Critical Review of Hydrolysis of Organic Compounds in Water
`Under Environmental Conditions
`
`W. Money and 1'. Mill
`
`Stanford Research institute. Mento Park. California 96025
`
`This reviewI examines the rate constants for hydrolysis in water of 12 classes of organic compounds with the
`objective at using these data to estimate the preststertce of these compounds in freshwater aquatic systems. l’rl-
`rnary data were obtained by literature review through most of 1975 and some of 19%. These data. which include
`values for acid. hose, and water promoted rate constants (in, t. h] and temperature coefficients are presented
`in 13 tables in section 4. Estimated rate constants for hydrolysis under environmental conditions are presented
`in l3 tables in section 5. including rate constants at 298 K and pH 1" for acid, hue, and vrater promoted reactions
`together with values for the estimated rate constant {3.) and the half-life it”).
`
`Key words: Acid; base; environmental conditions: freshwater systems; hydrolysis; organic compounds; rate eon-
`lllfl'ls.
`
`Contents
`Page
`334
`384
`385
`385
`335
`335
`386 -
`386
`
`1. Introduction ............................
`1.1. Background .........................
`1.2. Content ofThis Review .................
`l3. Errnr hnalyeie
`..........
`L4. Literature Review .....................
`1.5. Format .............................
`1.6 Acknowledgments .....................
`References for Section 1 ....................
`2. Physical and Chemical Properties of Freshwater
`Aquatic Systems ........................
`2.1. Characteristic: of U.S. Freshwater Stream:
`
`and Rivers ............................
`Reference for Section 2.....................
`3. Hydrolysis Kinetics .......................
`3.!. Rate Laws ..........................
`
`3.2. Effect of PH .........................
`3.3. Effect of Temperature ..................
`3.4. Effects of Ionic Strength and Buffers .......
`3.5. Effect of Solvent Composition ............
`3.6. Effects of Metal Ion Catalysis .............
`References for Section 3 ....................
`
`4. Rates of Hydrolysis: Literature Review ..........
`4.1. Alkyl,A]lyl,and Benzyl Halides and
`Polyhaloalkanus ........................
`References for Section 4.] ...................
`
`4_2_ Epoxides ______________________
`References for Section 4.2___________________
`4.3. Esters .............................
`4.3.1. Aliphatic Acid Esters ..............
`References for seem," 4.3.1 ______________
`4.3.2. Aromatic Acid Esters ..............
`References for Section 4.3.2 ..............
`4,4, Amides _____________________________
`References for Section 4.4 ...................
`4_5_ Carbamates ______________________
`References for Section 4.5 ___________________
`4.6. Phosphoric and Phosphonic Acid Esters .....
`References for Section 4.5___________________
`
`386
`
`386
`386
`386
`386
`
`387
`337
`338
`389
`389
`339
`
`390
`
`390
`392
`
`393
`395
`395
`395
`393
`398
`4-00
`400
`402
`402
`4.04
`404
`405
`
`4.7. Acylating and Alkylating Agents
`and Pesticides .........................
`References for Section 4.7...................
`S Rates of Hydrolysis: Estimates of Lifetimes
`Under Environmental Conditions ............
`5.]. Alkyl, Allyl. and Honey] Halides and
`Polyhaloalltanes ........................
`5.2. Epoxides .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`; ...............
`5.3. Esters .............................
`5.4. Amides .............................
`5.5. Calbatltulco .........................
`
`5.6. Phosphoric and Phosphunic Acid Esters .....
`53’. Acylating and Alkylating Agents and
`Pesticides ............................
`
`Page
`
`40?
`'4-07
`
`408
`
`4-08
`410
`4| ]
`413
`413
`
`414
`
`415
`
`List 0' FlgUr.S
`
`FIGURE 1. pH Dependence of it. for hydrolysis by
`acid, water. and base promoted processes .
`
`387
`
`list of Tables
`
`TI“!
`
`386
`388
`
`2.1. Analysis for U.S. rivers and streams ...........
`3.}. Salt effects in hydrolysis reactions ............
`3-2. Nucleophillctty constants (c) {0" displacement
`388
`reactions [5] ---------------------------
`3.3. Effect of solvent;rcomposition on the rate of hydrolysis
`”f l'BUC] in ethanol/water at 293 K [6] -------
`339
`{1° Alky] halides --------------------------
`390
`4.2. Methyl halides .........................
