Can Reaction Mechanisms Be Proven? - ACS Publications

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Commentary

Can Reaction Mechanisms Be Proven? by Allen Buskirk and Hediyeh Baradaran

Note from the Editor: A Discussion “Can Reaction Mechanisms Be Proven?” g enerated spirited responses from its reviewers. The reviews were approximately evenly divided and all were of very high quality. The authors agreed with the editor’s proposal that the reviewers convert their reviews into rebuttals or affirmations of the authors’ position for publication along with the article, which has been revised based on the reviews. Most agreed to such a Organic chemistry textbooks commonly teach that reaction mechanisms can never be proven. As one popular text reads, “How can we determine reaction mechanisms? The strict answer to this question is, we cannot… although we cannot strictly prove a mechanism, we can certainly rule out many (or even all) reasonable alternatives” (1). A strong version of this claim is found in a biochemistry textbook that includes the following quote attributed to Einstein in its discussion of mechanistic enzymology: “No amount of experimentation can ever prove me right; a single experiment can prove me wrong” (2). Taken to its extreme, this view claims that experimental data that match our predictions do not confirm or even increase our confidence in a proposed mechanism. The only data that matter are those that refute or falsify a theory. We argue that these statements reflect an outdated philosophy of science that does not accurately describe the practice of chemistry today. Chemists obtain evidence to confirm their theories, not merely to refute them, and have accumulated an impressive body of mechanistic knowledge over the decades. Progress has accelerated in recent years due to technological advances that allow reaction intermediates to be observed directly. Yet textbooks continue to teach that mechanisms can only be proven false. Not only does this approach fail to reflect current practice, it also limits the possibilities for new generations of chemists by denying the value of supporting evidence. Students should be open to the option of designing experiments to confirm a mechanistic proposal and not be constrained by a theoretical approach that maintains that only falsifying experiments have value. What reasons do we have to believe that reaction mechanisms can only be proven false? Given the progress in studying mechanisms in recent years, can we in good conscience reject this claim? Some have argued that while there is a logical or philosophical limitation on our ability to prove mechanisms true, they can be proven false. This claim, examined in detail below, reflects a view of science popularized by Karl Popper in the 1940s and 1950s and criticized by later philosophers. During this same time period, at the height of Popper’s influence, chemists were constrained in their study of reaction mechanisms by methodological limitations inherent in classical kinetics. In the minds of chemists, Popper’s theoretical foundation became linked to these experimental limitations. Modern chemists

process and their comments appear here. We hope that publication of this paper and well-reasoned rebuttals such as those provided here will initiate a wide-ranging discussion. JCE will provide an online forum for further discussion of the issue. Our hope is that both faculty and students will contribute their opinions and ideas to this discussion. JWM have moved beyond these limitations and should abandon the philosophical restrictions and outdated ways of thinking that accompanied them. Philosophical Limitations The textbook quotes above imply that there is a philosophical limitation on our ability to prove chemical reaction mechanisms. It is true that mechanisms cannot be proven with philosophical certainty. Chemists collect observations, identify similarities between them, and postulate an underlying order that provides explanatory and predictive power. Einstein was logically correct in saying that no amount of observation can prove him right; inductive reasoning cannot provide absolute proof. This limit applies to all scientific activity, not just the study of reaction mechanisms. Even the most fundamental and well-tested theories may be overturned by future experiments. While science cannot prove a theory in the philosophical sense, it can in the practical and empirical sense (beyond a reasonable doubt). “Confirmed” theories are reliable in practice, offering explanatory and predictive power that is impossible for researchers to wholly doubt or deny (e.g. the tetrahedral geometry of the carbon atom). This is the best that any scientific activity can hope to achieve. In the vast majority of cases, chemists use inductive reasoning to confirm hypotheses in this practical sense. Organic chemistry journals generally require 1H and 13C NMR and high resolution mass spectrometry data for the characterization of new compounds. If there is stereochemical ambiguity, an X-ray crystal structure may be required as well. It is difficult to imagine falsifying tests being used to interpret data from NMR, MS, or X-ray diffraction studies to determine the structure of a compound. Data from these techniques are taken as strongly supporting the proposed chemical structure, especially when taken together. Though it makes little sense to have a separate philosophy of science and standard of proof for reaction mechanisms, textbooks teach that since mechanisms cannot be proven true (in the philosophical sense), the only option is to prove them false. According to a text on chemical kinetics, “with several options at hand, falsifying tests are devised so as to eliminate some contenders. With the range narrowed, one or only a few mechanisms

