singly was realized \ h e n the agents were used together. I t will be well to explain the terms "effect" and "agent" in the definition given above. First as to "effect," this may be either physical or chemical in nat,ure; for the former there would be included: pressure, temperature, color, intensity of light emitted, conductivit,y, frcezing point, boiling point,, osmotic pressure, refractive index, evolution or absorption of heat, etc.; for chemical effects some transformation of matter should rcsult. I n many cases both types of effects could be noted simultaneously. Further the effects could be noted under equilibrium conditions or under non-equilibrium conditions. As to t,he word "agent" they could both he chemical in nature or both he physical in nature or one agent could be in each class. One more variable may be mentioned: for agents of a chemical nature the concentration of the agent will generally be important while for agents of a physical nature t,he intensit,y of the agent and the length of time involved =.ill generally be of importance. Examples illustrating some of these classes will now be given. G e n e m l Examples
The first. example vill be that of mixtures of hydrochloric and nitric acids and t>heireffect on gold. This appears to be the oldest case known where the agents and effects are all chemical. Hundreds of years ago it was found that neither acid attacked gold but certain mixtures dissolved gold quite readily; these mixtures
were called aqua regia (royal water). The variable of concentration is fairly important in t,his case; most old recipes give a volume ratio of HC1 to HK03 of 1: 3 when concentrated acids are used. I t is very probable that heat is also generat,ed in this case; if so this example would fall in the class of combined physical and chemical effects. Also the rate of the dissolution process is usually the important consideration rather than conditions existing when equilibrium is attained. It should be emphasized that this is a rather unusual case in that neither agent vhen used singley produces any effect. In the realm of living matter, in recent years, it has been found that Freons and certain insecticides when used singly producc no undesirable effects on the organism but if used together cancerous tissue is produced; this has led t,he discoverer to organize the Environmental Mutagens Society (1). For the class involving a physical effcct., one may take the case of 1 mole of gaseous substance A producing a pressure of 1 atm in a certain vessel and 1 mole of B alone in the same vessel producing the same pressure but if both are introduced the resulting pressure would experimentally be 2.2 atm or a positive synergistic effcct. Many such cases are lcnolvn ~vherethere is a negative synergistic effect and others \vhere there is no synergistic effect. For the case of t,mo physical agents yielding a chemical effect the Haber process for synt,hesizing ammonia may be cited. At 100 atm and 300°C a 3 : l HZ-N\TZ mixture held till equilibrium is attained gives a yield of 52 volume Yo of ammonia. If the temperature is held constant and the pressure is changed t,o 300 at,m the yield of ammonia becomes 71%, ~vhilefor the case of constant pressure of 100 atm and a tempcraturc change to 400°C the percentage of ammonia is 2.5P/,. Now if both temperature and pressure are changed the yield of ammonia is found to be 47% or a negative synergistic effect is noted. In this example the rate of reaction is very much faster at 400' than 300°C so the equilibrium conditions alone are considered among the effects (g). I n the present case the degree of synergism can be calculated with the help of thermodynamics. An example may be given v.here both agents are chcmicals and three effects are noted-one chemical and two physical. Flash light bulbs usually contain magnesium in the form of t,hin foil (exposing much surface) and oxygen. When brought to a certain temperature oxidation rapidly takes place forming magnesium oxide, and heat and light are both given off. The above examples should be sufficient to encourage the reader to supply many other examples for the classes mentioned and for the numerous other classes delineated above. It will he well to note that agent A may proVolume 49, Number 12, December 1972
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duce a positive effect of say three arbitrary units while B may produce a negative effect of three arbitrary units when used singly; when used together three effects are possible: for any values greater than zero there would be a positive synergistic effect, for values smaller than zero a negative synergistic effect, and finally for the value of zero no synergistic effect would be involved. The term "algebraic sum" in t,he original definition thus opens up many more possibilities. Detailed Discussion of One Specific Example
The well-known esterificatiou reaction will serve admirably to illustrate how synergistic effects are related to the Law of Mass Action enunciated over one hundred years ago by Guldberg and Waage. For the reaction: ethyl alcohol acetic acid = ethyl acetate water let A,B,C,D, stand for the chemical substances from left to right. At room temperature K = ([C] [D])/([A][B]) = 4.0 where numbers in brackets are moles per liter. Calculations a t the start will be simpler if we assume a value for K of unity. It should be obvious that if a liter vessel contained 1' mole of each of the substances the system would be at equilibrium. If now to this system 1 mole of A is added the reaction will proceed to the right until the moles of each will be 1.8, 0.8, 1.2, 1.2, respectively; therefore 0.2moles of C (the wanted substance) have been produced. The same effect would be noted if 1 mole of B had been added in place of A. If now 1 mole of each (A and B) are added the reaction proceeds to the right until the moles of each are 1.5, 1.5, 1.5, 1.5 or 0.5 of C is produced, which when compared to 0.2 0.2 = 0.4 displays a positive synergistic effect. If a new set of equilibrium conditions are set up, for instance: 0.5, 2.0, 1.0, 1.0 and 1 mole of A and 1 mole of B are added singly and then together, the moles of C obtained are, respectively, 0.36, 0.095 and 0.54 showing a positive synergistic effect somewhat greater t,han the last case. With still another equilibrium mixture: 0.1, 10.0, 1.0, 1.0 the corresponding yields of C are: 0.77, 0.01, 0.79. There is a positive synergistic effect but i t is the smallest of the threevalues. Since all of these calculations are made with an equationasfollows: ([C x] [D x])/([A - x] [B -XI) = 1.0 it should be evident that the value of the synergistic effect will depend on the specific values of A, B, C, and D and also on the value of K. This statement should be borne in mind when some other type of reaction than a double decomposition is being considered; for instance the Haber process referred to above: Nz 3H2 = 2NH3. If E, F, and G stand for the moles of the substances from left to right and x stands for the moles of PITHI produced whcn the system comes to equilibriumtherelevant equationis: [G 2xI2/([E-XI [F - 3xI3) = K. I t should be obvious that theresultsof changes similar to those discussed above udl be very different, thus a high degree of specificity will exist amongst the different typcs of reactions.
