Chemical Reaction Network Theory

1.A. Chemical Reaction Network Theory: Early Review Articles 

Although they are now a little outdated, the following reviews for a general audience give a fairly good summary of some early results in chemical reaction network theory. These early results tie the qualitative behavior of mass action systems to a property of the underlying network called the network’s deficiency. (The deficiency is a non-negative integer index with which reaction networks can be classified.) 

1. A very early deficiency-oriented article: M. Feinberg and F. J. M. Horn. Dynamics of open chemical systems and the algebraic structure of the underlying reaction network. Chemical Engineering Science, 29:775–787, 1974.
2. I think the following review is a good place to begin. It was written in connection with a symposium attended by a nice mix of chemists, engineers, and mathematicians: Martin Feinberg. Chemical oscillations, multiple equilibria, and reaction network structure. In Warren E. Stewart, W. Harmon Ray, and Charles C. Conley, editors, Dynamics and Modeling of Reactive Systems, pages 59-130. Academic Press, New York, 1980
3. This two-part review, written a little later than the 1980 review, takes things somewhat further and provides much more detail. Part One: M. Feinberg. Chemical reaction network structure and the stability of complex isothermal reactors I. The deficiency zero and deficiency one theo­rems. Chemical Engineering Science, 42:2229–2268, 1987. Part Two: M. Feinberg. Chemical reaction network structure and the stability of complex isothermal reactors II. Multiple steady states for networks of defi­ciency one. Chemical Engineering Science, 43:1–25, 1988.
4. The review, Mathematical Aspects of Mass Action Kinetics, was written even earlier than any of the previous ones. Among other things, it attempts to explain for a chemical engineering audi­ence a little bit about the proof of the Deficiency Zero Theorem. It highlights the crucial work of Horn and Jackson, but it also uses a line of argument that’s a little different from theirs. Citation: M. Feinberg. Mathematical aspects of mass action kinetics. In N. Amund­son and L. Lapidus, editors, Chemical Reactor Theory: A Review, pages 1–78. Prentice-Hall, Englewood Cliffs, NJ, 1977.
5. If, however, you are a mathematician seeking proofs, then I’d strongly recommend Lectures on Chemical Reaction Networks, which are a written ver­sion of about half the lectures I gave in 1979 at the Mathematics Research Center of the University of Wisconsin. (I got distracted by foundations of classical thermodynamics before I wrote the remaining half. You’ll see some of that work, appearing at about the same time, elsewhere in this bibliog­raphy.) Lectures will take you up through a proof of the Deficiency Zero Theorem.
6. Although it was written substantially later, I am including with this set of articles the following one because it travels further down the same road. The article describes progress, based on the PhD work of Phillipp Ellison, toward extending previous results about deficiency one networks to networks of higher deficiency. In particular, Phillipp’s work, like deficiency one theory, aims to translate questions about a network's capacity for multiple steady states (and therefore questions about systems of nonlinear equations) into questions about systems of linear inequalities, which are far more tractable. Phillipp’s work in both theory and software development provided the basis for a major improvement in The Chemical Reaction Network Toolbox. See P. Ellison and M. Feinberg. How catalytic mechanisms reveal themselves in multiple steady-state data: I. Basic principles. Journal of Molecular Catal­ysis. A: Chemical, 154(1-2):155–167, 2000.

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1.C. Chemical Reaction Network Theory: More Mathematical Articles