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Commentary remain. Even then, a mechanism is never really ‘proved’” (3). The job of the chemist in this model is to invent plausible hypotheses and then attempt to refute each one, provisionally accepting the last mechanism left standing. This model of scientific activity stems from the work of philosopher Karl Popper (4, 5). Scientists may know his ideas by the name “strong inference”, as it was popularized by John Platt in an influential paper in Science in 1964 (6). There is much to be said for this as a method: it captures the creative, imaginative side of science (inventing models and hypotheses) and the deductive, critical side (dispassionately refuting our own best models). It puts theories at risk and forces us to deduce predictions from a theory that can be rigorously tested. Although it serves as a productive methodology for working scientists, this cycle of conjecture and refutation breaks down as a general theory of knowledge. All true knowledge is negative in Popper’s philosophy of science—knowledge that a specific theory is false. Scientists can never provide evidence to logically support a theory; evidence can only refute theories. What led Popper to propose such a counterintuitive relationship of theory and evidence? He began by seeking criteria to differentiate true science from the pseudoscientific claims of Freudian psychology and Marxism. These systems of thought, while claiming scientific validity, seem to hold true no matter what result is observed. According to Popper, theories must be capable of being proven false by experiment in order to qualify as science (i.e. they must be falsifiable). Popper’s work also sought to restore certainty to the philosophy of science as logical positivism faltered. The logical positivists were a group of early 20th century philosophers (e.g. Schlick, Carnap, Ayer) who attempted to provide a sure logical foundation for scientific activity. One roadblock that prevented them from achieving this goal was the problem of induction: no amount of observation can result in necessary universal laws. Observing 100 white swans does not logically justify the conclusion that “all swans are white”—the next one very well may be black. On the other hand, the observation of a black swan would be sufficient to refute this hypothesis. This method of reasoning has its roots in logic and is known as denying the consequent. Suppose there is a proposed mechanistic intermediate A that cannot be observed directly. If A exists, it always produces an observable consequence B such that if A then B (A→B). If B is not observed, we conclude that A is not an intermediate in the pathway (~B→~A). On the other hand, even if B is always observed, this does not prove the existence of A. The arrow of necessity and causation only goes from A→B, not from B→A, because it is possible that several theoretical intermediates besides A could result in the observation of B. Thus it appears that evidence against a theory can refute it (~B→~A) with deductive logic while evidence for a theory cannot prove it (we cannot conclude B→A). Building upon these ideas, Popper created a philosophy that he believed restored certainty to science. (In this sense he continued the legacy of the positivists.) He “solved” the problem of induction by denying that it is the basis of knowledge. Instead of collecting observations to confirm theories, we obtain knowledge from refuting the many possibilities we can imagine. The refutations are certain because they are based on deductive 552

