RUTHERFORD A R E

This paper conducts a tour through a maze that links the divergent fields of kinetics and mathematics

Mathematical Aspects of CHEMICAL REACTION

t might be useful to introduce the term formal chemkinetics to denote that segment of natural philosophy that concerns itself with those aspects of chemical kinetics which are independent of the specific nature of the substances taking part in a reaction. T o do so is not an attempt to canonize the notorious A+B or the ubiquitous Z a Z j A , = 0, but is a recognition that the fundamental principles will become much clearer and important distinctions can be sharpened, when the subject is treated more abstractly. Such an abstraction has proved its worth repeatedly in diverse branches of science, as, for example, when the distinction among kinematical notions, dynamical laws, and constitutive relations allows the structure of fluid mechanics to be perceived. In an introduction to a recent ACS symposium of the above title ( I ) , I used Kuhns term paradigm ( 2 ) . This has been questioned (3) on the grounds that the subject has not yet assumed that framework of accepted ideas which a t once commands the attention of a sufficient number of workers and is sufficiently openended to leave them a number of problems to resolve. That there are quite a few people working in this area was clear from the interest in the symposium, and that there are any number of interesting problems to be solved has never been in doubt, but the relationship among the various ideas is well worth inquiring into, for what emerged at that meeting was an impression of the intricate web of cross-connections among the ideas of various scholars pursuing their studies quite independently. This essay is not a comprehensive review of the kind that this journal so usefully provides on various chemical engineering topics, though it will attempt to direct attention to as many references as possible. Nor is it a report on the symposium held a t the Illinois Institute of Technology, though it will refer to the papers given there, but it will be convenient to substantiate the claim

I ical

that there is a fabric of interconnections by attempting to chart those papers (4-16) in the following diagram. Such a diagram can only roughly indicate the relationships that we are trying to discern for these are naturally more subtle and tenuous than a block diagram. To take an illustration, the concept of reaction mechanism and the associated notion of the pseudo-steady state is a pervasive one. Sellers combinatorial approach

Figure 1. Some interconnectiom among the papers of the 35th ACS December Symposium
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(6, 78) provides a way of relating the mechanism to the overall reaction and of describing the complete set of independent mechanisms. I t is algebraic and does not take directly into account the analytical aspects that come in when the stoichiometry or kinematics of a reaction system is invested with kinetic laws or a dynamics. The motivation behind the analysis of lumping by Wei and Kuo (77, 79, 79a) is similar to that of the kineticist in respect of the desirability of simplification of complex systems, and it clearly has a bearing on the notion of mechanism. Their interest, however, was first to discover the conditions under which a lumped system would remain monomolecular, whereas a reaction mechanism is almost always an example of what they would term improper lumping-z.e., it leads to a totally different kinetic expression. Zimmermans presentation of the kinetics of replicating macromolecules (72, 20,27) paid some attention to the mechanism though it was primarily concerned with a very beautiful analysis involving stochastic and combinatorial ideas and the solution of the differential equations, as was Gavalas example of an autocatalytic reaction (9) though it principally featured the elegant methods of nonlinear differential operators. Similarly, Bartholomays valuable exposition of stochastic formulations of kinetics ( 4 ) )necessarily made passing reference to mechanism though it has had his more direct attention elsewhere (22). I t was in Silvestons (75) and Higgins (76) works that the whole question of the pseudo-steadystate hypothesis was raised most directly. I n the first case by direct calculations intended to check out some criteria proposed for its validity; in the second, by showing the degree to which assumption would break down under certain frequencies of perturbation. Again, Higgins paper was related to the notion of lumping, and an extremely complex biological pathway was broken down into a smaller number of lumped steps. The notion of a reaction mechanism could scarcely fail to have a prominent role to play in any discussion of chemical reaction, but to illustrate the role of a less obvious concept we may turn to that of fading memory. In the mechanics of materials, it is now commonplace to recognize that the present state of stress can be a functional of the whole past history of strain. The mixtures considered by Bowen (5) [extending his earlier work (23)]and by Coleman (8, 24) are of materials with this memory. But Othmer and Scriven (73), in discussing the interaction of diffusion and reaction in surfaces, pointed out that at the limits of their analysis a hereditary or memory effect could not be ignored. Halsey (25) has used the phrase short term memory to describe nonequilibrium adsorption in catalysis, and it has been shown (26) that the same assumptions that justify the pseudo-steady-state hypothesis will obliviate the memory in a reaction rate functional. Here again is a link back to the notion of mechanism. With these indications of the intricate weave that we must expect to see in the fabric of formal chemical kinetics, let us attempt to sketch a more systematic cartoon.
18
INDUSTRIAL AND E N G I N E E R I N G CHEMISTRY

Axiornatics

Risible though it might appear to the experimental chemist, a strictly deductive theory of chemical kinetics is a worthy goal. Bunge has outlined this program for various branches of physics (27), and Basri has actually carried it out in detail for the fundamentally important theory of space and time (28). IVe are still a good deal farther away from this goal in chemical subjects than in physical, for chemistry has, on the whole, been much more resistant than physics to the incursions of the philosophy of science. The only attempt at axiomatization of kinetics is that of Wei (29), who presents the following simple and attractive set for a closed reaction system: 1. The total mass of the mixture is conserved 2. The masses of each species are never negative 3. T h e rates of change of each mass are smooth functions of the masses 4. The principle of microscopic reversibility obtains 5. There exists an appropriate Liapunov function assuring the stability of a unique equilibrium point I t may well be true that Tot homines, quot propositiones per se notae, et de gustibus non est disputandum, but it is interesting to inquire how primitive and complete this set may be. Thus, if we accept the continuum equations of continuity of distinguishable species we can replace item 1 above by two propositions which might be taken to be axiomatic : l a . Every property of the mean motion of a mixture is a mathematical consequence of the properties of the motions of its constituents l b . If all effects of diffusion are taken into account properly, the equations for the mean motion are the same as those governing the motion of a simple medium From these two postulates it follows as a theorem that if the mean motion of a heterogeneous medium is to satisfy the ordinary equation of continuity, then it is necessary and sufficient that the sum of the rates of change of the masses of the several components should be zero a t each point [cf. Truesdell (30)]. Thus, two propositions can be made to yield Weis first axiom as a theorem, though whether they are more reasonably per se notae, as the Doctor Communis would have put it, is open to discussion. O n the other hand, if we start with a proposition of structure, that the molecular species may be uniquely defined in terms of constituent atomic species, we may add a conservation law, that
AUTHOR Rutherford Aris is Professor of Chemical Engineer-

ing at the University of Minnesota, Minneapolis, Minn. 55455.

