Internet Enthalpy-Entropy Compensation Documents written in University of Aberdeen Research Laboratories and continued expansion updates from home which developed ideas stemming from prior publications of D. Grant arising from various periods of academic and industrial research lab activities e.g. ref. (1) (1) Pyrolysis of chlorinated organic substances D. Grant (I.C.I. Ltd.) J Appl Chem Biotechnol. 1974 24 49-58 This research confirmed the results from a previous paper ref. (1a). (1a) N.E. Aubrey and J.R. Van Wazer (Monsanto Co) J. Amer Chem Soc. 1964 86 4380-4383 that the pyrolysis of any fully chlorinated organic molecule produces: CCl4+ C2Cl6 + C6Cl6 (hexachlorobenzene) in amounts determined only by the Cl/C ratio of the starting substances (or substances) and a single equilibrium constant. Whilst the Monsanto researchers had believed that the reaction products obtained from all chlorocarbons were solely determined by a reversible thermodynamic equilibrium between the above three substances, following-on studies conducted at I.C.I. Ltd. which I reported in ref. (1) however suggested that the Aubrey-Van Wazer chlorocarbon apparent-equilibrium was not fully reversible, and further, that it was probably determined by extrathermodynamic processes involving critical ratedetermining (fluid phase) nucleation mechanisms rather than operation of fully reversible classical thermodynamic driven equilibration processes. The nature of the nucleation process(es) was however not established. Similar general nucleation process may also apply widely, it might be supposed, and apply to the initiation of numerous other types of chemical reactions; if may, e.g., be afforded by small nucleating particles for which the Evans Fluctuation Theorem (in which, for small particles the natural time direction of increased entropy which applies to large particles is reversed; (the smaller the particles and the time interval, the probability of Evans Fluctuation Theorem reverse entropy effects increases exponentially. The ultimate such reverse entropy self assembly of order effect could arise from a mathematical ‘point-in-space’-nucleating-system). The relevance of the Fluctuation Theorem putatively requires that preceding ideas of how chemical substance react and how such reactivity allows the complexity of biology to emerge, should be reassessed. Since the phenomenon of enthalpy entropy compensation has turned up throughout physics, chemistry and physics, such a re-assessment might be most fruitfully conducted with those chemical reaction processes which demonstrate enthalpy-entropy correlation and isokinetic behavior. What might be a useful hypothesis here is that this compensation might arise from the dependence of rate processes on often-not-acknowledged nucleation phenomena: these seem to be a mystery of a similar magnitude to that which is associated with the enthalpy-entropy compensation phenomenon. I had previously worked in J.R. Van Wazer’s Monsanto Co St Louis laboratory where I investigated (as a member of the same team which had included N.E. Aubrey (cf. ref (1)) some other (apparent) equilibration processes* which can be achieved in the fluid phase. The realm of “no-mechanism” or “where-mechanism-is replaced-by-reorganization-equilibria-chemistry” which was the topic of such researches was reviewed by J.R. Van Wazer in 1962 (ref. 1a). (1a) J.R. Van Wazer Amer Scientist. 1962 50 450-472 *[My studies included polysulfides, polyselenides, polyphosphonates, polysulfates and ligand exchanges between organo-tin compounds (cf. refs. cited in (2) as well as preliminary investigations into the structural reorganization of organo-vanadium compounds and of the sealed-tube chlorination of organic molecules by sulfuryl chloride (for which the preliminary results had suggested that (quasi)