reasoning. We tentatively accept whichever theories withstand falsification. In this way Popper expanded the use of his concept of falsifiability from a mark of true scientific activity into a fullblown epistemology, or theory of knowledge. This is why he claims that no scientific activity can support or confirm a theory, and this is where the trouble starts. Later philosophers of science criticized Popper’s philosophy of falsification as a theory of knowledge (7). The asymmetry of what evidence can do in Popper’s philosophy is unsettling. Repeated successful tests of a theory have no logical basis in Popper’s philosophy to increase our confidence in it. In contrast, a single piece of contradictory evidence can topple an entire theory. A common objection to Popper, the bridge-building problem, considers a situation in which engineers set out to build a bridge. Should they use the tried-and-true theory or the newer and simpler one that has not yet been tested? Popper’s method of conjecture and refutation, rigorously applied, would suggest that the engineers would have no logical warrant to choose one theory over the other, as successful tests of a theory are worthless and neither has yet been falsified. This problem is the result of Popper’s denial of inductive reasoning. Working scientists, however, rely on induction and recognize that successful tests of a theory constitute support for it. Perhaps the most serious problem for Popper’s theory of knowledge is that whenever we make an observation, we rely on theories and assumptions beyond those that we are testing. A negative finding could result from flawed assumptions or methodologies rather than reflecting the truth of the theory itself. Quine wrote that “our statements about the external world face the tribunal of sense experience not individually but only as a corporate body” (8). We cannot test an individual theory about the world in isolation. A good scientific example of this is the chilly reception of Copernicus’ heliocentric model of the universe. One prediction of his model was a stellar parallax, but none was observed at the time. By 1729, when with better instrumentation the parallax became visible, it was realized that stars are much farther away from the Earth than earlier astronomers believed. In testing Copernicus’ predicted stellar parallax, the early astronomers were simultaneously testing both Copernicus’ model and the theory used to calculate the distance to the stars. When no parallax was observed, their mistaken assumption about the size of the universe led them to reject the Copernican system. Another aphorism attributed to Einstein illustrates the inability of observations to rigorously falsify theories: “If the facts don’t fit the theory, change the facts.” This is always a possible move because “facts” rely on other theories and assumptions. Returning to the world of chemistry, the same problematic relationship of theory and fact prevents chemists from proving reaction mechanisms false (in the philosophical sense). Mechanisms are mental constructs of how a reaction proceeds. The concepts and ideas that make up mechanisms (e.g. the electron, the atom, charge) are also metaphorical representations—models that help us relate our own embodied experience to the real world (9). Chemists cannot get outside the world of the mind to compare these concepts directly with the physical objects they represent. Evidence that could be used to falsify a mechanism is always interpreted through the lens of other metaphorical men-

Journal of Chemical Education • Vol. 86 No. 5 May 2009 • www.JCE.DivCHED.org • © Division of Chemical Education


Commentary tal constructs. Once again, facts are inescapably contaminated with theory. The important conclusion is that because facts are theory-laden, mechanisms cannot be logically proven false any more than they can be proven correct. In summary, the philosophical argument that reaction mechanisms can only be falsified stems from Popper’s efforts to create a theory of knowledge that solves the problem of induction and restores certainty to science. Later philosophers criticized these ideas because of the theory-laden nature of facts and the sense that positive evidence does support theories (scientists do use inductive reasoning). Popper’s method does not give us philosophical certainty, but chemists do not require it, only enough reliability to explain and predict phenomena at a practical level. Chemists can in good conscience continue to use Popper’s method of conjecture and refutation to design experiments—it is a useful methodology. But instead of limiting the range of experiments to falsifying tests, striving for an unattainable certainty, we should use whatever means are available, including experiments designed to provide supporting or confirming evidence. Technological Limitations Setting aside Popper’s philosophical limitations, are there valid scientific reasons why mechanisms can only be falsified? We argue that this was historically the case due to limitations in the techniques used to study mechanisms. Reactions could only be characterized at the macroscopic level, not the microscopic level. These constraints have been overcome over the years by technological advances that allow us to more directly observe reaction intermediates. In the past, steady-state kinetics was the primary means of generating data to determine organic reaction mechanisms. Classical kinetic studies relied on detecting changes in the concentration of reactants and products. Limited to the macroscopic properties of the reaction, such experiments can only refute proposed intermediates in the pathway. In such cases, Popper’s theory and the logic described above seem to be applicable. But if we can directly observe an intermediate at the microscopic level and show that it is along the reaction pathway, we can prove a mechanism correct (in the practical, empirical sense). In the words of enzymologist Alan Fersht, “It is often said that kinetics can never prove mechanisms but can only rule out alternatives. Although this is certainly true of steady-state kinetics, in which the only measurements made are those of the rate of appearance of products or disappearance of reagents, it is not true of presteady-state kinetics. If the intermediates on a reaction pathway are directly observed and their rates of formation and decay are measured, kinetics can prove a particular mechanism” (10). In certain simple gas reactions, chemists have achieved exhaustive descriptions of the dynamics of chemical reactions. In 1986 Herschbach, Lee, and Polanyi were awarded the Nobel Prize in Chemistry for their ground-breaking cross-beam studies in which beams of atoms or molecules are combined, localizing the reaction to a single point in space (11). Reacting molecules can be carefully controlled and exhaustively characterized, including their chemical composition, their angular distribution from the collision, their speed, rotational and vibrational