The author is indebted to Octave Levenspiel and Dan Luss for raising several points of interest in correspondence. In particular, the former points out that the term formal kinetics (la cinitique formelle) was used b y Jungers to denote the area of the dzferential equations of kinetics and determination of rate constants and mechanisms. Since writing this paper the author has also seen a manuscript b y F. J . Krambeck on The Structure of Chemical Kinetics which develops an axiomatic treatment of kinetics paying particular attention to the thermodynamic basis,

the masses of the latter are all constant and obtain the equivalent of Weis first two axioms. Then Bowen has shown that in the absence of diffusion, or in a closed, uniform system, the changes in composition can be uniquely expressed in terms of a fixed number of independent reactions (31, Theorem 6). We can then impose Weis third axiom on the reaction rate expressions and, because the reactions are independent, the principle of microscopic reversibility emerges as a theorem. Wei shows that the existence of an equilibrium point is a consequence of his first three axioms and the fixed point theorem of Brouwer, but this does not ensure its uniqueness or stability. Likewise the principle of microscopic reversibility only ensures an ultimately monotonic approach to equilibrium by guaranteeing the symmetrizability of the local linearization (32). Weis fifth axiom is therefore necessary if the commonly observed uniqueness of equilibrium is to be reproduced in the mathematical system. This uniqueness is a feature of statically thermodynamic conditions (33) and so can be claimed for all mass-action kinetic expressions which are consistent with equilibrium (34, 35). This brief discussion does not exhaust the question of axiometic foundations but is intended to show that further work is needed along these lines. We shall allude to that question again in connection with Bartholomays stochastic formulation and very briefly in the next section. As indicated above, it needs to be related to the whole business of constructing deductive theories (cf. 27, 36-40) in the context of the physical and chemical sciences, but this is a large matter.
Structure

matrix of the products of the reaction (in fact, the steps of such a reaction can be written down as a sequence of such matrices), but this does not appear to be fruitful. An approach more directly related to truly topological notions is that of Lederberg (45-47). This has involved the classification of regular trivalent graphs (since the diagram of the organic molecule rarely has more than three branches at any one node) and the association of these with certain polyhedra. Nothing has been done to connect this theory with a representation of reaction. Topological notions have been introduced to elucidate complex molecular structures by Wasserman (48). Sellers treatment of chemical complexes is capable of sustaining a representation of structure (18)) but little of the detail has been worked out.
Combinatorial Problems

The work of Sellers (6, 17, 78) represents a remarkable synthesis of combinatorial topology and chemistry, and its articulation should give lead to great advances in the art of discovering and proving the mechanism of a reaction. Though there is a need to soften the forbidding aspect that his principal account (78) may have for the

The mathematical representation of molecular structure is not our main concern here; but since it has a bearing on reaction we can scarcely avoid some mention of it, even though this connection has been little developed. J. J. Mulckhuyse has an axiomatic treatment of structure in organic chemistry (41)) but this does not seem to have been followed up. Spialter has devised a computer-oriented chemical nomenclature in which the names of the atoms are literal entries A , on the diagonal of a matrix, and the numerical off-diagonal elements b,, denote the number of bonds between A i and A , (4244). Since such a representation should be invariant with respect to permutations of rows and columns, Spialter suggest that the characteristic polynomial is a good representation. The difficulty here is that if there are two atoms of the same chemical element in the molecule and if they are not literally distinguished, then the matrix often cannot be uniquely reconstructed from its polynomial. O n the other hand, if every atom is distinguished only the three highest powers of the polynomial are needed. Moreover this representation does not seem to lend itself to the discussion of a reaction. It is true that a mixture of molecules can be represented by a partitioned matrix. If a matrix of the reactants is written down, a bond-breaking and -making matrix can be added to it, which will give the

Figure 2. Model of enzyme-catalyzed synthesis

nonmathematician, a brief summary of the representation of a reaction and its mechanism may be useful. Consider an enzyme-catalyzed synthesis of two substances, R and S, to form a product, P. If this is a balanced reaction the empirical formula for P must in fact be the sum of those for R and S and we might write P SOIR, when 0 1 represents a bond of some sort between the two parts of the molecule. Let the sides of the triangle, 2, in Figure 2 represent the species R, S, and P as shown. The triangle itself may represent the overall reaction which, since it is a combination of S and R , we write as S g 1 R where 8 1 is an abstract product of the two entities R and S. I n fact, we can write the chemical equation of the reaction in various ways. The stanS = P is easily seen to be equivalent to dard form R R S - P = 0, where all the species are written on

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one side of the equation and the product species is given a negative stoichiometric coefficient. Writing R S P = 0 in its equivalent form

R - SOlR

+S = 0

suggests a simple relation to the abstract product

S@ 1R
I n fact, if we put an orientation on the face, 8,as shown by the anticlockwise arrow, we see that R - SOIR S is just the boundary of the face, the signs being given according to whether the orientation of the side is in the same (+) or the opposite (-) direction to that of the face. This may be written

d(SC31R) = R - SOlR

+S
Figure 3. Cutal3.zution model

where the rule for the boundary operator, b, is to delete the first term of the abstract product, subtract the species obtained by replacing @ I by the bond 0 1 , and finally add the species obtained by deleting the last factor of the product. This rule of deletion and changing of @ to 0 can be extended to any number of terms and corresponds to the geometric notion of taking the boundary. Because the face S@IR represents a properly balanced chemical reaction, its boundary is zero, for S O I R or P is just the sum of R and S. Xow suppose the reaction mechanism involves a catalyst, E , which first binds to R to form a complex, C, which then allows S and R to combine to P in a double complex, D, and finally releases itself from the catalyst. These steps might be written

