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4 . 1 Int roduction

The following chap ter is a dis cussion o f the p res ent understanding of the hydrophobic effect and i ts relationship to the various proces ses which are apparently driven by this effec t . This d i s cuss ion will

provid e a basis for t�e unders tanding of the role of the hydrophob ic e f f e c t in th e assoc iat ion o f pept ides wi th reversed phase bond ed

si licas ( HPLC) and wi th phospholipids and henc e enhance the con tinui ty o f the remainder o f the text .

The hyd rophob ic effect is evid ent as the obs erved unwil lingness o f nonpolar sub s tances t o intera c t wi th aqueous environments ( 86-90 , 95 ) . The term hydrophobic implies a hatred for wa ter , however , this is not the c as e . To quote Hartley : "The ant ipathy of the paraffin-chain for water , is however , frequently misunders too d . Th ere is no question of

actual repuls ion be tween individual water mo lecules and paraffin chains , nor is there any very s trong a t trac tion of para f f in chains for one

anothe r . Th ere is , however , a very s trong a t tra c t ion o f wat er mo lecules for one ano ther in comparis on with which the paraf f in-paraffin or

paraffin-wa ter attractions are very s ligh t , as is well known f rom the work o f Harkins on c ohesion of l iquids . I t is this wat er-water

at trac t i on whi ch satis fies itself by the ext rus i on of paraffin chains

. . . • . • " ( 8 9 ) . Cons idering the relatively simp le concept of the hydro­

phob i c e f fect outlined ab ove , i t is surpr ising to find the large degree of cont roversy and confus ion whi ch exis ts in this field ( 88 , 9 3 , 9 9) .

A common misconcept ion is that the ob s erved a f f ini ty o f hydrophob i c groups for each other i n the p resence of wa ter i s the result of van der Waals ' b onding between th e hyd rophob ic groups ( 7 , 9 1 ,9 2 ) . This improper cons ideration has no doub t aris en from the use of the express ion

"hydroph obic b onding" which imp lies a d irect form o f b onding between hydrophobic groups ( 9 3 ) . It has been reas oned that van der Waals '

forces would not b e influenced by temperature ( as the hydrophob ic effect is) . Furthermore these non-covalent in teract ions are a lso found b e tween water and hyd rocarb ons ( 88 , 9 3 , 94 , 9 6 ) . A comparis on of the s trengths o f bon ding has revealed that van d e r Waals ' forces are a n o rder of

From the out s et we mus t cons ider two types of process driven by the hyd r ophobic effect wh ich are o f ten not separat ed and thus j oint ly referred t o as " the hyd rophob ic ef fect " . Thes e are defined by Ben-Naim

(94) .

(a) re fers to the relative preference of a s olute for two solvents when one o f thes e s olvents is wa t er . This p ro cess is describ ed b y s tandard of t rans fer .

It should be noted that only so lute-s olvent and s olven t-solvent interac tions are cons id ered .

(b ) Int eract ion refers to the inte rac tion b etween two or mo re nonpolar or amph ipathi c solute mol ecules in wa ter .

*

Th i s t e rm repl aces the bond us ed previous ly .

In the l imi t of very large aggrega tes formed by hydrophob i c in terac tions , the process o f hydrophob i c int eract ion becomes hydrophobi c hyd ra tion . This i s b ec ause each added solut e molecule i s accommoda ted in the interior of the aggregate , completely s eparat e from the aqueous environment , and th erefore is effectively partitioning into ano ther solvent ( 9 4 ) .

Hydrophob ic interact ions have b een pos tulat ed to b e an integral part of the p rocess es of conforma t ional changes of biopo lymers , b inding of sub s trate to enzyme , the as sociat ion of subuni ts to form a mul ti­ subunit enzyme and pro cesses invo lving high levels of aggregation such as formation of bio logical membranes and the organis ati on o f b i ol ogical mo lecules to form a func tional uni t in a l iving sys tem ( 88 , 9 4 , 95 ) . Considering the importance o f these proces ses it is s urp ris ing to find that our p res ent knowl edge and unders tanding of hydrophob i c int eractions is only in i t s very el ementary s tages ( 9 4 ) .