1. It’s worth repeating here that, for mathematicians who want to go deeply into chemical reaction network theory, I think the best entry point is Feinberg, M., Lectures on Chemical Reaction Networks, written ver­sions of lectures given at the Mathematics Research Center of the University of Wisconsin, 1979.
2. The following article was my first venture into the mathematics of com­plex chemical systems. Its aim was to determined what can be said about rate constants and the reaction network itself when one has information about composition dynamics near an equilibrium point. (It’s assumed that the ki­netics is mass action and exhibits detailed balance.) Martin Feinberg. On chemical kinetics of a certain class. Archive for Rational Mechanics and Analysis, 46(1):1–41, 1972.
3. The following article is a “pure math” article that was a consequence of things in the previous article listed in #2:: Martin Feinberg. On a generalization of linear independence in finite-dimensional vector spaces. Journal of Combinatorial Theory, Series B, 30(1):61– 69, 1981.
4. The papers [1.C3]–[1.C5] below provide the basis for what is now known as the Deficiency Zero Theorem. (Although they do not derive from work by me or my students, the articles by Fritz Horn and Roy Jackson are listed here because they provide the foundation for the Deficiency Zero Theorem story.)  [1.C3] F. Horn and R. Jackson. General mass action kinetics. Archive for Rational Mechanics and Analysis, 47:81–116, 1972 and [1.C5] Martin Feinberg. Complex balancing in general kinetic systems. Archive for Rational Mechanics and Analysis, 49:187–194, 1972.
5. In a seminal and beautiful paper [1.C3, above], Horn and Jackson invented the idea of complex balancing at an equilibrium as a generalization of what chemists call detailed balancing. They showed in [1.C3] that if a mass action system admits a complex balanced equilibrium at which all species concen­trations are positive, then the corresponding differential equations admit only behavior of a special dull kind. In [1.C4] Horn went further; in particular, he examined conditions on rate constants in a mass action system (analogous to the Wegscheider conditions for detailed balancing) that ensure the exis­tence of a positive complex balanced equilibrium. 1.C4] F. Horn. Necessary and sufficient conditions for complex balancing in chemical kinetics. Archive for Rational Mechanics and Analysis, 49:172–186, 1972.
6. In [1.C5] above I showed that, when what has come to be called the deficiency of the underlying reaction network is zero, then complex balancing must obtain at every equilibrium, independent of what the kinetics might be.
7. The following paper is out of chronological sequence, but it is close in spirit to the immediately preceding ones. The paper was in response to a question put to me by Roy Jackson. He wanted to know of a systematic way to state conditions on mass action rate constants that are necessary and sufficient for the existence of a positive equilibrium at which detailed balance obtains. It turns out that there is a nice connection of this with the underlying network’s deficiency and its cycle structure. [1.C6] M. Feinberg. Necessary and sufficient conditions for detailed balancing in mass action systems of arbitrary complexity. Chemical Engineering Science, 44:1819–1827, 1989.
8. The next paper is largely a technical one, but it is a workhorse in many of the reaction network theory papers that followed it. Especially impor­tant is the Appendix. Readers familiar with the mathematics of reaction network theory will perhaps know that, when the kinetics is mass action, the species formation rate function is often written in the decomposed form YA_kΨ(c) — see for example §4.A in  Lectures on Chem­ical Reaction Networks. The Appendix of [1.C7] deals with the connection between reaction network structure and qualitative properties of the kernel (nullspace) of A_k. [1.C7] Martin Feinberg and F. J. M. Horn. Chemical mechanism structure and the coincidence of the stoichiometric and kinetic subspaces. Archive for Rational Mechanics and Analysis, 66:83–97, 1977.
9. Papers [1.C8] and [1.C9] provide the foundations for deficiency one theory. In particular, [1.C8] has a proof of the Deficiency One Theorem, and [1.C9] gives the mathematics behind the Deficiency One Algorithm, which was im­plemented in even the earliest versions of The Chemical Reaction Network Toolbox. The algorithm converts questions about the capacity of deficiency one mass action systems to admit multiple steady states (essentially ques­tions about systems of nonlinear polynomial equations) into questions about systems of linear inequalities, for which there is a well-developed theory. [1.C8] Martin Feinberg. The existence and uniqueness of steady states for a class of chemical reaction networks. Archive for Rational Mechanics and Analysis, 132(4):311–370, December 1995. and [1.C9] Martin Feinberg. Multiple steady states for chemical reaction networks of deficiency one. Archive for Rational Mechanics and Analysis, 132:371–406, 1995.
10. Correction
11. The next article [1.C10] is out of chronological order, but it has resonances with papers dealing with detailed balancing, complex balancing, the Defi­ciency Zero Theorem, and the Deficiency One Theorem. The central question in [1.C10] is about the robustness of steady states: How does reaction network structure alone influence the sensitivity of the steady state concentration of a particular species to a perturbation in the supply of another species? [1.C10] Guy Shinar, Uri Alon, and Martin Feinberg. Sensitivity and robust­ness in chemical reaction networks. SIAM Journal on Applied Mathematics, 69(4):977–998, January 2009. It turns out that such sensitivities often have bounds that depend in a striking way on the extent to which the various molecular species are con­structed from a large number of distinct building blocks (as are proteins) and, also, the extent to which those building blocks combine gregariously. I have great affection for this paper because it was the beginning of my col­laboration with Guy Shinar. The paper is an elaboration on work done by Guy when he was a student in Uri Alon’s lab at Weizmann Institute. (The relationship between [1.B4] and [1.C10] is discussed in [1.B5].)
12. Another robustness/sensitivity article can be found here: [1.C11] Guy Shinar, Avi Mayo, Haixia Ji, and Martin Feinberg. Constraints on reciprocal flux sensitivities in biochemical reaction networks. Biophysical Journal, 100(6):1383–1391, 2011.