`39]
`4‘33 All!” halides ---------------------------
`39'
`4.4. Polyhalomethanes: rate constants k” and k. .....
`391
`4.5. Polyhalomelhanes: temperature coefficients for k...
`Md in -------------------------------
`4.6. Benzyl halides ..........................
`
`391
`392
`
`©1973 by the US. Secretary of Commerce on behalf of the United States.
`This copyright
`is assigned lo the American Institute of Physics and the
`American Chemical Society.
`
`4‘7' Epoxides """"""""""""""" 393
`4-8. Aliphatic Mild ESleTS ---------------------
`396
`4.9. Aromatic acid esters ......
`39¢
`
`“47-ifl‘fllt’2‘lld-03Im4fio
`
`383
`
`Ll’hjrl- Chltn. Rel. Doin.\iol. ?. No.2. 191'.
`
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`384
`
`W. MABEY AND T. Mlll.
`
`Tl'ble
`4.10. Amides ..............................
`4.11. Carbamates...........................
`4.12. Phosphonic acid esters: it. ................
`4.13.1’hosphonic acid esters: in. ................
`4.14. Phosphoric acid esters ...................
`‘1- 15 Methylphosphates ......................
`4.16. Thiophosphoric acid esters ................
`4.17. Dialkylhalophosphonates and phosphorates..
`4.18. Acylating and alkylating agents and pesticides..
`5.1. Organic halides .........................
`5.2. Alkyl halides ...........................
`
`Contents—Continued
`'l’lg!
`TIMI
`401
`5.3. Allyl and benayl halides ...................
`403
`5.4. Polyhalornelhanes .......................
`404
`5.5. Epoxides .............................
`4-05
`5.6. Aliphatic acid esters .....................
`405
`5.7. Aromatic acid esters .
`.
`.
`.
`.
`; ...............
`4-05
`5.3. Am ides ...............................
`406
`5.9. Carbarnates ...........................
`406
`5.10. Phosphonic acid esters. dialkyl phosphonates. .
`.
`40?
`5.} 1. Phosphoric acid and thiophaspltoric acid esters .
`408
`5.12. Dialltylhalophosphonates and phosphoratcs. .
`.
`.
`‘108
`5.13. Acylating and alkylatrng agents and pesticides .
`.
`
`Page
`409
`409
`410
`411
`412
`413
`413
`4-14
`414
`4-14
`11-13
`
`‘1. Introduction
`
`1.1. Background
`
`During 1975. 293 billion pounds of about 8.000 different
`organic compounds were manufactured in the United States,
`exclusive of petroleum products [l].' Each year about 5.000
`new compounds are synthesized. and 200 to 300 of them
`come into commercial use [21.Mony millions of pounds of
`synthetic organic compounds are deliberately introduced into
`the environment for weed and pest control. and many mil-
`iutts of pounds of other chemicals are introduced into the
`environmental through dispersive uses.
`The effects on the biosphere of these often persistent, often
`biologically active synthetic chemicals are only now becom-
`ing fully apparent: fish ltills. species extinction or enervation.
`and perhaps as many as several hundred thousand human
`cancers per year have been associated with the increasing
`production and dispersion of synthetic chemicals [3}. In an
`effort to avert further. and perhaps tragic. biological conse-
`quences of a continuing and unrestricted discharge of chem-
`icalo to the air, water, and mil, tl'tP government hogan some
`years ago to regulate the manufacture and use of selected
`compounds, such as DDT. which had been shown to be ex‘
`ceptionally hazardous to the biological environment. The
`Toxic Substances Control Act of 1976 is one further step
`toward regulating the introduction of hazardous chemicals
`into the environment.
`
`Fortunately. the environment has the capacity to cleanse
`itself of many kinds of chemicals through a variety of chem-
`ical and biological processes. An understanding of this proc-
`ess. especially how rapidly the environment can degrade a
`specific chemical structure to a simpler and potentially less
`harmful chemical, is a key to the rational use of natural re-
`sources with minimal abuse. The ability to predict the proba-
`ble fate of specific compounds in the environment is also es-
`sential for screening the thousands of chemicals that may he
`considered for applications leading to their ultimate intro-
`duction into water. soil. or air.
`The objective of this review is to provide one kind of pre-
`dictor of environmental fate—hydrolysis of organic com-
`pounds in freshwater systems—based on lhe best available
`ltinetic data for hydrolysis in water.