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Underlying Causes of Synergism
When considering various phenomena in chemistry it has become common practice to speak of "ideal" systems; these can be composed of one or more substances. The ideal or perfect gas law is one most 806
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Journal o f Chemical Education
freshman students encounter. Before long the student must face the fact that no known gas or mixture of gases at all temperatures and pressures conforms to this law; furthermore some gases display a positive deviation, others a negative deviation and a feu- display both deviations under varying pressures. Early work in this area was limited to accumulating much data and developing equations which would enable the scientist to interpolate or even extrapolate more precisely than was possible without the equation. But as more light seemed to be shed on the structure of atoms and molecules scientists felt the time was ripe to seek to explain why the different gases behaved as they did. In recent years definite progress has been made when the properties of electrons and nuclei are considered along with the nelrer quantum mechanics. In the area of mixtures of liquids much the same state of affairs has existed, centering about Raoult's Law; a mixture of liquids which yields a vapor pressure conforming to the lav is said to be ideal and thus no synergistic effect is involved. The facts are that relatively few mixtures are known which conform to the law even throughout a small range of temperature and t,hat hundreds of pairs are knoll-n vhich display either a positive or negative synergistic effect and within the past few years one pair has been discovered which displays a positive effect over one range of concentration and a negative effect over another range of concentration and at one specific concentration no synergistic effect is noted, all at constant temperature. In the realm of electrolytes or ionized solubions the difficulties become much greater but through the work of Debye and Huckel and also Lewis and Randall a fair foundation has been laid, but new concepts and terms such as ionic activities, ionic strength, etc., have been necessary to cope with the situation, at times only empirical. The conviction appears strong, vith deep thinkers in this area, that a molecule or ion behaves differently when in close proximity to other molecules or ions even if they are exactly similar to themselves, than when it is alone. The degree to which it behaves differently will depend upon its own ultimate structure and that of its neighbors, as well as upon temperature, and pressure, electromagnetic radiation, concentration, etc. It is then to be expected that in the future many more cases of synergism uill be discovered compared t,o cases where no synergistic effects are noted. A word may be allowed on the probable importance of the above considerations in the realm of ecology and the environment. Since it is now nearly universally believed that there is a molecular basis for nearly every phenomenon in the biological area it is only a step to the view that the phenomenon of synergism in ecology and the environment in general has a molecular basis as developed in the last few paragraphs. Scientists should in one sense suspect every grouping of molecules or ions to have some effect upon one another and the system in which they are found unless it is proven to the contrary or proven that such effect as exists will not be deleterious to any organism present. Several of the few papers in the area of chemistry which make a point of synergistic effects are given in the list (3-6).
The mechanisms by which synergistic effects are produced are a part of any comprehensive s h d y of the phenomenon but thus far a great lack exists on this score. For present purposes one easily accessible reference (7) to the case of aqua regia will suffice. Grateful acknowledgment is here made of the facilit,ies of Dartmouth College Library placed at the disposal of the author. Literature Cited (1) Enuiron. Sci. Tsehnol., 3, 105 (1969). ( 2 ) YOST,D.
a., AND
RUSSELL. H. JR., .'Systematic Inorganic chemistry
of the Fifth-and-Sixth Group Nonmetallie ~ i e ~ e ~ pt r~e n. t"i c p ~ d l . Ino., New York. 1944, p. 74. A more hooeaible but less extensive and precise table ia found in: MASTERTON. W . L., A N D SLOWINSKI. E. 1969, J.. P. "Chemical 386. Principles." W. B. Saunders s n d CO., philadelphia.
Jn., Bm8. C. F. Jr.. COLEYAN, C. F., BROWN,K. B.. AND WXLTE.J. C., "Proceedings of the Second United Nations International Conference on the Peaceful Uses of Atomio Energy." Geneva, United Nations, 1958, VOI. 28, pp. 280-298. (4) BROWN.K. 8 . . COLEMAN, C. F.. CROUSE. D. J.. BLAKE.C . A,, A N D Rroli. A. D.. ibid.. Vol. 3, pp. 472487. (5) RAHAMAN, ~ d STGDOR. . A N D F ~ N B T O H. N . L.. A ~ ~ cham., I . 40, 1709 (3) B L AC.~A.
(1968). (6) GRIENIE, RONALD A., A N D MARE, HARRY B. ~ a . ~, ~ - chern., 1 . 38, 1001 (1966). (7) "Encyclopedia Britannioa." Encyclopedia Britanniea Ino.. Chicago 1969, Vol. 14, p. 444.
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