13. In one way or another the articles [1.C12]-[1.C17] provide mathematical foundations for [1.B.2], the more friendly expository PNAS paper that draws connections between the capacity of a (mass action) network to give multi­ple steady states and the nature of the network’s Species-Reaction Graph.  I now think that the self-contained articles [1.C16] and [1.C17] substantially transcend [1.C12]-[1.C15] in terms of results, while at the same time proceed­ing in a different, more economical way. Some readers might want to start there. However, [1.C12]-[1.C15] give an alternative route, based largely on Gheorghe Craciun’s remarkable PhD work — a route that remains highly compelling.
14. Both [1.C12] and [1.C13] presume mass action kinetics. In this context, [1.C12] provides a determinant condition which, for a given reaction network, serves to ensure injectivity. Injectivity is a network property that, among other things, precludes the possibility of multiple positive steady states, regardless of rate constant values. In turn, [1.C13] provides conditions on a network’s Species-Reaction Graph that suffice to ensure that the determinant condi­tion of [1.C12] is satisfied. From this, injectivity and multiple-steady-state­-preclusion follow. [1.C12] G. Craciun and M. Feinberg. Multiple equilibria in complex chemical reaction networks. I. The injectivity property. SIAM Journal on Applied Mathematics, 65:1526–1546, 2005 and [1.C13] G. Craciun and M. Feinberg. Multiple equilibria in complex chemical reaction networks. II. The species-reaction graph. SIAM Journal on Applied Mathematics, 66:1321–1338, 2006.
15. In very surprising subsequent work, Gheorghe Craciun and Murad Ba­naji subsequently proceeded in a different way to show that Species-Reaction Graph conditions that suffice for injectivity (and, therefore, the preclusion of multiple steady states) in the context of mass action kinetics also suffice for injectivity for the far wider class they called non-autocatalytic (NAC) kinetics. However, [1.C12], [1.C13] — and the Craciun-Banaji work — have limita­tions: Crucial to the mathematics is the presumption that the reaction network under consideration is fully open. This amounts to saying that every species is “removed” (perhaps through an unspecified degradation reaction) at a rate proportional to its current concentration. Although this presumption is natural for continuous flow stirred tank reactors (CFSTRs) in a chemical engineering setting, it is less compelling for models of cellular reaction sys­tems, in which only certain species (or none at all) might suffer degradation. Removal of the fully open presumption makes the mathematics substantially more delicate.
16. The papers [1.C14] and [1.C15] are aimed at establishing conditions under which results in [1.C12] and [1.C13] can, in fact, be invoked in the absence of the “fully open” presumption. The analysis in [1.C.14] shows that results of the kind given in [1.C12] and [1.C13] can be invoked in quite general settings, provided that one restricts attention to steady states that are, in a certain sense, non-degenerate. The argument in [1.C14] for extending “fully open” results to more general settings does not rely on mass action kinetics. The paper [1.C15] does invoke mass action kinetics, but it gives far sharper results, without limiting considerations to non-degenerate steady states. Among other things, it shows that the results in [1.C12] and [1.C13] do apply even in consideration of systems that are not fully open, provided that the reaction network in question falls within the large class of normal networks — in particular, if it is reversible or even weakly reversible. (A weakly reversible network is one in which every reaction arrow is in at least one directed arrow cycle. [1.C14] G. Craciun and M. Feinberg. Multiple equilibria in complex chemical reaction networks: extensions to entrapped species models. IEE Proc. Syst. Biol, 153:179–186, 2006 and  [1.C15] Gheorghe Craciun and Martin Feinberg. Multiple equilibria in com­plex chemical reaction networks: Semiopen mass action systems. SIAM Jour­nal on Applied Mathematics, 70(6):1859–1877, 2010.
17. In many ways, the following papers with Guy Shinar and Daniel Knight subsume results of [1.C12]-[1.C15] and go further. As with the work of Craciun and Banaji, these papers embrace very wide and natural classes of kinetics. But here, from the very beginning, systems that are not “fully open” are admitted for study along­side those that are. In [1.C16] we describe and examine properties of a large class of reaction networks that possess a structural property called concor­dance. (Whether or not a particular network of interest is concordant can be determined by The Chemical Reaction Network Toolbox.)
18. Among other things, we show in [1.C16]  [1.C16] Guy Shinar and Martin Feinberg. Concordant chemical reaction net­works. Mathematical Biosciences, 240:92–113, 2012 that, in at least some respects, concordance is the structural property that confers upon a network the as­surance of certain dull behaviors against every assignment of kinetics within a very large class called weakly monotonic. In particular, a reaction network exhibits injectivity when taken with every weakly monotonic kinetics if and only if it is concordant. On the other hand, reaction network “discordance” provides a source for unstable behavior in the following sense: For any weakly reversible network that is not concordant, there exists a weakly monotonic kinetics such that the resulting kinetics system exhibits a positive unstable equilibrium. (In [1.C16] we also consider variants of the concordance prop­erty in connection with still wider classes of kinetics, in which certain species might inhibit the occurrence of a particular reaction while others might promote it.)
19. In [1.C17] and [1.C18] we connect the concordance of a reaction network to properties of its Species-Reaction Graph. In particular, we show that Species-Reaction Graph properties which, in [1.C13], sufficed for injectivity in the fully-open mass action context also suffice for network concordance — and therefore for injectivity against all weakly monotonic (and still broader) kinetics. This is true not only in the fully open context but also whenever the network under study is “nondegenerate,” in particular whenever it is weakly reversible. [1.C17] Guy Shinar and Martin Feinberg. Concordant chemical reaction net­works and the species-reaction graph. Mathematical Biosciences, 241:1–23,  2013. (Corrigendum) and [1.C18] Daniel Knight, Guy Shinar, and Martin Feinberg, Sharper graph-theoretical conditions for the stabilization of complex reaction networks. Mathematical BioSciences, 262:10-27, 2015.