`
`' Figure: in brackets indicate literature references at the end of each section or
`subsection.
`
`I.W.Clloln. III. Mfl'ol. 3'. Ito. 2.1!}.
`
`There are at least two reasons why hydrolysis may be a sig
`nificant chemical process in the environment. First, many
`hydrolyaable chemicals. including pesticides and plasticizers.
`eventually find their way into groundwater. streams. and
`rivers through leaching and runoff. Second. rates of hydroly-
`sis in aquatic systems are independent of commonly used bul
`rapidly changeable indicators of the degradative capacity of
`aquatic systems, such as sunlight. microbial populations, and
`oxygen supply; rates do depend on pH, temperature. and
`concentration of chemical—properties that may change only
`slowly and seasonally.
`In undertaking a review of this kind, which claims to pre-
`dict rates of hydrolysis in aquatic (freshwater) systems on the
`basis of laboratory data. we are aware of the belief that such
`estimates are oflittlc value because the rates of hydrolysis ob-
`tained in laboratory studies do not reflect the complexity
`found in the environment. This concern, although under‘
`standable. is not well founded. There are several examples
`where rates of hydrolysis have been measured in both pure
`and natural waters and which showed good agreement be-
`tween the two kinds of measurements for a variety of chem-
`ical structures [4,5,0] providing that both pH and tempera-
`ture were measured.
`
`Another objection raised occasionally concerns the validity
`of the extrapolation of data for hydrolyses measured in the
`laboratory at concentrations of chemicals that often exceed
`0.01 M to environmental conditions where typical concentra-
`tions of trace organics rarely exceed 10" M. The apparent
`implication of this concern is that at high dilution other corn‘
`plications may arise but in fact it is axiomatic that rate proc-
`esses found to be simple at high concentrations remain so at
`low concentrations; mot-cover. with only one exception, the
`rate laws for hydrolysis reviewed here show a simple first-
`order dependence on the chemical. Thus the actual half-life
`of the chemical
`is independent of its concentration and
`depends only on easily and accurately measurable param—
`eters lilte pH and temperature.
`For these reasons we believe that in most cases extrapola-
`tion from laboratory to field site is relatively uncomplicated
`and that estimates of persistence summarised in section 5
`provide valuable information on the upper limit for persis-
`tence of hydrolyrable dissolved organic compounds. From
`these estimates it should be possible to also assess possible
`effects of intervention by other environmental processes.
`Thus, if field measurements of the half-lives {persistence} of
`
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`HYDROLYSIS OF ORGANIC COMPOUNDS
`
`385
`
`specific chemicals depart significantly (by factors of 5 or
`more) from those predicted in section 5 after taking into ac-
`count differences in pH and temperature, then some other
`process such as biodegradation. or photolysis or insolubiliza-
`lion may have changed the measured half-life. These esti~
`mates apply only to chemicals dissolved in water;
`in most
`cases any suspended or oil soluhlized chemicals will hydrol-
`yse much more slowly than predicted.
`Only recently has little but]: “1|.th ililctvsl ll] Ittcusuliug Ul
`estimating the rates of hydrolysis of organic compounds
`under environmental conditions which include very dilute
`solute concentrations in pure or natural waters in the pH
`region 4 to 8 at or below 298 K. [n the absence of much
`environmentallyfiintended" data,
`this review has drawn
`upon a large amount of hydrolysis data from studies con-
`cerned with kinetics and mechanism. Some of these data were
`
`obtained from experiments in minted solvents. or at high tem-
`peratures l[to 393 K) or extreme pH values. and often lack
`data On temperature dependence.
`in some cases data are given for compounds which are not
`of environmental concern; however these data do describe
`the range of rate constants for the class of compounds and
`make it possible to estimate the rate constantls) for and per-
`sistence toward hydrolysis of organic compounds not
`in‘
`cluded in this review.
`
`We hope this review will stimulate more and better studies
`of hydrolysis of synthetic chemicals in water under carefully
`defined conditions. both in the laboratory and in the field, to
`supplement the data presented here and further validate the
`concept
`that careful
`laboratory studies on individual proc‘
`esses can accurately predict the fate and persistence of chem-
`icals in the environment.