energy, and electronic states. Although this procedure is limited to simple molecular reactions, these results show that a complete description of a reaction pathway is possible. Over the years it has become increasingly possible to detect intermediates, even ones so short-lived that they approach transition states. Transition-state theory assumes that the high-energy structure in the transition state breaks down as rapidly as a molecular vibration (10–100 femtoseconds). No chemistry can happen faster than this. Using ultra-short laser pulses, physical chemists can now study reaction dynamics on the femtosecond time scale, a development for which Zewail received the Nobel Prize in Chemistry in 1999 (12). The time resolution is determined by the use of two laser pulses: the “pump pulse” excites molecules to a higher energy state, and the follow-up “probe pulse” at a second wavelength detects changes during the reaction. In an example of interest to organic chemists, Zewail studied the dissociation of cyclobutane into ethylene and observed a diradical intermediate with a lifetime of 700 fs, arguing for a stepwise rather than a concerted mechanism under these conditions (13). Others have expanded the use of these techniques to monitor increasingly complex organic and biochemical reactions using femtosecond absorption, fluorescence, or Raman spectroscopy. In summary, time-resolved spectroscopic techniques and improvements in theory provide the means for us to directly observe and understand reaction pathways at the microscopic level. Classical kinetic experiments, in contrast, were limited to observing the macroscopic properties of the reaction. These methodological limitations led to the adoption of a kind of skepticism toward reaction mechanisms where falsifying tests were thought to be the only way of studying reactions. These limitations no longer apply to modern chemists, who can make use of strongly supporting evidence. Can we therefore prove reaction mechanisms? Philosophically speaking, the answer is no. We can never prove a mechanism or any other scientific theory absolutely. Due to the inductive character of scientific reasoning and the theory-laden nature of facts, scientists cannot achieve philosophical certainty. These arguments cut both ways, however: we cannot logically prove a mechanism false any more than we can prove it correct. Popper’s method does not restore certainty, and chemists should not feel obliged to use it. Chemists are free to use evidence to either support or disprove mechanistic hypotheses. Mechanisms can be proven on a practical basis to the same extent as other scientific theories can be. Reaction mechanisms are not categorically different from other kinds of scientific theories, nor does their study require a specialized philosophical approach. It is inconsistent for chemists to ascribe to Popper’s philosophy for mechanistic studies alone—if Popper is right, then his arguments should apply to all scientific reasoning. The application of falsifying tests would seem very out of place in other contexts in chemistry. In spite of Popper’s rejection of inductive reasoning, chemists rely on induction to pragmatically confirm chemical structures and reaction mechanisms. While historically there was reason for guarded skepticism, today’s chemists are capable of understanding molecular dynamics in the same depth as molecular structure.

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Commentary We recognize that the motivation behind mechanistic skepticism may be pedagogical. Arrow pushing is an important means of communication, of keeping electrons straight, and of predicting reactivity. It is important to remind students that reaction mechanisms are theories, not facts. They should not be believed dogmatically and are open to refutation by later work. We fear, however, that the idea that mechanisms can never be proven or even supported by evidence will discourage students from using all the tools at their disposal. We should continue to encourage students to seek confirmation of their mechanistic hypotheses and use theories for which there is the most support. We should abandon the outdated claim that reaction mechanisms can only be proven false. Literature Cited 1. Vollhardt, K. P. C.; Shore, N. E. Organic Chemistry: Structure and Function, 3rd ed.; Freeman: New York, 1999; p 5. 2. Nelson, D. L.; Cox, M. M. Lehninger Principles of Biochemistry, 4th ed.; Freeman: New York, 2005; p 222. 3. Espenson, J. H. Chemical Kinetics and Reaction Mechanisms, 2nd ed.; McGraw-Hill: New York, 1995; p 1. 4. Popper, Karl. The Logic of Scientific Discovery; Hutchinson: London, 1959. 5. Popper, Karl. Conjectures and Refutations: The Growth of Scientific