Consider now the double product S@ 1R@SE, and apply the extension of the rule for the boundary

d(S@lR@pE)= R@zE - SOiRC3zE

S@IR
=

r -n+A

+ SBiROzE - 2

R+E=C

S+C=D

D=P+E

and the sum of them is the overall reaction R S = P. But if we represent the binding to the catalyst by a second symbol 0 2 , then C is represented by ROzE and D by S 0 1 R 0 2 E . Thus, the overall reaction
2: R

- SOiR

+S = 0

has three steps

+E = 0 + ROzE = 0 I I : E - SOlROzE + SOiR = 0

A:

I: R - ROzE S - SOlROzE

and clearly

~ : = r - - n + ~
KOW just as 2 may be represented by the abstract product &@ 1R so that the boundary b(S@1R) is the chemical equation R - SOlR S = 0, so may r, A, and 1 1 be represented by R @ 2E, S@1R02E, and SOiR @ sE, re-

spectively. For example, in taking the boundary b ( S O I R @ p E )we , delete the first factor, SO& giving E, subtract the result of replacing 8 2 by 0 2 , namely, SOIR02E, and add SOlR obtained by deleting the = E - SOiROzE second factor, E; thus, d(SO1R@?E), SOiR. Now the four triangles 8, r, A, and II can be fitted together as shown in Figure 3, where the orientations of faces and edges are shown by arrows.

Thus, just as the faces, which are two-dimensional triangles, have boundaries which are one-dimensional edges, so the three-dimensional tetrahedron has a boundary consisting of the faces. Moreover, just as the chemical equation for the reaction associated with a face is obtained by setting its boundary equal to zero, so the mechanism is obtained by setting the boundary of the tetrahedron equal to zero. For ~ ( S @ D R @ , = E )r - II A -Z = 0 can be written Z = F - II A , just as above. Sellers has called the three-dimensional complex, here a tetrahedron, a catalyzation. The boundary of a catalyzation is a signed collection of reactions or a mechanism. The boundary of a reaction is a signed collection of chemical species or a reaction equation. This is a bald description of Sellers concepts, but we hope it shows that the notions of chemical reaction and mechanism can be tied in with those of combinatorial topology. The power of these ideas arises from the fact that the resources of combinatorial mathematics are now harnessed to the tasks of the kineticist, such as that of computing the full independent set of possible mechanisms of a reaction. Another place where combinatorial considerations must be entertained has been shown by Zimmerman (72, 20, 21) in his work on the kinetics of polymerization. If growth starts at two centers on a long molecule, the possibility of interference between independently propagating chains must be considercd. In fact, all stochastic formulations have a combinatorial element since the basic probabilities are usually calculated in this fashion.

Stochastic Formulations of Chemical Kinetics

That the course of a chemical reaction can be regarded as a stochastic process has been the observation

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I N D U S T R I A L A N D E N G I N E E R I N G CHEMISTRY

of several authors (22, 49-67). This formulation has the advantage over the deterministic approach of giving a measure of the intrinsic variability of the process. For example, if the irreversible first-order reaction A --c B is considered deterministically, the number of molecules of A that time, t, would satisfy are expressed by

dn _- -kn dt
or

if the total number of molecules is large. It is always valid if the processes are all first order, but only approximate for higher-order processes when the numbers are small. Fredrickson (59) has given a careful treatment of the triangular reaction, which could easily be extended to a n arbitrary linear system. Very similar methods are used and similar equations obtained in discussions of the dynamics of microbial cell populations (62, 63).
Algebraic Structure of Systems of Kinetics Equations

n(t) =

nee-"

O n the other hand, suppose that (no - n) molecules have decomposed in the time interval (0,t) and that the probability of a single decomposition in (t, t 4- st) is knst o ( 6 t ) and that the probability of more than one decomposition is o ( 6 t ) . Then, the probability of going from a state with i molecules to one withj(<i) in time interval, t, is

First-order or monomolecular systems. A general system of first-order kinetic equations for the concentrations ci(t) for n species will take the form

5
dt

j=1

5 k,F,, i

= 1, 2,
n

. .n
The structure

where k,, > 0 if i # j and k,, =

j=l,i#z

-c kji.

Thus, starting with i = no at time t = 0, the expected number of molecules at time, t, is

nn

which agrees with the deterministic process. However, we can also find the variance of the number of molecules about the expected value, namely

of this first-order system has been well known in chemical engineering circles since Wei and Prater published a study notable both for its elegance of theory and usefulness of practical application (64, 65). This systematized a subject that had been touched on rather lightly in various ways by various workers (66-69) and which, in fact, bore close resemblance to the so-called compartmental analysis of biologists (see references in 70). If an equilibrium composition ci* exists with c,* > 0, all i, the system is fully reversible. These equations can be written in matrix form

2 ( t ) = noe-"(l

- e-")

no/4

dc _ - KC dt
and the equilibrium composition is such that

T h e standard error of the process is proportional to no-'I2. When a number of experimental runs are performed and observations taken at times t , = sr, s = 0,1, . . . S = T / T ,N , , sbeing the observation of n(t,) in the rth run, then the maximum likelihood estimate of k is

Kc* = 0
By the principle of microscopic reversibility ki,cj* = kf2ct*, and this implies that the matrix is symmetrizable since kt,(cf*/cZ*)1/2 = k3i(ct*/c3*)1/2. I t follows that the eigenvalues are all real and further, that they are all nonpositive. I n the concentration space, there are straight paths which are solutions of the equations. Recently Wei, Prater, and Silvestri (77-73) have investigated the case when there are irreversible reactions and some of the ci* may actually be zero. I n practice, even when knowledge or optimistic ignorance allows a system to be regarded as of the first order, there are many more components than one would wish to deal with and Wei and KUO'S recent attack on the problem of "lumping" is of the first importance (79, 7 9 ~ ) . By "lumping" we undertsand that m(<n) linear combinations of the concentrations c, are to be taken in place of the full set. Thus, if M is a matrix, the vector of lumped species ^G is given by
I = Mc