`
`1.2. Content of "It; Review
`
`This review provides information on kinetics of hydrolysis
`in water of 13 classes or organic structures. with sufficient
`detail within each class to enable the reader to find either the
`specific compound or one close enough to estimate reliably
`the rate eonstant(s) for hydrolysis. The classes of compounds
`reviewed are:
`{1) Organic halides
`(a) Alkyl halides
`(bl Aliyl halides
`(c) Benaylhalidcs
`(d) Polyhalomethanes
`(2) Epoxides
`(3) Esters
`(a) Aliphatic acids
`(b) Aromatic acids
`{4} Amides
`(5} Carbamates
`(6) Phosphorus esters
`(a) Phosphonates
`(b) Phosphates and thiophosphates
`{c} Phosphonohalidates
`(7} Acylating and alkylating agents and pesticides
`Kinetic data are presented in two sections. Section 4.
`"Hydrolysis Rate Data," summarises primary kinetic data on
`
`hydrolysis of these compounds in water or {in a few cases) in
`mixed solvents; section 5, “Estimated Hydrolysis Hates under
`Environmental Conditions.” uses data from section 4 to
`estimate rate constants and half-lives for these same com-
`pounds at 298 K. pH 7. and zero ionic strength. conditions
`typical of a great majority of freshwater systems {section 2.1).
`The classes of compounds reviewed here cover a significant
`fraction of the hydrolyzable structures found in organic
`molaeulca..Mnny of the individual compounds listed in this
`review are used in quantity in industrial or agricultural ap-
`plications; others are unique to laboratory studies. Most of
`them have been subiect to study in water solvent under condi-
`tions that require few assumptions and relatively short extra-
`polations to environmental conditions.
`SeVeral classes of hydrolysable compounds have not been
`included in this review because some are hydrolytically inert
`under ordinary conditions and are best considered as refrac-
`tory toward water (nitriles, vinyl, and aromatic chlorides are
`examples), and others are hydmlytirally unstable but have
`not been examined in any quantitatively useful way.
`
`1.3. Error Analysis
`
`Because many different ltinds of experimental procedures
`are used to measure hydrolysis reactions, no one error analy-
`sis proeedurc is applicable to all-sets of data. Rate constants
`for hydrolysis of most compounds appear to be of high preci-
`sion. often with less than 2% standard deviation. Different
`investigators have reproduced individual rate constants to
`within 150%. Some sets of experimental data are reported
`with error limits that involve a judgmental factor in selection
`of data. These error limits may be considered equal to twice
`the standard deviation.
`Most experimental measurements of E or AH’ are made
`over temperature spans of 40-80 K and usually around 345
`K. Benson’s "rule" {ll indicates that with a random error of
`2% in rate constant k. activation energy 5 may be deter-
`mined with an accuracy ofabout 5%: however, with a random
`error of 10% in It, Eis only accurate to 100% or a factor of 2.
`Put another way, if E is known only with an accuracy of
`210%, It is known only with an accuracy of 160%.
`Values for k. estimated in section 5 at 298 K are probably
`not more accurate than a factor of 2 [:tl00%)or less accurate
`than a factor of 5 (i250%} owing to uncertainties in pH.
`temperature coefficients, and. in some cases. solvent effects.
`
`Ll. literature Sources
`
`A thorough search of the current literature through 1975
`was made using Chemical Abstracts. Data were searched
`under the major subject headings for specific compounds.
`
`1.5. Format
`
`The review is divided into five sections; to assist the user,
`references are renumbered as appropriate within each sec-
`tion. Although every effort has been made to use a consistent
`format throughout, some differences among tables are un-
`avoidable owing to differences in the kinds of compounds
`and the reliability of data available for various compounds.
`
`J. Phys. Churn. M. Date. Vol. 3'. No. 2. I91"
`
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`

`386
`
`W. MADE? AND T. Mill.
`
`Section 4 reports primary kinetic data in the form of rate
`constants for acid (In), neutral (rim). and base catalyzed Us.)
`hydrolysis reactions, together with available temperature co-
`efficients. Data are summarized in 18 tables. Section 5 uses
`
`data from section 4 to estimate In at 293 K and pH 7 for se-
`lected compounds in 13 tahles.
`In each table. compounds are grouped by class, such as
`alkyl halides. epoxides, and esters, and are listed in order of
`increasing complexity. Line formulas are used in most cases
`to avoid ambiguities of nomenclature.