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Knowledge; Routledge & Kegan: London, 1963. 6. Platt, J. R. Science 1964, 146, 347–353. 7. Godfrey-Smith, Peter. Theory and Reality; University of Chicago: Chicago, 2003; pp 57–74. 8. Quine, W. V. The Philosophical Review 1951, 60, 20–43. 9. Brown, Theodore. Making Truth: Metaphor in Science; University of Illinois Press: Chicago, 2003. 10. Fersht, A. Structure and Mechanism in Protein Science; Freeman: New York, 1999; p 216. 11. Herschbach, D. R. Angew. Chem. Int. Ed. Engl. 1987, 26, 1221–1243. 12. Zewail, A. H. J. Phys. Chem. A 2000, 104, 5660–5694. 13. Pedersen, S.; Herek, J. L.; Zewail, A. H. Science 1994, 266, 1359–1364.

Supporting JCE Online Material http://www.jce.divched.org/Journal/Issues/2009/May/abs551.html Abstract and keywords Full text (PDF)

Allen Buskirk* and Hediyeh Baradaran are in the Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602; *[email protected].



Commentary: Reviewer Comments

A Discussion of “Can Reaction Mechanisms Be Proven?” Theodore L. Brown Department of Chemistry, University of Illinois, Urbana, IL 61801; [email protected]

When I reviewed the initially submitted manuscript, I had quite a few things to offer by way of constructive criticism. Many of the points I made have been addressed in revision, so I won’t belabor them. Instead I want to comment on what seems to me to have been a turn in revision toward a more critical analysis of Popper’s philosophy of science and the ways in which it applies to chemistry. In several places the authors go out of their way to drill home the notion that Popper argued that one could only prove a theory wrong, and that having acquired an accumulation of experimental results consistent with it did nothing to strengthen the theory. Clearly, however, a theory that has been tested by many different experiments that could have in principle proven it to be incorrect is a “better explanation” for having been so tested. Popper would agree that while a useful theory is always subject to falsification, it becomes more “fit” for having successfully passed real tests. Similarly the idea of “strong inference” is that a viable theory is one for which an experiment can be devised that could in principle produce results that refute the theory. If the theory is so ambiguous that no experimental test can be imagined that could in principle render it false, it is not a good theory. One aspect of the paper in its present form that concerns me is the authors’ tendency to see confirmatory experiments as distinct from those that actually provide a test of a theory or hypothesis. The authors talk about confirmatory experiments such as acquiring NMR or mass spectral data in drawing conclusions about molecular structures, as though these were counterexamples to Popper’s approach. But such experiments are not simply confirmatory; they test the hypothesis that the molecule has a particular structure. If the NMR spectrum comes out other than in a way that makes sense in terms of the hypothesized structure, the hypothesis will have been disproved, and a new structure will have to be proposed. Many a natural product chemist has had the experience of having a hypothesized structure disproven by spectroscopic data. I’m not sure that it is possible to devise a useful purely confirmatory experiment. Consider an instance in which we