thermodynamic principles also dictated the outcome of these reactions). Numerous systems like the carbon chlorine system could be fitted to (quasi) thermodynamic-equilibrium-based-models which allowed the outcome of the observed reorganization processes to be rationalized). A similar paradigm applied also to the polysilicate esters (I researched these systems at Monsanto, Ruabon, Wales, UK (assisted by the University of Keele); cf., ref. (2)]. (2) D. Grant J Inorg Nucl Chem. 1967 29 69-81 Another research topic from my time at the Monsanto research facility in Ruabon was the selfassembly of silica sol particles. Aspects of this process which benefited from the ability of seeds of specifically microstructures silica sol particles, surprisingly seemed to resemble biological reproduction. The overtly nucleation-determined processes of the seeding of silica sol formation were the basis of novel methods of preparing silica sols (ref. (3)). (3) Patents: British Pat. 1,134118 and 1143019 (Chem Abs. 70 P50947e and P98389b). Cf. also D Grant et al. Med Hypotheses 1992 38 46-48 and ref. (4) (4) S.T. Hyde et al. Physica A. 2004 339 24-33 {There is a hint (ref. (4) that the process of seeded generation of specific species of silica sols could kick start pre-biological cellular activities which might evolve using Evans reverse entropy into conventional types of biological cells}. The Hammett σ (and Taft σ∗) extrathermodynamic linear free energy relationships had previously been discovered by synthetic organic chemists to gave an empirical prediction of (aromatic) chemical reactivity. Since these relationships seemed to contravene the second law of thermodynamics they have been dismissed by some chemists as being trivial and highly misleading (cf. e.g. A. R. Butler Chem Brit 1989 997-998). Hammett and Taft factors are, however, closely linearly-correlated with NMR (1H and 31P) chemical shift δ values, cf. ref (5) (5) Cf. e.g. for 1H NMR shifts of aromatic phenol OH M.W. Dietrich et al. Anal Chem. 1966 38 11 1479-84 and 31P NMR shifts for (O)P(R)2X where R=C6H5 and CH3 and XP(R)2NP(R)2X where R = C6H5 by A. Schmidpeter and H. Brecht Angew Chem Internat Edit. 1967 6 (11) 945-946 J.E. Leffler, ref. (6) (6) J.E. Leffler J. Org Chem. 1955 20 1202-1231 had however earlier clearly demonstrated that Hammett equations were actually sub-class of a much more general and widely applicable-to-organic-chemistry-enthalpy-entropy correlation system. This general process like the Hammett (and Taft etc.) sub-processes is an extrathermodynamic phenomenon, meaning that it apparently breaches the physics laws especially the 2nd law. The enthalpy-entropy correlation for sets of rate constant terms creates to an isokinetic temperature where all reactions rate constants for the different chemical molecule starting material undergoing the same class of chemical transformation react at the same rate; furthermore for other temperatures the general overall occurrence of compensation between pre-exponential and activation energy terms which causes their effects on the rate constants to oppose each other, tends to make the reaction rates for Hammett and related enthalpy-entropy compensated series of chemical substances to be more equal and therefore more likely to engage in stochastic (randomization of product) processes than is the case for noncompensated chemical reaction rate processes. My ICI Ltd. CIRL researches had included a discussion with a then scientific leader in this field P.J. Thomas a co-worker of Allan Maccoll (UCL) who had established that the transition states formed in rate determining processes occurring during the pyrolysis of chlorinated organic substances involved the formation of some kind of unconventional (partially activated carbonium ion) intermediate. This idea was later extended (cf. ref. (7)) by E. Uggerud

(7) E. Uggerud et al. (Eur J Mass Spectrom. 2006 131-134 a paper which was dedicated to the memory of Allan Maccoll) who showed that alkyl group substituent reactivity effects (found in the types of reactions studied by Thomas and Maccoll) could be linearly correlated with Taft σ∗-values. This indicates that enthalpyentropy compensation is an inherent component of reactions involving aliphatic as well as for aromatic starting materials. Whilst Thomas et al. had conceded that some form of linear correlation between logA and Ea values often showed up in rate constants for series of related chemical reactions, this was not the case for true homogeneous gas phase dehydrohalogenation of organic molecules for which the logA values were most often found, they believed, to be 1013 sec-1 (the thermal activation collision number or bond vibration rate). Data from a Chemical Abstracts survey (made in 1968 using Reading University library) in connection with my I.C.I. researches has however suggested that a clear linear correlation existed between log A and Ea for my accessed published dataset which bracketed homogeneous as well as heterogeneous dehydrochlorination reactions; (cf. Fig. 1, below which includes not only the homogenous but also rate constants) which were though to be determined by surface effects.