`Rate constants k are expressed in units of s'1 or M"s".
`where M=mol - dm". Very large and very small values of it are
`listed in two ways: a column heading 10‘ it requires that cvcry
`listing in that column be multiplied by 10" to retrieve k; a
`column listing of 5(-ll} means SXIO'". Throughout this re-
`view, we have used the SI unit of joules for energy and en-
`tropy; conversion of joules to calories requires division by
`4.184. Units for A are the same as for it; units for AS‘ are
`.l/mol; units for Band 113' are U/rnol. To simplify presenta-
`tion of data in the tables. we have fixed the value of R at
`0.01914. kJ/mol K. which includes a conversion factor of
`2.303 for base 10 log units.
`
`LG. Acknowledgments
`
`This review was prepared under Contract No. 5—35905 with
`the Office of Standard Reference Data. National Bureau of
`Standards. We thank Dr. L. Cevantman for his advice. on-
`couragement. and considerable patienCe. Ms. Kathleen
`Williams typed the many versions of. this manuscript with
`persistence and skill.
`
`References for Section I
`
`[II US. Tariff Commission Report for 1974.
`12‘) Estimate provided by Chemical Economics Department. am.
`[3] Higginson. 1.. cheedings 8th Canadian Cancer Conference. Honey
`Harbour. Pergaunon Press. New York, 1968'. p. 40.
`[4] Zepp. R. 0., Wolfe. N. L. Gordon. J. A. and Baughman. C. l... Environ.
`Sci.Teclt.9.llel9?5].
`[S] Mabey. WE. Barue. at. Lao. 3.. Richardson. H.. Hendry. D. 0.. and
`Mill. T., Abstr. 172 Meeting Amer. Chem. Soc. San Francisco, Ca..
`Aug. [976. PEST 06].
`-
`[0] Wolft. N. L. chp. R. 6.. Baughman. G. L. Finciler, II. C., and Gor-
`don. .I'. A., Chemical and Photochemical Transformation of Selected
`Pesticides in Aquatic Systems, EPA 6001’3-76-067. September 19%.
`[T] Benson. 5. W.. The Foundations of Chemicmf Kinetics. McCraw-Hill
`Book Co. New Tot-HIM).
`
`2.1. diurnctorlstica of [1.5. Freshwater Streams
`and Rivers
`
`Detailed information on most freshwater systems in the
`United States. including temperature range. pH. and mineral
`content, is available from the United States Geological Sur-
`vey [l]. These data have been summarized for Ill streams
`and rivers in the United States that account for over 95% of
`the water volume; table 2.1 summarizes mean concentration
`values for 11 inorganic constituents found in natural waters
`at pH 7.5 and 287 K.
`Table 2.1 Analysis for v.5. rivers and streams
` (moan Valium in El fl}
`-—————t
`fl
`,__
`.3.-
`
`ea” as” in" H FeZ+JHC0:
`soi‘
`c1‘
`so;
`130:- coil
`36
`9
`25
`2
`dosiizr
`as m u. D.6$]0.1E)l
`pH LS, Temperature 28“
`
`The following values represent average conditions in most
`freshwater systems in nonwinter months: temperature 293 K,
`pH 7.0, and ionic strength 0.00.
`Review of the hydrolysis literature for organic chemicals
`shows that many rate constants have been evaluated at 298 K
`or higher; only a few data have been obtained at lower tem-
`peratures. Although higher than either the mean or the
`average temperature of the rivers and streams, we have
`chosen 298 K as the environmental reference temperature for
`this review in order to use as much primary kinetic data as
`possible for estimates of persistence without temperature ex-
`trapolations.
`Estimates of persistence {half-lives) summarized in Section
`5. will be 50 percent longer at 293 K and 130 percent longer
`at 287 K, based on an average energy of activation for
`hydrolysis of 65 mm].
`
`Reference for Section 2
`
`[1} Quality of Surface- Waters of the United States. Parts 2-16, US. film
`logical Survey IWater Supply Papers 2092—2099. 1972-73.
`
`3. Hydrolysis Kinetics
`
`3.1. Rate Lows
`
`Hydrolysis refers to reaction of a compound in water with
`net exchange of some group X with 0H at the reaction
`center:
`
`RX+H;O-'ROH+HX.