believe we know the general form of the potential energy surface over which a chemical reaction proceeds and the pathway with lowest energy barrier for getting from reactants to products. A “confirmatory” sort of experiment might then be to use a new technology to probe some aspect of that pathway, such as whether electron transfer occurs early or late, or at what stage in the process a particular bond opens up. But these experiments themselves rest on new hypotheses—for example, that the electron transfers at an early stage, or that bond A opens up before a new bond is formed—which are subject to falsification by the experiments. I agree with the authors’ statement that “Although it [strong inference] serves as a productive methodology for working scientists, this cycle of conjecture and refutation breaks down as a general theory of knowledge.” Indeed Platt was criticized for taking an unwarrantedly narrow view of what constitutes scientific practice, and the criticism applies as well to Popper’s work. A biologist studying the behaviors of an animal species in the field, or a chemist probing the limits of applicability of a new synthetic route, serve as examples of scientific work that does not readily fit into a falsification or strong inference modality. Popper wrote as he did partly because he lived in a time when psychology and many other nascent fields of science were making inroads into public consciousness. Popper’s training was in psychology. In his youth he was a Marxist, but he later rejected Marxism and other “isms” that he saw as lacking in intellectual rigor. He believed that it was important to differentiate what he saw as “real” science from “pseudosciences” that masqueraded as real science. So his particular take on experimental methods and what constitutes “falsification” must be seen in light of his background and time. Since Popper, many philosophers of science have focused more on what scientists actually do, what makes for a good explanation, and on use of abductive reasoning (or inference to the best explanation), introduced in the late 19th century by the American philosopher Charles S. Peirce. Incidentally, Peirce was educated as a chemist.

This article has been reformatted from its original appearance in the print Journal.

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A Discussion of “Can Reaction Mechanisms Be Proven?” David E. Lewis Department of Chemistry, University of Wisconsin–Eau Claire, Eau Claire, WI 54702; [email protected]

This is an interesting paper [by Buskirk and Baradaran] that raises the philosophical question of exactly what constitutes proof in a scientific study: how the term proof is to be defined, and what level of certainty constitutes proof. While I do not necessarily agree with the authors’ premise or conclusions, I expect that the paper will spark an interesting debate among the readers of the Journal. In the field of mathematics, the term proof is absolute— proof provides absolute certainty of truth. In the field of juris prudence, however, proof carries the qualification, beyond a reasonable doubt. In contrast to the mathematical definition of proof, this is not absolute certainty, and “not guilty” is not a synonym for “innocent”. Likewise, I believe that proven is not synonymous with proven beyond a reasonable doubt. In a practical sense, I would assert that most professional chemists use the legal definition of proof when they accept evi dence for or against a particular hypothesis or theory. At some point, the experimental (circumstantial) evidence in favor of the mechanism under study becomes overwhelming, and at that point one might argue with considerable justification that the mechanism has been proved beyond a reasonable doubt. Some of the authors’ points are valid and pertinent: as we currently teach it, the concept that a mechanism cannot be proven is, indeed, the dogma of introductory organic chemistry. The authors’ logical extension of this dogma—that this means (in a formal sense, at least) that repetitious experiments that fail to disprove a mechanism, do not prove it—is formally correct, but their argument is something of a reductio ad absurdum, in my opinion. As the authors are well aware (the major thesis of their argument makes exactly this point), chemists do take re peated experiments that fail to falsify a mechanism as evidence in its support, even if they do not formally designate this as proof. For many of us, myself included, this level of confirmation becomes a de facto proof of a mechanism’s validity—in practice, we apply a less stringent standard than we do in the classroom. Failure to be falsified by repeated experiments is one hallmark that is used to elevate a hypothesis to the status of a theory, and in this aspect a well-tested reaction mechanism is more akin to a theory than a hypothesis. What we teach to beginning students, however, is not a subtly nuanced argument about levels of confidence, but is, instead, based on the absolute definition of proof. While this may be a little hypocritical, I do not think it is necessarily wrong: most students at the beginning of their studies are likely to be