The least-squares estimate based on the deterministic model differs of course from this, though the estimates are usually close. The difference lies in the fact that the deterministic model regards the random error as lying solely in the experimental procedure whereas the stochastic model supposes that there is an intrinsic randomness in the reaction process itself. For more complicated reactions, the equations for the transition probability are not so readily solved and approximations have to be made. The set theoretic approach takes over the deterministic mean and takes exp --kt and (1 - exp -kt) to be the probabilities that a given molecule is A or B, respectively. This gives the expression for Pno7(t) directly, by calculating the probability that j of the total number of molecules are A, rather than by setting u p and solving equations for the transition probabilities. This assumption of equivalence of deterministic and stochastic means is reasonable

and two compositions c1 and c2 are M-equivalent if they map into the same lumped composition-i.e.,

Mci = Mc2
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But if there exists a matrix then

de - =

such that MK = KM,

dt

and the system is said to be exactly lumpable. The compositions in any two lumped subsystems of a n exactly lumpable system remain M-equivalent if the initial compositions are M-equivalent. This notion of equivalence has far-reaching consequences, and Wei and Kuo have gone on to discuss semiproper, improper, and approximate lumpability. The normal concept of a mechanism for a reaction usually involves improper lumping, since even if the original equations are first order, the kinetic expression obtained by using steadystate hypotheses is rarely that simple. When infinitely many components are involved, a first-order system may be lumped into virtually any kinetic law (35), and probably a n approximate form of such lumping accounts for the success of some of the less enlightening empirical rate expressions. Higher order systems. The first-order system is very fully understood because the resources of linear algebra are available. The equivalence classes of reactions are those of the matrix K, and lumping represents a projection into a lower dimensional space. With higher order reactions the same degree of insight has not yet been obtained, though a canonical form has been proposed (74). A beginning study of second-order reactions was made (75) using the relationship between quadratic equations and nonassociative algebras that Marcus had discovered (76). This is not an easy approach, though it gives a certain insight, and Wei has shown that the simplifying features of the first-order system, such as straight line paths, will rarely be present (77). Some of the advances in polynomial differential equations (e.g., 78, 79) have yet to be interpreted in the context of chemical kinetics. One difficulty has been that the nonassociative algebras that have attracted mathematicians' attention have been rather special ones such as Lie (80), Jordan (81), or genetic algebras (82, 83); Schafer's is the only general survey of the field (84), though there are passing references to some of the basic problems in many other papers and books. Systems with a denumerably or continuously infinite number of components. Large systems of equations which contain certain regularities, such as the hydride exchange scheme of Wei and Mikovsky (85) or some multiplace enzyme systems (86), can often be solved by the introduction of generating functions. This can be extended to denumerably infinite sets of equations and in simple cases gives solutions in closed form (87). An extensive review of polymerization equations is given by Liu and Amundson (88), and in later work Amundson and Zeman set up a continuous model in which the polymer P, of integral length, j , was replaced by P, and j regarded as a continuous real variable (89). This method goes back to the work of Bamford and has been used extensively. We shall
22

not attempt to review all these methods in detail as this has been done elsewhere (90). The notion of the continuous mixture and the connection with monomolecular systems is worth indicating, however; a more complete treatment has been given elsewhere (97). I n place of a discrete index i to denote the ith component and its concentration c d ( t ) , we use a continuous parameter x, a 6 x 6 6 , and let c(x,t)dx denote the concentration of material in the parametric interval (x, x dx). Balances can be done for this interval just as for a discrete species and the analog of Wei's monomolecular system

CAt) =

1-1

(kijcj

- h,cJ

is

t(~,t) =

sa

( k ( x , u ) c(u,t) - k(u,x) c ( x , t ) ) du

where the dot denotes d/dt. This is an integro-differential equation, with many of the simplicities of linearity, but distinctly more complex than the discrete equations. However, it can be shown that the principle of microscopic reversibility ensures a unique and stable equilibrium point, though it does not guarantee the reality of the spectrum. Nonlinear kinetic equations can be postulated, even if they cannot be readily solved and the partial differential equations of polymerization can be obtained from the same formalism. For example the sequential first-order reactions A I -+ A2 -+ A a -+ . . , generalize to d A ( x ) / d x = 0 and the concentration density c(x,t) satisfies the equation

ac
at

b +(kc) = 0 ax

where k(x) is the rate constant for substance of parameter, x. The continuous mixture can also be used to simulate independent parallel reactions, and the remark made about lumping comes up again. Thus, if c(x,t)dx is the concentration of material which decomposes (e.g., desulfurizes) with first-order constant x, then a t time, t,
c ( x , t ) = c(x,o)exp - x t

where c(x,o) is the original concentration of material of index, x. If x can take any positive value and we lump the whole mixture into one (ix.,consider only, total sulfur), then
Prn

In particular if c ( x , o )

Cok-' exp -x/k, then

C(t) = Co(1

+ kt)-'

which is the way in which a substance decomposing irreversibly by a second-order reaction would behave. Almost any kinetic law could be simulated by taking the appropriate initial distribution
c(x,o) = .e-'[C(t)]

I N D U S T R I A L A N D ENGINEERING C H E M I S T R Y

Determination of kinetic constants. One of the beauties of Wei and Prater's work on monomolecular systems was to show how the straight line paths could be used to determine the rate constants. Constants in any set of differential equations may be estimated by choosing them to give the best fit between the experimental data and values of the same quantities calculated from equations (92). The usual criterion of goodness of fit is a form of weighted least squares and a search procedure, though Bayesian methods of estimation also have been proposed (93) and a large number of papers have appeared (94-700). More recently, it has been questioned whether much is to be learned by fitting overall reaction rate expressions without supplementing kinetic data with theoretical insight (707). I n the so-called Langmuir-Hinshelwood or Hougen-Watson kinetic expression, commonly used in heterogeneous catalysis, the constant in the denominator need not be the equilibrium adsorption constants if, in fact, the rates of adsorption and desorption are comparable with that of reaction (cf. Sec. 6.2 of 87). The technique of slight displacement from equilibrium, used by Eigen on elementary reactions with great success (702) is now being applied to biological systems by Czerlinski (703, 703u) and to heterogeneously catalyzed reactions by Parravano and others (704). There may be problems of mathematical interest in this area. Some of the fundamental mathematical questions involved in various schemes of measuring rate constants were examined by Cannon (705, 706). Power series solutions have also been proposed for determining kinetic constants (707). From the mathematical point of view the situation is perplexing. A great variety of methods exists and finds useful application in all branches of chemistry and biochemistry, but no major organizing principle emerges. The state of the art would seem to be comparable to that of non-Newtonian mechanics a few years ago when exponents were being fitted to equations for power law fluids and no really searching analysis of the concept of a constitutive relation had been made.
Oscillating Reactions