`
`2. Physical and Chemical Properties of
`Freshwater Aquatic Systems
`
`The freshwater systems of North America‘s streams. rivers,
`lakes. and groundwater comprise several hundred thousand
`square miles of area draining 7 million square miles of
`diverse environmental regions. Since one objective of this
`review is to provide reliable estimates oflifetirnes for organic
`compounds in freshwater aquatic systems. some review of the
`range of physical and chemical properties of freshwater is
`desirable.
`
`The detailed mechanism may involve a protonated or anionic
`intermediate or a carbonium ion, or any combination of these
`intermediates. But whatever the mechanism. the rate law for
`hydrolysis of substrate RX usually can be put in the form
`
`afl£=t.[RX]=k.[0H-][RX]+k,.[H‘][RX}
`dt
`
`(1)
`
`+ftN‘IH30HRXI.
`
`where its, it... and is“: are the second-order rate constants for
`acid and base catalyzed and neutral processes. respectively.
`
`J. eh“. Cit-m. w. Dotti. Vol. 3*. No. 2. Im
`
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`

`HYDROLYSIS OF ORGANIC COMPOUNDS
`
`33}
`
`In water kN'IHIO] is a constant (kn). The pseudo-flrstorder
`rate constantJri, is the observed or estimated rate constant
`for hydrolysis at constant pH. Equation {1) assumes that the
`individual rate processes for
`the acid, base. and neutral
`hydrolysea are each first order in substrate. With only a few
`exceptions. this is the case, and
`
`i.=k,[0H-]+i,.[H*]+r,..
`
`{2)
`
`From the autoprotolysis water equilibrium, eq (3), eq {2)
`may be rewritten as eq (4-).
`
`[H‘][0H‘]=K.,
`
`_ IssK.
`h—
`[m
`
`.
`+15. H +11...
`[
`l
`
`3.2. Effect of pH
`
`(3)
`
`4)
`
`(
`
`From eq (4) it is evident how pH affects the overall rate: at
`high or low pH (high OH‘ or H‘) one of the first two terms is
`usually dominant, while at pH 7 the last term can often be
`most important. However. the detailed relationship of pH and
`rate depends on the specific values of 13, L4, ram] in. Al any
`fixed pH, the overall rate process is pseudo first orderl and
`the halHife of the substrate is independent of its concentra-
`tion:
`
`tb=0.693/k...
`
`{5)
`
`Equation (4} is conveniently expressed graphically as three
`equations—one each for. the acid, base. and neutral hydrol-
`ysis reactionswin which log ff). is plotted against pH. The
`curves obtained are especially useful for estimating the effect
`of acid or base on the rate of hydrolysis. Figure 1 depicts a
`typical log Ira vs pH plot for compounds which undergo acid,
`
`water. and base promoted hydrolysis. It is obvious from eq (4)
`that
`the upper curve in figure 1
`is a composite of three
`straight lines-4a) log kh=log (k.K.}l-pH; (b) log lr.=log by.
`and (c) log kifllog h-pH—with slopes +1, 0. and -1. respec-
`tively. The lower curve results when k..=o.
`Most log in. vs pH curves are found to have one or two in-
`tercepts corresponding to pH values where two kinds of rate
`processes contribute equally to the overall process. Thus in
`figure 1 the intercept Luv corresponds to a value of pH where
`h[l-l‘]=k~; similarly,
`in. corresponds to k,[0H‘]=l:N.
`in
`cases where h, h, or kfifl. only one intercept is observed.
`Values of pH corresponding to I may be calculated readily
`from the values of h, is" and *5:
`
`IMF—log {kw/AM)
`
`lufi‘lflg (hKkal
`
`IMF—[log (ksKJkall/Z
`
`(6)
`
`(7)
`
`(3)
`
`Use of intercepts in tabulating data on rates ofhydrolysis as a
`function of pH greatly simplifies the task of estimating the
`effect of pH on the rate constant k. for a specific compound.
`For example, In for alkyl halides lie above pH ll. Obviously,
`the base-catalyzed process for hydrolysis of alkyl halides is
`never of concern in estimating persistence in aquatic systems.
`Values of I”, In, and L", are tabulated for specific com-
`pounds in section 5.
`
`3.3. Effect of Temperature
`
`Section 5 reports estimated half-lives at 298 K based on
`rate data listed in section 4 at several different temperatures
`and with temperature coefficients for the rate constants.
