Thermodynamic Versus Kinetic

Traditional shake-flask or gold standard solubility methods start from solid material vigorously mixed with an aqueous buffer until equilibrium is reached between undissolved and dissolved materials. This may take only a minute or 72 h or more and is compound specific. 

These equilibrium solubility conditions are defined as being thermodynamic -the most stable species is in solution at equilibrium and not necessarily the fastest 

Assays starting with a compound predissolved in an organic solvent (typically DM SO) tend to have shorter incubation times, do not include time course measurements, and therefore the position of equilibrium is not determined, and for highly soluble species the compound may not be present in excess. This type of measurement is typically referred to as kinetic.  

In the hit-to-lead stage of drug discovery, compounds are generally only available in solvents such as DMSO for a number of reasons  

Attempting to measure a thermodynamic solubility of compounds which will then be used under these screening conditions, will not necessarily give a useful picture of the compounds performance. They will not reflect the more transient nature of the compound that is present in nonequilibrium systems. The presence of organic solvents changes the dielectric constant of an aqueous solution and thus helps to solvate lipophilic compounds in particular, and will give an increased solubility for some series of compounds across the Biopharmaceutics Classification System (BCS) [4]. This is an important consideration in the ultimate use of the solubility data, and a lack of full solubility of the analyte at the test concentration will lead to an underestimation of the compound s true activity. Measuring the solubility of the compounds in close approximation to the assay conditions to which they will be exposed will be more relevant. Indeed, if sensitivity is not an issue, then the quantities, concentrations, and incubation conditions used should reflect those available in the discovery assays. 

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Some of the distinctions that we shall have to examine in more detail before proceeding much further are the considerations of order versus disorder, solid versus liquid, and thermodynamics versus kinetics. These dualities are taken up in the next section. With those distinctions as background, we shall examine both the glassy and crystalline states from both the experimental and modelistic viewpoint. 

Thermodynamic Versus Kinetic Control of Product Distributions. 228... 

Slade, L. and Levine, H. 1985. Intermediate moisture systems concentrated and supersaturated solutions pastes and dispersions water as plasticizer the mystique of bound water thermodynamics versus kinetics (Number 24). Presented at Faraday Division, Royal Society of Chemistry Discussion Conference - Water Activity A Credible Measure of Technological Performance and Physiological Viability Cambridge, July 1-3. 

Very good yields, mild conditions, regioselectivity, versatility in the choice of the two reacting species (easy access to thermodynamic versus kinetic silyl enol ethers as well as to the required a-chloroalkyl phenyl sulfides) give to these sequences a particularly wide scope. Neopentylation is one illustration of their utility [325]. 

A PM0-CND04 analysis6 of thiatriazole and several 5-substituted derivatives (R = Ph—, MeS—, NH2—, CH2=CH—) leads to the prediction that alkylation at position 4 is favored, the relative order being N-4 > N-2 > N-3 (see also Section III, B). Companion potential surface calculations suggest that both H+ and CHi prefer in-plane attack on the nitrogen a-lone pairs.2 Position 3 is again the least-favored attack site, in direct contradiction to experiment.6 Either the calculations are misleading or the complexity of thermodynamic versus kinetic control in the thiatriazole system has yet to be unraveled. 

Formation of a highly electrophilic iodonium species, transiently formed by treatment of an alkene with iodine, followed by intramolecular quenching with a nucleophile leads to iodocyclization. The use of iodine to form lactones has been elegantly developed. Bartlett and co-workers216 reported on what they described as thermodynamic versus kinetic control in the formation of lactones. Treatment of the alkenoic acid 158 (Scheme 46) with iodine in the presence of base afforded a preponderance of the kinetic product 159, whereas the same reaction in the absence of base afforded the thermodynamic product 160. This approach was used in the synthesis of serricorin. The idea of kinetic versus thermodynamic control of the reaction was first discussed in a paper by Bartlett and Myerson217 from 1978. It was reasoned that in the absence of base, thermodynamic control could be achieved in that a proton was available to allow equilibration to the most stable ester. In the absence of such a proton, for example by addition of base, this equilibration is not possible, and the kinetic product is favored. 

Many reviews deal with the main mechanistic aspects of the metathesis reaction [10]. There are three basic metathesis reactions (apart from polymerization reactions) the ring-closing metathesis (RCM), the cross-metathesis (CM) and the ringopening metathesis (ROM) [11]. Among the fundamental aspects that govern the reaction course, the thermodynamic versus kinetic issue is particularly important when considering the application of RCM to the construction of macrocydes. 

Understanding the behaviour of organic bases in solution requires some knowledge of their gas-phase (intrinsic) basicities [proton affinities (PAs)]. These can be determined by ICR methods or by variable-temperature pulsed high-pressure mass spectrometry. Both methods afford basicities termed thermodynamic versus kinetic basicity. 

Balzer W. (1982) On the distribution of iron and manganese at the sediment/water interface thermodynamic versus kinetic control. Geochim. Cosmochim. Acta 46, 1153-1161. 

For a discussion of thermodynamic versus kinetic control, see Klumpp, G.W. Reactivity in Organic Chemistry, Wiley, NY, 1982, pp. 36-89. 

Lu N, Yin D, Li Z, Yang J (2011) Structure of graphene oxide thermodynamics versus kinetics. J Phys ChemC 115 11991-11995... 

Section 8.7 Thermodynamic Versus Kinetic Controi of Reactions... 

Veldhuyzen WF, Shallop AJ, Jones IkA, Rokita SE. Thermodynamic versus kinetic products of DNA alkylation as modeled by reaction of deoxyadenosine. J Am Chem Soc. 2001 123 11126-11132. 

The potentials for the reduction of water ([H+] = 10 moldm ) to H2, and for the reduction of O2 to H2O (the reverse of the oxidation of H2O to O2) are of particular significance in aqueous solution chemistry. They provide general guidance (subject to the limitations of thermodynamic versus kinetic control) concerning the nature of chemical species that can exist under aqueous conditions. For reduction process 8.25, " = 0 V (by definition). 

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