A closed chemical system obeying the principle of microscopic reversibility cannot approach equilibrium in an oscillatory manner ( 3 2 ) . One can, of course, construct rather artificial systems such as A -+ B -+ C-c A in which each step is autocatalytic and, for example, ci = kzcu - k&. This has solutions which are closed paths kJog(u/uo) kzlog(b/bo) kslog(c/co) = 0 in a triangular diagram. A very ingenious example constructed by Wei (708) obeys the principle of microscopic reversibility and supposes that A -+ B is catalyzed by three ' , Y,Z,according to the scheme forms of a catalyst, A A +X=B Y, A + Y e B + Z ,A Z--,B+X. When the concentration ratio ( x y z)/(u 6) is small, the concentrations of X,Y,and 2 oscillate about their equilibrium values a finite number of times before settling down to a monotonic approach. Moreover this number may be made arbitrarily large by taking the concentration ratio sufficiently small.

I n open systems where certain reactants are supplied and products removed, the situation can of course be quite different. The simplest example is the stirred tank reactor, where even A 4 B can show limit cycles under nonisothermal condition ( 709), but many other examples have been given, usually of biological significance (67, 770, 717). A valuable and extensive review is given by Higgins ( 7 72) and it would be impertinent to cover the same ground here; we shall only attempt to point out topics that may be of mathematical interest. For first-order systems, or systems that can be made pseudo-first-order by assuming certain concentrations to be constant, the eigenvalues are always always real, provided that the principle of microscopic reversibility is imposed ( 7 70). If the system possesses closed loops and the product of the equilibrium constants around the loop is not unity (this is the so-called Wegscheider condition, which can only be violated for pseudo-first-order reactions), then damped oscillatory behavior may be observed ( 7 72). For higher-order reactions, Higgins has developed the notions of inhibitition and activation corresponding to negative and positive signs of the partial derivative of a rate of reaction with respect to a concentration; thus self-activation would correspond to autocatalytic behavior, for example. For two components Higgins suggests that some of the self-coupling terms must be of opposite character, as also must be some of the crosscoupling terms, if oscillatory behavior is to be observed. This conclusion is obtained partly from the use of theorems in nonlinear oscillation theory and partly from a very considerable experience with computer solutions and biological experiment. I t would be most valuable to see them established rigorously and extended to larger systems for they are backed by a great deal of insight into physical systems. Similar oscillations in inorganic systems have been discussed by Bray (773) and more recently by Mason and Bischoff ( 7 74). The important interaction of physical and chemical process has interesting mathematical overtones. We shall note a few of them in connection with diffusion problems but phase changes may also be of significance (775).
Pseudo-Steady-State Hypothesis

+ + +

There are few more pervasive or useful assumptions than that of the steady state introduced into chemical kinetics a little over 60 years ago. Indeed its introduction, acceptance, and elucidation would be an interesting study in the history of science. Quite evidently, it has been and is still being used in many quarters with great practical success and complete indifference to its conceptual and theoretical foundations, for its cruder expositions are often mathematically ludicrous, and the literature abounds with loose statements. Yet it should provide a case study of the function of mathematics in the refinement of concepts-the role which makes her the queen, as well as the handmaiden, of the sciences. By this hypothesis we understand the doctrine that in many circumstances certain changes are so slow as to be negligiVOL. 6 1

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ble, and that important simplifications can thereby be introduced. This has been stated rather vaguely, and in practice it takes one of three forms: 1. Steady state of intermediate concentrations 2. Rate-determining step 3. Long chain approximation I n the first case, by setting the derivative of such concentrations equal to zero, we obtain algebraic equations which can be used to eliminate these concentrations. I n the second, equilibrium relationships are used for the same purpose. In the third, only the propagation reactions are used to determine relative concentration distributions, and the initiation and termination reactions are brought in to give the overall reaction rate. Hypotheses of this kind were introduced in the context of enzyme kinetics by Henri in 1903 (776) and again by Michaelis and Menten in 1913 (777) in the form of a rate-determining step. Thus, if in the scheme
1 2

S+E+C-+P+E
-1

the first reaction is much faster than the second, we might assert the equilibrium relation klc = k-Ise, which together with the stoichiometric relation e c = eo gives c = eos/(K s), K = k - l / k ~ . The overall rate of reaction would then be

The specious argument, that when p is small, the concentrations e and c are small and so dcldt is negligible, was accepted in support of the Briggs-Haldane kinetics long before mathematical rigor was invoked. Fragmentary though the mathematical argument was, its consequences had a tremendous practical importance and such mechanisms were established by experiment, as in Chances ingenious work with peroxidase (725). Of course the structure of the solution of the complete equation is such that the concentration of c rises very rapidly during a brief induction period and decays slowly enough thereafter that during the main part of the reaction its derivative is indeed negative. But how should this feature, which is also exhibited in much more complex systems, be made precise? The validation of the pseudo-steady-state hypothesis has been approached from a number of different angles. Walter (727, 726, 727) has made detailed maps of the following kind. Given the rate constants, k,, and initial concentrations, one can find the per cent reaction a t which some arbitrary, but small, value (say, 0.01, 0.02, or 0.05) of (e/#) is still encountered or, conversely, values of (t/b)at various small values of conversion may be determined. Such maps are interesting, for the biochemist commonly takes initial rate data a t some low conversion, but they do little to clarify the concept involved. Hirschfelder (728) suggested an iterative scheme, which when applied to the enzyme reaction equations gives