`
`we sh - Ins has“, a nu
`log k” - to. ea - uH
` tal
`
` lcl
`“a.
`
`
`
`
`
`
`
`Iqlhh't'‘I
`
`[bl
`
`log Irh - log k”
`
`cit—q-
`
`l-‘IGURI: 1. pH dependence oflr. for hydrolysis by acid, waler. and base promoted processes.
`
`J. Phys. Chem. lief. Data, Vol. 1'. No. 2. "3'8
`
`NOVARTIS EXHIBIT 2042
`Noven v. Novartis and LTS Lohmann
`iPR2014-00549
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`
`

`

`388
`
`W. MABEY 1ND T. Mill.
`
`dict: they can lead either to rate acceleration or retardation.
`depending on the substrate. the specific salts, and their con-
`centration. Salt effects of this kind are associated with
`
`changes in activity coefficients of ionic or polar species or
`transition states with significant charge separation; no bond
`making or breaking is involved in such interactions.
`Table 3.1 which lists some effects of different non-nucleo-
`philic salts on the hydrolysis of several kinds of compounds,
`shows that in most cases rather massive amounts of these
`
`The effect of temperature on the rate constant for a spe-
`cific hydrolysis process can be expressed in several ways, all
`of which are variants of the general relation
`
`log (ls/s“)=—A/T+B log T+C.
`
`(9)
`
`There is no uniform practice for expressing values of A. B, or
`C; different investigators have used different versions of eq
`(9}. usually in more familiar Arrhenius or absolute rate theory
`format
`
`log (k/s")=log AcEXRT Arrhenius (IO)
`
`(11)
`log{l¢/s“)=log[kTJh)—W/RT+AS7R Absolute
`Rate Theory
`
`Equation (9) can also be used to describe more accurately the
`effect of temperature on the rate constant and activation
`parameters by inclusion ofa heat capacity contribution in the
`constants B and C. When the heat capacity term, AC; is
`known or can be estimated, 53* and 65* are then calculable
`at a specific temperature, T}, from AH: and AS: or 11H:- and
`AS?I
`
`salts cause only 30-40% changes in rate constant. Concentra-
`tions necessary to effect these rate changes are found only in
`ocean or brackish waters or in highly buffered laboratory ex-
`periments.
`
`Table 3.1.. Salt: effects in hydrolysis reactions.
`
`
`Solvent. UK
`
`90110 acetone-water.
`323
`
`1.08
`0.10“ Ital, 398
`T-iunyrolm-Lmo Nanci. 0.51
`0.95
`"81:104., can 0.1an Motor, 298
`1 . 35
`LiCl . 2. OICI
`0. 15H H010. . 2§8
`
`1.00
`NaClD“ 2.00 0.15" KCIDs. 293
`
`
`0.95 |
`'i‘rQF’t'lL.... as. one am mu- m
`
`kfko Reference
`I.“
`
`
`
`Coupounrt
`{LB-"3," I
`
`Salt, H
`Llflr. 0.166—5
`
`
`
`utsUUxEt
`
`m,=ss:+sc;r, or m=m—s cart—n)
`
`.1:ka is the ratio at rates with (k) and without {kn} salt.
`
`mzssmsos ac; (log T.)
`
`or ASr_=uSt+2.303 ACJoe (Tl/T1}
`
`A few authors have expressed rate parameters for a reac-
`tion in the mixed terms of E and AS‘. Although such a prac-
`tice is not immediately useful within the individual firrhenius
`or absolute rate theory treatments, the rationale appears to
`be that AS‘and E are more easily conceptualized for diagnosis
`of the reaction mechanism.
`
`Recasting of data to fit a uniform temperature dependent
`relationship might assist
`in mechanistic interpretations;
`however. the probable loss of precision for some data argues
`against such a practice. Therefore this review uses the origi—
`rial
`temperature dependence relationships developed for
`each compound to extrapolate rate constants to the chosen
`environmental temperature of 293 K.
`Each table of data in section 4 lists the appropriate tem-
`perature coefficients together with values of coefficients in
`appropriate units. For a few compounds where no tempera-
`ture coefficients were determined and the reported data are
`not at 298 K, we have extrapolated to 298 K using a stated
`temperature coefficient, based no a similar reaction with
`known temperature dependence relationships. In a very few
`examples where data are reported within :t:5 K of 298 K. we
`have used the data without further correction.