confused by the more subtle nuances of mechanistic discussion. This does not, however, make it right, and this is where I differ with the authors: I maintain that the difference between the two standards is significant and would argue for the absolute standard. Of course, this does lay me open to the criticisms in the paper that one cannot actually falsify a theory. This assertion is an important part of the authors’ arguments in favor of being able to prove a mechanism. However, I would maintain that obtaining evidence against a mechanism does prove that something is false, either the mechanism proposed or the theory used to interpret the experimental results. In the absolute sense, one may not be able to state with total confidence which of the two is incorrect, but repeated experiments aimed at testing the two theories separately should provide evidence in favor of one of the two being more likely to be wrong. Another seminal idea raised in the paper is the suggestion that modern technology allows us to prove a mechanism. In my opinion, a complete description of a mechanism must incorpo rate a description of each intermediate between the reactants and products, and the transition states separating them. While it is true that ultrafast spectroscopy has allowed us to probe very short-lived intermediates, we cannot now (and, I venture, will not in my lifetime) see a transition state directly. Absent the ability to study the transition states of the elementary steps of a mechanism directly, at least some of the detail of a reaction mechanism must still rest with the chemist’s application of de ductive logic and Occam’s razor to the experimental results. I also have some misgivings about taking computational results as gospel. Like everything else, their value depends on the strength of the underlying theory. Computational results are getting extremely good, and modern, high-level computational results do inspire considerable confidence. Nevertheless, the Luddite in me still has some nagging little doubts about their absolute validity. Again, they may serve as evidence for proof beyond a reasonable doubt, but I cannot allow them the level of absolute proof. In conclusion, while I can see the merits of the arguments being made by the authors, I respectfully disagree with their conclusions. What we have here, ultimately, is a difference between theory and practice—we teach the absolute definition of proof, but use the legal definition when it comes to reaction mechanisms. Nevertheless, I maintain that the term proof is best defined in the absolute sense.


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A Discussion of “Can Reaction Mechanisms Be Proven?” Tehshik Yoon Department of Chemistry, University of Wisconsin–Madison, Madison, WI 53706; [email protected]

In their Commentary, Buskirk and Baradaran argue against the well-accepted axiom that reaction mechanisms can never be conclusively proven but only experimentally falsified. Their argument has both a philosophical basis (that Popper’s falsifiability standard is impractically strong) and a technological one (that contemporary high-resolution spectroscopic methods rescue us from our weak epistemological position). The crux of the authors’ philosophical objection is that “[r]epeated successful tests of a theory have no logical basis in Popper’s philosophy to increase our confidence in it.” Indeed, a strong version of Popper’s falsifiability standard could leave us unsure of any experimental observation. Scientific knowledge would become inaccessible, and theories would be mere conceptual models devoid of any concrete relationship to physical reality. Certainly, Popper had contemporaries who articulated similar critiques of his approach to the problem of inductive reasoning. On the other hand, I think that it’s fair to say that Popper is not the only modern philosopher who has had a significant influence on the way scientists conduct research. Kuhn (1) would tell us that the value of a scientific theory rests upon its ability to predict future outcomes. Theories that are supported by repeated experimental validation become accepted as “paradigms”, which succumb to falsification only with great difficulty. In Kuhn’s description of scientific inquiry, the practical value of a theory is independent of the ontological status of the theory itself. We can (and we do) behave as if a well-validated theory is true even if we have no epistemologically rigorous way of showing it to be so. I would argue that this is exactly the same standard we apply to the study of chemical mechanisms. As experimental chemists, we do indeed perform experiments designed to corroborate our mechanistic hypotheses. Nevertheless, there is a meaningful distinction between the “proof ” and “validation” of a scientific theory, and by extension of a reaction mechanism. For any given discrete set of data, there exist an infinite number of possible explanations consistent with all the data. No matter how well validated a mechanism is, we can always posit alternative mechanisms that also fit our experimental observations. We winnow through these alternatives using two tools—Occam’s razor, the indispensable but logically inconclusive principle that the simplest explanation consistent with the data is the one most likely to be true; and the careful design of experiments to falsify the reasonable alternative mechanistic interpretations of the existing data. The best and