This was criticized by Briggs and Haldane in 1925 ( 7 78) who asserted rather that the derivative of the intermediate concentration
dc _ dt - kles

S = - k leos
6 = kleos

+ (kls +
+
k-1

k-1)~

(kls

+ k2)c

(k-1

+ kz)c
+
+

would first lead to solving the second equation in the form c = (hens - t ) / ( k l s k-1 kz)

s) and a was negligible. This leads to c = eos/(K rate expression of the same form but with K = ( k z k - l ) / k I . We see this to be a hypothesis of the first rather than of the second kind, and such a hypothesis had in fact been suggested carlier by Bodenstein (779) in 1913. [The history of this basic enzyme kinetics has been reviewed by Reiner (86, 720) and by Walter (727), and Benson gives some references on the chemical side (722). See also Christiansens paper (723).] The interesting feature of this case is that though the two hypotheses lead to similar reaction rate expressions, namely

k-1 kz) and Setting t = 0 gives: c1 = kleos/(kls SI = kzeosl/(K S I ) as an equation to be solved. The next iterate is

cz

( k m

- Il)/(kls

k-1

+ kz)

where t 1 = (dcl/ds)S1, and substituting c1 into the first equation gives the equation for s1. I n general,

e< =
c,+1
~,+1 =

(dc,/ds)S,

= (kleos,+l

((klsi+l

+ k - - d t t + knkleost+l}/

- dJ/(k1+1

+ k-1 + k z ) + k-1 + k z )

eokzs/(K
with

+ s) and eokns/(K + s)
and K =
(k-1

{klJ,+l

= k-l/kl

+ k*)/kl

only the second can be rigorously justified (724). I n fact, the hypothesis that 1.1 = eo/so 4 0 does lead to the limiting form in the second case whereas the other hypothesis kz/kl and kz/k-1 0 leads to a cumbersome rate expression quite different from the first. It is ironic that the name Michaelis-Menten kinetics has become firmly attached to the Briggs-Haldane kinetic equation.

Thus, the first approximation is that of the pseudosteady-state, and successive iterates can be calculated. Giddings and others have looked a t the second term (729, 730) and suggested using its magnitude as a test of the validity of the hypothesis, but in the absence of any real understanding of the conrrergence of the iteration, this also is inconclusive. Hirschfelders method is used by Higgins (76) to compute the solution with an impressed oscillation in the feed. If the steady-state hypothesis were perfectly valid, the path of the solution would always lie in the surface given by the hypothesis

24

INDUSTRIAL A N D ENGINEERING CHEMISTRY

( i , e , , the surface 6 = 0 in the above example). This it does at low frequencies of perturbation, but as the impressed changes become more rapid the path oscillates out of the steady-state surface. This approach reflects the biological importance of oscillating systems in Higgins work. O n the basis of some numerical calculations, Benson (731) suggested certain criteria for validity based on the degree of conversion at the end of the induction period and this type of criterion Silveston (75) has subjected to much greater scrutiny. Similar considerations have been raised by Frank-Kamenetski (732). All these methods, however, suffer from an ineradicable element of arbitrariness, entering either in the definition of the induction period or in the fixing of a certain percentage deviation. Credit for discovering the true mathematical significance of the steady-state hypothesis as an instance of singular perturbation is due to Acrivos and coworkers (733). Later work by others (724) is really only an application of more recent techniques of asymptotic expansion (134)to their idea. By throwing the kinetic equations into dimensionless form using the variables

The least upper bound of ao thus provides an unambiguous measure of the validity of the steady-state hypothesis which is free from any arbitrariness. The notions of the singular perturbation approach have been sketched for a particularly simple reaction, but they can be readily applied to more complicated ones revealing what the consequences of the limiting hypothesis are and how many parameters must be considered in the system. If the accuracy of the actual method of estimating the rate constants (say by a Lineweaver-Burke plot) is to be discussed, then further calculations may be necessary to be faithful to the method of estimation. From the conceptual point of view, the important point is that the singular perturbation approach reveals the analytical nature of the projection implicit in the notion of a chemical mechanism, just as the work of Sellers (77) or Aris (35) shows the algebraic aspect of this project. The justification of the long chain approximation also involves the ideas of perturbation theory as Gavalas has shown (735). The notion of memory introduced by Halsey (25) may be justified by observing that if y ( ~ is ) an arbitrary function of time, then the equation
Pi =

y = s/so, z = c/co,
and the parameters

= kleot

- (x + r)Z

z(0) = 0

+ kd/krso, X kdklso, we have the equations y -y + ( y + - X)z

K

= (k-1

p = edso

pk = y

- 0, + x)z

withy = 1, z = 0 at T = 0. I n the degenerate case p = 0, the second equation is algebraic rather than differential and gives the dimensionless form, z = y/(y N), of the steady-state relation c = eokls/(kls k-1 kz). Substitution in the first differential equation then H) which is just the dimensionless gives i, = -Xy/(y form of the Michaelis-Menten kinetic expression ds/dt = -kzeos/(s K ) . The value of the dimensionless form of the equations is that it shows clearly that the parameter p is indeed the one leading in the limit p + 0 to the degenerate case corresponding to the pseudo-steady-state hypothesis. What is even more important is that the theory of the singular perturbation of differential equations tells us what to expect in the solution. There will be an inner solution which lasts for a few multiples of the dimensionless time interval p / ( l H) [;.e., a real time interval of (klso k-1 k ~ ) - during ~] which z , or c, will rise to its maximum value and after which the pseudo-steady-state assumption is a good approximation and the so-called outer solution obtains. But all this can be made precise in a systematic way and a solution in powers of p, say y = Yn(7),z = Zn(7),can be developed which is related to the true solution y = Y ( T , p ) , z = Z ( T , p ) in the sense that as p + 0, the bounds

can be solved for z as a function of the whole past history of y. Substituted in the rate equation it therefore makes the rate of formation of the product a functional of ) , 0 6 u 6 the past history of the concentration Y ( T - u T. The functional obtained satisfies the principles of fading memory laid down by Coleman and Mizel (736, 737) and the same hypothesis p + 0 that leads to the steady-state assumption also obliviates the memory and leads to the Michaelis-Menten kinetics (26). This notion can also be generalized, though it remains to be seen what its power may be.
Diffusion ahd Reaction

lYn(7) - y(7,

~ l ) l < % and ~ ~ ~ Iz~ n(7)

- ~ ( 7p)l<b,p+ ,

hold in the interval 0 < T 6 T. The constants a, and b n depend only on T , and in many cases are bounded.