Martin Feinberg Group for
Chemical Reaction Network Theory

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1. In the 1990s I got interested in optimal reactor design, mainly because there was a resurgence of interest in old attainable region ideas of Fritz Horn, my late collaborator in chemical reaction network theory. I am very proud of the attainable region work I did — more on that later. However, I now think that the most important work to emerge from my temporary foray into design came from a different line of thought entirely, a line that (strangely) traces back to my seemingly unrelated paper [2.2] on Gibbs’s phase rule!
2. This work in design theory is summarized in [3.1] below, and its mathematical founda­tions are described in [3.2]. In rough terms, the central idea is this: Given a network of chemical reactions (with kinetics) and given a specified commit­ment of resources, there is an absolute and computable limit to what can be achieved in ANY steady-state reactor-separator design — a limit that is differ­ent from that afforded by stoichiometry or thermodynamics. Knowledge of such a limit is of practical importance, for it gives a benchmark against which actual designs can be judged. (Connections to the mathematics underlying the Gibbs phase rule are discussed in Remark A.1 of the paper [3.1] Yangzhong Tang and Martin Feinberg. Carnot-like limits to steady-state productivity. Industrial & Engineering Chemistry Research, 46(17):5624– 5630, 2007 and [3.2] Martin Feinberg and Phillipp Ellison. General kinetic bounds on pro­ductivity and selectivity in reactor-separator systems of arbitrary design: Principles. Industrial & Engineering Chemistry Research, 40(14):3181–3194, 2001.
3. As I said earlier, I am very proud of my attainable region work. There are some surprising and beautiful conclusions, and very different parts of mathematics come together in interesting ways. (For me it remains stunning that, associated with a given reaction network with kinetics and a given feed composition, there are certain exceptional numbers — something like eigenvalues — having special significance for reactor synthesis: A classical steady-state CFSTR design can have an optimal conversion relative to all other steady-state designs only if the CFSTR residence time assumes one of those exceptional values.) The review [3.3] Martin Feinberg. Toward a theory of process synthesis. Industrial & Engineering Chemistry Research, 41(16):3751–3761, 2002. was written after I had moved away from attainable region work, and it gives an indication of why I came to prefer ideas in [3.1] and [3.2].
4. The conference paper [3.4] Martin Feinberg. Geometric control theory and classical problems in chemical reactor design. In Proceedings of 15th IFAC World Congress, Barcelona, 2002 is  also friendly review, this time written for control theorists — I’m not one of those — to indicate why ideas in modern geometric control theory have somewhat surprising connections with Horn’s attainable region approach to optimal reactor design. Despite its intended control-theorist target, I think this article is suited to a much wider chemical engineering audience.
5. Mathematical underpinnings of [3.3] and [3.4] are given in the three-article series [3.5]-[3.7] below. The paper [3.8], based on Thomas Abraham’s PhD thesis, is an extension of these, viewed from a different perspective.

• [3.5] M. Feinberg and D. Hildebrandt. Optimal reactor design from a geo­metric viewpoint: I. Universal properties of the attainable region. Chemical Engineering Science, 52(10):1637-1665, 1997.
• [3.6] M. Feinberg. Optimal reactor design from a geometric viewpoint: II. Critical sidestream reactors. Chemical Engineering Science, 55(13):2455–2479, 2000.
• [3.7] M. Feinberg. Optimal reactor design from a geometric viewpoint: III. Critical CFSTRs. Chemical Engineering Science, 55(17):3553–3565, 2000.
• [3.8] T. K. Abraham and M. Feinberg. Kinetic bounds on attainability in the reactor synthesis problem. Industrial & Engineering Chemistry Research, 43(2):449–457, 2004.

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