most useful mechanistic hypotheses are those that have been experimentally validated and have survived falsification. The authors argue that techniques such as molecular beam and femtosecond spectroscopy allow us to gain insights into reaction mechanisms that were inaccessible using classical kinetic methods alone. This is certainly true, but I submit that no amount of technological sophistication rescues us from the overabundance of possible alternate explanations for any given discrete data set. Another well-accepted axiom of classical kinetics holds that the ability to observe an intermediate does not imply that this intermediate is on the productive pathway toward the product; there exist an infinite number of alternate possibilities. This continues to be true of data gathered by newer techniques, no matter how fleeting the lifetime of the intermediates observed. The intermediate may merely be en route to decomposition. It may exist in non-productive equilibrium with the resting state. There may be another kinetically invisible step following production of the intermediate. There may be another pathway kinetically accessible under experimentally relevant conditions. There may be an alternate structure consistent with the spectral data collected. And so on. New methods to probe reaction mechanisms in greater detail can certainly increase our confidence in our mechanistic hypotheses by enabling us to design more sophisticated corroborating and falsifying experiments, but they ultimately cannot provide us with affirmative proof. Finally, the authors state as a motivation for their argument that “the idea that mechanisms can never be proven or even supported by evidence will discourage students from using all the tools at their disposal.” My experience suggests the opposite problem. Far too often, I find that beginning graduate students accept the results of computation rather uncritically, treat important control experiments as afterthoughts, and accept the chemical literature as an inerrant source of truth. It seems to me that learning to adopt a position of healthy scientific skepticism is an important part of our intellectual development as research scientists. I maintain that the falsifiability standard, as used by chemists for decades, stands up to the critique articulated in Can Reaction Mechanisms Be Proven? and is as relevant and important as ever. Literature Cited 1. Kuhn, T. S. The Structure of Scientific Revolutions, 3rd ed.; University of Chicago Press: Chicago, 1996.


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A Discussion of “Can Reaction Mechanisms Be Proven?” Peter A. Wade Department of Chemistry, Drexel University, Philadelphia, PA 19104; [email protected]

The aphorism that “Mechanisms cannot be proven, only disproven” is a cornerstone of modern science. However this aphorism has never stopped scientists from obtaining data to support a mechanism. Supporting data are an ingrained part of the scientific method as practiced. A mechanism that has a large body of supporting data is considered well-established and is provisionally treated as correct. In short, logic prevails in the current state of affairs. In my opinion, Buskirk and Baradaran have taken an extreme position in claiming that the aphorism requires us to accept that, “Only evidence that refutes or falsifies a mechanism is meaningful”. This has never been mainstream scientific practice. There is no conflict between the concept that “mechanisms cannot be proven” and the concept that with sufficient supporting data, mechanisms can be considered well-established and treated (always provisionally) as correct. Many well-established mechanisms have stood the test of time and will continue to do so. Others will likely need to be altered as new data become available. Alterations will continue despite—indeed because of—our ever more sophisticated tools and techniques. “Proving” a mechanism will remain elusive since all mechanisms are established on the basis of indirect evidence of one form or another. This is true whether or not there are direct spectroscopic observations of all suspected intermediates, since there is always the possibility others are

present or that one of those present is incorrectly placed in the overall scheme. Computational results, even those based on ab initio calculations, contain assumptions and are therefore subject to future refinement that just might substantially alter conclusions. It is unnecessary, even dangerous, to throw out the aphorism that “mechanisms cannot be proven, only disproven”. Which mechanisms are to be regarded as “proven”? Who will decide? Can this concept of “proven” be extended elsewhere in science? Let’s take an extreme example: there are undoubtedly those who would assert that creation science has “proven” the intelligent design theory of species selection. As in Karl Popper’s day, there are those who would abuse generally accepted alternatives to testability as precepts for studying scientific phenomena. Testability was defined by Popper as falsifiability. In conclusion, I take strong exception with Buskirk and Baradaran’s premise that “mechanisms can now be proven”. Perhaps this is mainly a semantic difference, since they have hedged this premise by saying, “It is true that mechanisms cannot be proven with philosophical certainty”. The current usage of “well-established” seems to equate to Buskirk and Baradaran’s suggested use of “proven”. However, it is my opinion that exchanging “proven” for “well-established” is a step backward in science. I plan to continue accepting mechanisms as well-established but not provable and doing chemistry rather than philosophy.


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Can Reaction Mechanisms Be Proven? - ACS Publications

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