I t should be not ed that in the following discussion the processes of hyd rophob ic hydrat ion and hydrophobic interact ion wi l l a lways b e expres sed i n th e d irec tion o f decreas ing interaction wi th water , e . g . water to hexano l partitioning , nonpo l ar solute associat ion and the

trans fer of nonpolar gases from water into the gas pha s e ( degassing ) .

* The t e rm bond is a mo re general definit ion not requir ing aqueous s o lution and thus thi s t e rm is b e tter replaced by

The most s tudied sys t emS inves tiga ting the hydrophobic effect involve relatively simple wa t er t o gas or wa t er to organi c s olvent t ransfers . Such s tudies will be summaris ed in the opening part o f this chapter , sections 4 . 3 . 1 and 4 . 3 . 2 . Later sect ions wi ll be dedicated to mor e c ompl ex sys t ems involving many sorts o f int erac tions , sect ions 4 . 4 . 1 and 4 . 4 . 2 . The r esul ts o f s tudies on simple sys tems are o f t en quot ed to support var ious experimental obs e rvations , however , it shoul d b e

rec ognised tha t i n some ways the simple processes are qu ite d i f f erent from the complex proces ses . Th erefore the direct utili zation of results from th e simple sys t ems to explain mor e c omplex processes should be conducted wi th caution . A s ummary of the c ontrasts between the thermo­ dynamic s o f the p rocesses is given in s e c t ion 4 . 5 .

4 . 2 The o f the Effect

Ac cording to Ben-Naim there is no complet ely satis factory theoret ical treatment of hydrophob ic hydration whi ch a l lows the calculation of the s t andard free energy of hydra tion (9 7 ) . S emi- theoret ical me thod s have therefore been emp loyed all of which involve serious approxima t i ons especia lly when applied to such a c ompl ex fluid as wat er . Neve r theless the theory of hydrophob i c interac tions has been dealt with in detail by Ben-Naim ( 90 ) . This author has s evere res ervations about the predictions

of pairwise hydrophobic interactions s ince knowledge o f the full pair correla t ion funct ions whi ch are used to c a lculat e the f ree energy change on dimerisat ion is far from satis fac tory ( 9 8 ) . In addit ion to the

ext reme technical difficulties involved in calculating the ful l pair correla t ion func tions , the lack of appropriate experimental data means tha t the success or fai lure of a par t i cular t rea tment cannot even b e qualitatively a s s essed . For this reason B en-Naim sugges ts tha t t h e maj o r ef fort in the field o f hydrophobic intera c tions should b e fo cus ed o n the experimental rather than the theore tical s id e of the p roblem , In view

o f thes e unc ertaint ies current th eore t i c a l models for hydrophob i c int er­ a c t ions wi ll no t be dis cuss ed here and the reader is referred to Ben-Naim

( 9 0 ) f o r details o f these models . Hal l has said that s uperfic ially the arguments may l ook impress ive but on closer examina tion i t turns out

*

4 . 3 . 1 The of Gases in Wa ter

There has b een int ense s tudy in the area o f solub ility o f nonpo lar gases in wat er as d is cussed in a recent review ( 10 3 ) . It is import ant to real is e that s t ud ies of the thermodynamics of these s imp le sys t ems requir e some assump t i ons as to the ideal b ehaviour of the gas and the resulting s olution . As a consequence , th e act ivi ty coefficients of the gas and solution may b e inco rrect resul t ing in the cal culat ion o f

incorrec t ent ropy va lues . The degree of inf luence these as sumptions have on thermodynami c quant ities is uncertain at pres ent (99) .