Fig. 1 (a plot of the gas phase dehydrochlorination rate constant data) Fig. 1 confirms that, for supposed homogeneous gas phase processes, values of logA tend to be correlated to Ea values and also that some reaction conditions create apparent logA pre-exponential values which are considerably in excess of the 1013 value (this according to the principal IngoldHinshelwood older-conventional-view of thermal activation should not be higher than 1013sec-1, an idea which was challenged by by Blackadder and Hinshelwood, ref. (7a) (7a) D.A. Blackadder & C. Hinshelwood J Chem Soc. 1958 2728)-2734 who considered that the inclusion of the energetic coupling between non-reacting but in phase covalent bond vibrations from distant parts of the reacting molecule could perhaps explain this anomalously large pre-exponential value effect; however this idea seems not to have been generally accepted

although a variant of it appears to have been used by W. Linert to explain compensated rate processes occurring in solution especially aqueous solution where hydrogen-bonded aggregates could allow very large unstable vibrational spectroscopic continua to be generated; cf. (ref. 8) a 2001 review of the enthalpy-entropy compensation phenomenon. (8) L. Liu and Q.-X. Guo Chem Rev. 2001 101 673-695 (Isokinetic Relationship ,Isoequilibrium Relationship and Enthalpy-Entropy Compensation) The above general applicability of a single correlation curve to a class of chemical reactions irrespective of the mechanism is usually suggestive of ‘thermodynamic control’ rather than ‘kinetic control’. The actual kind of ‘thermodynamic control’ is perhaps more accurately labeled ‘enthalpy-entropy extrathermodynamic counter-thermodynamic control’ where the underlying control process which tend to make rate constants more similar than they could rationally be, on the basis of the accepted laws of physics, is, apparently a facet of a general all-pervasive (perhaps e.g. from. vacuum zero point energy) mechanism of nucleation of structure building which could conceivalbly derive from the reverse-entropy characteristics of the Evans Fluctuation Theorem [which proposes reverse time entropy change (i.e.. entropy tends not always to increase with positive time as required by the second law) but decreases with positive time or time has changed direction; the ability of systems to accomplish this bizarre behavior is hypothesized to vary exponentially with (entropy)/(time) {which are extensive properties meaning that small sized (e.g. nucleation site) entities (‘engines’) will tend (it is now postulated) to create order naturally by processes which are equivalent to reversing direction of time (as for 2nd law conditions)}]. The enthalpy-entropy compensation effect applies to semiconductor (traps) (for both inorganic and organic including proteins). The dark currents show individual pixel generated very large datapoint point linear curves shown in ref. (9) which are analogous to those indicated in Figs. 1 (above) and Fig. 2 (below). (9) R. Widenhorn et al. J Appl Phys. 2001 89 (12) 8179-8182 Enthapy-entropy compensation apparently controls the nucleation of helix coil (phase) transition in proteins (cf. ref. (10) (and putatively also is widely applicable to the phenomenon of protein folding). (10) O.K. Vorov et al. Biophys J. 2009 97 (11) 3000-3009 Fig. 2 shows the effect of inorganic counterions (putative water structure generation related? enthalpyentropy correlation in rate constant transition states) (data accessed from literature obtained during my University of Aberdeen polysaccharide group researches) enthalpy-entropy compensation and the and associated isokinetic T (= ca. 20oC) is apparent in the rates of nucleated phase change processes of marine algal biological anionic polysaccharides, [each point is for different inorganic counterion conditions]. The (enthalpy-entropy controlled supramolecular structuring) which occurs with of the marine algal polysaccharides which are of analogous structure to the mammalian anionic polysaccharides suggests that similar enthalpy-entropy controlled nucleation may putatively also also control nucleation of structure therein and hence may be a driving force for animal development and evolution. The data plotted in Fig 2 are for kappa κ carrageenan (□ ■ points) from K.R.J. Austen Biopolymers. 1988 27 139-155 p 150 and Table II; the other points are for iota ι carrageenan I.T. Norton et al. J Chem Soc Faraday Trans. 1983 79 2501-2515 Fig. 2 (n.b. 4.1859J = 1cal)