When diffusion as well as reaction is brought into the picture we rise immediately from systems of first-order, ordinary differential equations to systems of parabolic, second-order, partial differential equations. While this ascent brings a fascinating new landscape of mathematical problems into view, it also reveals that the exploration of this new terrain will involve much rougher going, particularly in the nonlinear direction. We suggest three general areas in which problems of mathematical interest may arise. The first is largely the province of the physical chemist and includes such topics as the diffusion limitation of the reaction of highly reactive species (138) and chemical reaction regarded as diffusion through phase space (739). Some results of considerable generality for complex geometries have been obtained by Prager (749) using variational principles : We shall take note of these methods a little later in another context. The second area is that of diffusion and reaction in catalyst pellets which has engaged the attention of chemical engineers for the past 30 years. Some reflections on the history of this subject have been given by one of its pioneers, E. W. Thiele (747). I t has already accumuVOL. 6 1
NO. 6

JUNE 1969

25

lated a literature of almost overwhelming proportions. I n this area there is a large amount of straightforward computational work giving the effectiveness factors for various shapes of particle, kinetics of reaction, and thermal conditions. I t would be a work of merit to bring this all together in one place, but it is the theoretical problems that come to light in the process which are of real mathematical interest. These concern the uniqueness and stability of the steady states and the existence periodic solutions of the nonlinear partial differential equations. An excellent review is to be found in Gavalas book (f42), and an elementary survey of some of the recent ideas on stability has been presented elsewhere (143),so that we shall not attempt to cover this ground again. Three points are worth noticing, however. The first is the power of the maximum principle as Luss has applied it to show that, when the Lewis number of the particle is one, the unique steady state is globally stable and the central unsteady state of three lies in the separatrix of function space (144). This is a beautiful use of a general, and to the engineer a still somewhat recondite result of differential equation theory. The second is the existence of periodic solutions when the Lewis number is not one, which Hlav6Eek and Marek (145) have reported and Luss has investigated more fully (10, 146). The third is range of multiplicities of solution that are coming to light. For a single exothermic reaction taking place nonisothermally in a catalyst particle it has long been known that three steady states exist for certain sizes of the particle. Now it appears that five can be obtained with a zeroth-order reaction in a sphere, though not in a slab (747), or when external transfer limitations are also important (148). The variational methods used by Prager (749) and others deserve more attention. He has used them with Strieder (150) to discuss Knudsen flow and it is this work that Strieder is taking further in the consideration of reaction (14). Luss and Aniundson also used variational arguments in discussing the effect of the shape of a particle (157). Finlayson and Scriven have shown how to exploit upper and lower bounds (152). An interesting question, within the context of these methods, is the relationship of the commonly accepted model of a catalyst particle to reality. I n the usual modcl, the catalyst particle is treated as a homogeneous phase with a uniform distribution of catalytic area. If c is the concentration of a species disappearing by reaction at a rate, kc, per unit catalytic area, u is the area per unit volume and D the effective diffusion coefficient, then for the homogeneous model of Figure 4a, we have the equations

Figure 4a,b.

Catalyst particle models

give the same result. But the equations for the second model, illustrated by Figure 4b, are clearly

Dv~c = 0 in bc bn

D - = kcon 2
c = co

(constant) on S

(B)

where a prime is used to denote quantities that may be different in this model and V denotes the free space within V . Now it can be shown that of all the functions which have a constant value co on S, the solution of Equations A minimizes the functional

Moreover the effectiveness factor, T ~ as , it is usually defined, is given by this minimum value, for by Greens theorem,

Again, of all the functions constant on S, the solution of Equations B minimizes the functional

and A complete investigation of these relationships is in progress, together with other general problems of this character. Tiot only does it have some mathematical interest, but its practical importance is likely to be enhanced by the use of molecular seive catalysts in which the surface 2 is indeed less uniformly distributed than i s the case with conventional catalysts. The third area of promise in diffusion and reaction problems is where some geometrical structure is found in the medium. O n the one hand, it may be deliberately laid down as a fixed structure as in some discussions of active transport (753, 154) or bifunctional catalysis (755). Or, it may arise naturally as the result of structureforming diffusion and reaction (73, 156). I t is this second possibility, opened up by the pioneer work of 1

DV2c = kac in V
c = cs (constant) on

(A)

I n reality, the species is diffusion through a free space of immensely complex geometry and reacting on an inner surface 2 distributed through V. If 2 is so uniformly distributed that for every element of volume dV, the reaction area is d 2 = a & , we would expect the two models to
26

INDUSTRIAL A N D ENGINEERING CHEMISTRY

Turing (757) but more fully developed by Scriven and his coworkers (758, 759), that is so interesting and holds promise of a greater insight into the problems of morphogenesis. Another crosslink that has been suggested by Scrivens work is that, a t the limit of high wave numbers and frequencies, he sees the need to consider memory effects in transport and even action at a distance. The former has received little attention outside Scrivens work (cf. 760) though it links with the formulation of constitutive relations using functionals, the latter is suggestive of Knudsen flow and Strieders work (739, 750). We have by no means exhausted the mathematical problems of diffusion and reaction. Some of the questions of multicomponent diffusion are exceedingly important and not a little delicate (767-763). But it is hoped that enough has been said to indicate the range and difficulty of the problems that may be usefully pursued in this milieu.
Questions of Equilibrium and Stoichiometry I n this somewhat circular tour of the domain of formal kinetics let us return by way of a discussion of some of the questions of equilibrium and stoichiometry. As an outgrowth of the interest in continuum mechanics and continuum thermodynamics it is natural that there should be an inquiry into the nature of thermodynamic equilibrium. T h e literature of modern continuum thermodynamics is already considerable and references 764-777 and 23 are just a sampling. Its objective is to set down general constitutive relations for a class of materials and to see what restrictions and relations are imposed upon them by the equations of balance, by the second law of thermodynamics (the Clausius-Duhem inequality), and by any symmetry assumed for the material. I t is, for example, shown that the specific free energy, specific entropy, and stress tensor cannot be functions of the temperature gradient. Coleman and Gurtins internal state variables, cy (766), may be interpreted as extents of reaction, so that their equations of change, d! = f(F, e, g, a), are the kinetic equations (F is the deformation gradient, 0 the temperature,p = W). The internal dissipation u is defined as -e-?),$ f, where $ is the free energy function, $(F, 0, CY). If q = Q(F, e, g, a) is the constitutive relation for the heat flux vector and p the density, the Clausius-Duhem inequality implies that
pu