`
`Another effect of nucleophilic added salts is to accelerate
`the rate of hydrolysis by a general acid or general base pro-
`moted process (where H‘ or 0H' promotcd reactions are apt:-
`cific acid or base processes). Some anions can effect dis-
`placement of leaving groups more rapidly than water {few} and
`in doing so catalyze hydrolysis via the sequence
`
`H~X+A‘-v RA+X‘,
`RA+H;0-r ROH+HA,
`(HA-Ht man's-Hm.
`
`The use of nucleophilic anions such as phosphate or acetate
`at 1.0 M to 0.01 M to buffer hydrolysis reactions is a common
`and useful practice. Unfortunately, the general acid or base
`catalyzed term kG[A*] added to eq (2} to give
`
`k.=k3[OH']+k,[H*]+.iN+ka[A‘].
`
`can often be as large as the specific acid or base terms be-
`cause both [H'] and [011‘] are relatively low in the bpt‘fered
`.....__
`Table 3.2. Nuctesshittcny com-rants (n) for dinplncelcnl reactione [s].
`
`Anion-ll n“
`c:
`i 3.0::-
`sn:-
`?.5
`
`
`
`I Losi
`‘so.
`choZ i3.s i
`Juror: 3.3 i
`
`3.4.
`
`lonle Strength and Butter Effects on Hydrolysis
`
`The ionic strength of most natural freshwater is quite low,
`usually much less than 0.01 M in total cation and anion con-
`centrations {see table 2.1}. This is
`fortunate since ionic
`strength effects on hydrolysis reaction: are difficult to pre-
`
`lose” lurl
`
`""‘ £E°l
`"he. the Swain—Scott rctszton Jogtlctkfll - as, where s is a snbnlrate-
`dependent nonslult which varies from 0.35 to 1.3;
`s for HIE!
`is 1.00 [5]
`"G Md "1 use: to ”mint use: what-nu Ivl mum. and mus-r. mercenary.
`
`JJ'IIye. Chem. Ref. Data, Itil'ol. I. No. 2. I”!
`
`NOVARTIS EXHIBIT 2042
`Noven v. Novartis and LTS Lohmann
`iPR2014-00549
`Page 6 of 33
`
`

`

`HYDROLYSIS OF ORGANIC COHI’OUNDS
`
`389
`
`region irorn pH 5 to 9. As a result. the value of In. may in-
`crease significantly. Table 3.2 lists values for to relative to kg
`for specific ions in displacement reactions. However, the fact
`that primary and secondary salt effects also may be important
`makes it difficult to predict the overall direction or magni-
`tude ofsuch rate changes.
`To ensure that hydrolysis measurements reported in buf-
`fered systems are not subject to these salt effects, the follow-
`ing procedures are recommended:
`(1) Measure rates of hydrolysis at concentrations of sub-
`state less
`than 10" M.
`In most cases
`this procedure
`eliminates or minimizes the need for buffers and avoids their
`possible effects on rate.
`(2} Check the effect of different buffers on the rate of
`hydrolysis; when possible use home or acetate instead of
`phosphate. With low concentrations of chemicals buffers may
`be used at 0.01 M concentrations to hold pH constant without
`introducing significant salt or buffer effects.
`(3) Compare the initial rates of hydrolysis in the absence
`and presence of buffers.
`
`3.5. Effect of Solvent Composition
`
`t-BuCl
`
`With a few exceptions, rate data reported here refer to
`water solvent. Many investigators have used mixed water-
`organic solvents to work at conveniently high concentrations
`of substrate. most of which are relatively insoluble in pure
`water. Although extrapolation of rate data from mixed sol-
`vents to water can be done with moderate success using
`schemes like the Winstein-Grunwald relation [6]. combined
`extrapolations of temperature and solvent composition
`together with the questionable meaning of pH in mixed sol»
`vents introduce sufficient error in the final estimate to make
`such effort of questionable value for purposes of this review.
`For the most part,these data were not included.
`The effect of solvent composition is most pronounced in
`those reactions in which charge separation is well developed
`in the transition state. as, for example, in solvolysis of t-buty]
`chloride. In ethanol-water mixtures this hydrolysis is purely
`aolvolytic—‘no effect of acid or base is noted. Table 3.3 sum-
`marizes values of It”, which increases by a factor of near 10‘
`on going from 90%