Fig. 2. Enthalpy-Entropy Correlation During Algal Polysaccharide Phase Change

The binding of counterions to heparin (mimetic of the heparan sulfate side chains of heparan sulfate proteoglycans (prime orchestrators of growth factor activities and other determinants of animal cellular activity and achievement of morphology during tissue homeostasis, wound healing (and also putatively embryo assembly etc.) apparently achieve selectivity at least partly via a similar nucleation of supramoecular structure to that shown by the alginates illustrated in Fig.2. A simple electrostatic binding mechanism (at least for most cations with a possible exception of Mg2+) the previously held hypothesis of such binding (the Manning electrostatic mechanism), was not confirmed , instead the binding process more closely resemble a phase change process of a similar character to that illustrated by Fig. 2. This is likely to be nucleated process; such compensated nucleation processes putatively again as in the discussion of gas phase reactions, allows Evans reverse-time entropy to generate order (in apparent breach of the classical laws of physics) and thereby puttively permits animal evolution to take place using reverse Evans entropy; such animal development programs can be adapted to optimize the organism’s most effective interactions with the environment). The involvement of water aggregates in the above nucleation process is suggested by the cation dependence of water cluster association with heparin. (This may conform to the Linert hypothesis further developed by Liu and Guo ref. (8) ). (Cf. also ref. 11) (11) Papers by D. Grant et al. listed in the W.F. Long and F.B. Williamson Aberdeen University group publications listed by University of Aberdeen http://www.abdn.ac.uk/~bch118/publications 2003march.doc or http://www.abdn.ac.uk/~bch118/index.htm (Professor William. F. Long, Research, click on Publications); cf., e.g., D. Grant et al. Biochem J. 1992 285, 477-480; ibid., 283 243-246, 282 601-604. Seeding of crystal formation was found to be inhibited by heparin and heparin-like substances

which apparently adsorbed onto seed crystal surfaces. This caused not only the blocking of crystal growth but also altered the morphologies of the inhibited crystals which were permitted to grow. Cf. refs (12) and (12a.) (12) D. Grant et al., Biochem J., 1989 259 41-45. Endogenous heparin apparently could protect tissues against the pro-inflammatory effects of pathologically formed crystals (e.g. at blood vessel walls) by this mechanism. (12a) D. Grant et al. Med Hypotheses. 1992 38 49-55 Enthalpy-entropy compensated sets of equilibrium and rate constants show up throughout physics, chemistry and biology. This seems to suggest some alternative paradigm which allows for a classification of natural phenomena which challenges the system of classical thermodynamics. The similar challenge to classical thermodynamics posed by the Evans Fluctuation Theorem Cf. Wang et al. (ref. (13)) (which proposes that reverse time flow entropy increase with positive direction of time. Is an inherent property of small-sized engines) is now suggested to allow a new paradigm of chemical reactivity especially as it applies to biology to be developed. (13) G.M. Wang et al. Phys Rev Lett. 2002 89 050601. Enthalpy-Entropy Compensation Note Concerning rate constant data accessed from Chemical Abstracts during 1966-8 by D Grant [at I.C.I. Ltd. Central Instruments Research Laboratory, UK] later discussed [at The University of Aberdeen, UK] in a 1984 research report. Enthalpy entropy compensation was found to apply to conventionally formulated (putative homogeneous gas phase) organic substance dehydrochlorination rate constants k, [log10k =A –Ea/4.6T] (where Ea is the (enthalpy-related) Arrhenius activation energy and log10A the (entropy-related) preexponential term) from the following
No. Ea log10A (kcal mol-1) 1 48 13 2 23 2.1 3 47 10.81 4 64(.5) 15.7 5 60.8 14.6 6 56.6 13.51 7 32 7.58 8 5.9 14.2 9 33.9 7.77 No. 11 12 13 14 15 16 17 18 19 Ea log10A (kcal mol-1) 27.1 6.2 38 9.74 36.5 9.62 15 4.6 29.2 7.91 55 13.45 55.1 13.5 34.2 8.21 55 13.45 No. 20 21 22 23 24 25 26 27 28 Ea log10A (kcal mol-1) 57 14 55.15 13.61 30.4 7.71 57 14 58.3 14.61 53.5 14.61 55.33 13.81 50.5 13.4 54.9 13.8




The following text, written later (at the University of Aberdeen on April/5/1984 discussed the above data in a note entitled : “COMPENSATION EFFECTS” an Apple II word processed, dot matrix printed (vide infra) (scanned) text follows,

The “Compensation Effect” may be defined by the following: log k = a-E / 4.6T

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