- $.g>O

but in general the two terms in the inequality cannot be separated. If there is no reaction f = 0 and so 4 . g 6 0, meaning that heat flows down the temperature gradient. If there is no temperature gradient, g 0 and the internal dissipation u must be positive. But it is not generally possible to assert that u 2 0 for nonzero g, nor cjg 6 0 for nonzero f. If, however, the rate equations, f, are independent of g, as is commonly assumed, then u 2 0. T h e quantity -?)+/bat is, of course, the affinity of the ith reaction and, a t constant strain and temperature and zero temperature gradient, u is the specific entropy production-i.e., u = -e-$ = when J? = 0, d = 0, and g = 0.

This approach has allowed Coleman and Gurtin to say some very precise things about equilibrium states, Their definition of an internal equilibrium state is a triplet (F*, e*, a*) at which f(F*, 8*,0, a*) = 0 and thus it would correspond to chemical equilibrium. If such an equilibrium state is asymptotically stable, then 9 must have a minimum there and the affinities vanish. A material is strictly dissipative if u > 0 except a t an equilibrium state. I n a strictly dissipative material, asymptotic stability at constant strain and temperature is equivalent to the statement that $(F*, e*, cy) > +*(F* e* cy*) in some neighborhood of the equilibrium state. I t is such results that Bowen has refined and extended (5, 772). He distinguishes between (a) Weak equilibrium, where reaction rates vanish, (b) Classical equilibrium, where affinities vanish, and (c) Strong equilibrium, where both vanish. Bowen shows that weak equilibrium implies the classical if baf is nonsingular and classical equilibrium implies the weak if ?),& is nonsingular. He has demonstrated some interesting results for waves propagation into a region of weak equilibrium. Coleman and Mizel (8, 773) have addressed themselves to the question of relating the thermodynamic condition for stability (that some free energy or equilibrium response function should be minimum) to the dynamical conditions. They have solved this problem completely for systems whose state can be described by a finite dimensional vector, which, however, may be governed by functional-differential equations. If, on the one hand, the continuum mechanics approach has enlarged the theoretical understanding of the nature of equilibrium, on the other, the resources of linear algebra and optimization techniques have been used to prove the uniqueness of equilibrium compositions and to calculate them. Shapiros work (7, 774-777) has led the way here to show very clearly the conditions under which the minimum of the free energy functional as constrained by the mass balance equations is unique (cf. 34, 35). These questions are important in view of the increasingly complex systems that are being considered, particularly in biological contexts, and the need to harness the techniques of optimization and machine computation to the efficient calculation of equilibria (778-789). These considerations lie very close to others of a purely stoichiometric nature, for Sellers has pointed out that stoichiometric equations are mathematical equations (790), and stoichiometric restrictions on equilibria have long been seen to be important (797, 792). Some discussion has centered on the form of the stoichiometric equation, which for a set of r reactions between s species, A,, can be written

Various normalization schemes have been suggested (793-796), and Petho has developed some algebraic apparatus for achieving a simple form (797-203). From an abstract point of view, it is important to retain a sense of the arbitrariness of stoichiometry (3, 3 7 , 34,
VOL. 6 1

NO. 6

JUNE 1 9 6 9

27

195, 204), for any nonsingular transformation of an independent set must be equivalent. The maximum number of independent reactions is governed by the rank of the structure matrix expressing the species A , in terms of their elements (34, 123, 204, 205). And here we return to some questions related to mechanism where linear combinations of the reactions are to be made, [the coefficients in this case are the stoichiometric numbers, as Horiuti (206) has defined them] and to count- I ing the possible mechanisms of reaction (78, 34, 207). Stoichiometric considerations have also been invoked in the discussion of thermodynamic coupling, the possibility that some reactions of a system may be absorbing the entropy generated by the others. Hooymans normalization (794) claims to have a certain intrinsic property alleged to be necessary in determining the existence of thermodynamic coupling (208) after Koenig and others had shown that system of reactions could always be uncoupled (209). Manes showed that near equilibrium reactions could be coupled or uncoupled by composition perturbations (270, 27 7) and the whole question is reminiscent of the arbitrariness surrounding the reciprocity relations of irreversible thermodynamics (212). It is very clear that algebraic artifice should not be allowed to replace real physical insight (213).
Epilog

I n this circular tour of some of the mathematical aspects of chemical reaction it should be evident that there is no neat linear succession of ideas. Rather there is a web of interconnections between the several distinguishable areas of kinetics and mathematical disciplines. There is plenty of scope for investigation of the many avenues that can be opened up, and the contributions of workers with quite diverse backgrounds and intentions have many points of convergence. One of the earliest mathematicians to recognize the affinity between his work on invariants and (the new Atomic Theory, that sublime invention of KekulC was J. J. Sylvester. Even if his ideas on the bearing of invariant theory (274) were to prove abortive (215) until transmuted into something rich and strange (cf. Weyls remarks, 216), his approach was consonant with the largeness of outlook proper to natural philosophy. Coming from an ampler age than ours, the Augustan measures of his prose may fall quaintly on our ears but it may be permissible to transpose one of his remarks to our subject. (The beautiful theory of atomicity-or for that matter of formal chemical kinetics-has its home in the attractive but somewhat misty border land lying between fancy and reality and cannot, I think, suffer from any not absolutely irrational guess which may assist the chemical enquirer to rise to a higher level of contemplation of the possibilities of his subject.
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