A cons t ant feature of the solubi lity o f nonpolar gases in wa t er appears t o b e the large pos i t ive ent ropy o f degassing (nega tive ent r opy o f solut ion) which is the maj or term in the f r ee energy calculat ion over

a wid e range of t emp erature . It has b een p roposed that the caus e of this large pos it ive e�t ropy change is the increas ed mobility o f wa t er mol ecules releas ed from propos ed regions of high order ( "ice-like" s t ructure) a t the nonpolar so lut e-wat er int erface ( 1 0 0 , 1 0 1 ) . An a l t ernat ive theory has b een propos ed by Wert z ( 1 02) who cl aims that the large pos i tive ent ropy change ob served on the d egass ing of a large numb er of gaseous solu t es can be explained simply by the gain in ent ropy o f the so lut e mo lecule

. lf **

1tse •

Another ob serva t ion is apparent ly common t o all the gas solub il i ty systems s tud ie d . This is the large value o f the change in heat c apacity

(6C ) f o r the wat er t o gas trans i tion which is exhib i t ed by the non-linear _p Van ' t Ho f f plots (6G v ' s 1 /T) . Such a nonlinear dependence of the

enthalpy change on t emp erature has b een viewed b y Tanford as b eing c aused by the varying s t ructure of water as t emperature is changed ( 1 0 0 , s ee also sect ion 4 . 3 . 2 ) .

* In t e rms o f the defined direction of reac t i on being the hydrated to the nonhydrated s t at e the process might b e better described as the degass ing o f nonpo lar gas es from wa t er .

** Ben-Naim and Tanford have claimed that such an �n tropy change would no t be l arge enough to explain the overall change in ent ropy .

4 . 3 . 2 Wat er - Solvent

The pro cess of wa ter-or ganic solvent part itioning is another easily studied area o f hydrophob i c hydra tion . This process has much in common wi th·the previous ly dis cuss ed solubility o f nonpolar gas es in wa ter . Many s tudies have shown the dec reasing t endency of nonpo lar and amphiphi lic solutes to par t i t ion into wa ter with the increas ing non­ polar character o f the so lute ( 1 0 5- 1 0 7 ) . The dominant t e rm in the free energy equat ion is again the large positive ent ropy· change for the hydrated to nonhydra ted t rans fer ( 87 , 1 00 , 1 06 ) . In addition non- linear van ' t Hof f plots are found implying that the heat capacity change (6C )

p

is large for the partit ion t rans fer ( 87 , 1 0 0 ) . It is wo r thwhile no t ing that t he ent ropies and enthalpies of t rans f er are mos t o f t en ca lculated near the minima for the s olub i l i ty o f the solutes in water a t d i f f er ent

0

t emperatures ( e . g . 25 C) . At higher temp eratures the 6H cont ribution may well be much more important . Tanford has not ed anomalous ent ropy and heat capacity effec ts in the s olubility o f a lkanes in aqueous s olut ion ( 1 0 0 ) . The heat capac i ty of the s olub i lization of the alkane is no t cons t ant but is i t s e l f a funct ion of t emp erature , as evidenced

by non- linear van ' t Ho f f p lo t s . Tanford a t t r ibut es the obs e rved change in heat capa c i ty to the change in state of water mo lecules brough t ab out by the presence of th e disso lved hydrocarbon ( 10 0 ) . Furthermore Tanford notes that , whereas the free energy o f the t rans fer increases l inearly with increas ing hydrocarb on chain length and seems to d epend upon hyd ro­

carbon-water int erfacial area , the corresponding enthalpy and ent ropy functions show no corresponding regularity ( 10 0 ) . This indicated t o Tanford tha t t h e water mol ecules of the hydrocarbon-wat er int erface d o n o t have a unique way o f arranging themselves , b u t tha t diff erent

arrangements are p ossib l e d epending on the precise spac ia l requirement s . He concluded that these d i f f erent arrangements must d i f f er in enthalpy and ent ropy , but mus t do so in a mutual ly compensating fashion so that no irregularity in free ene rgy can be detected . Tanford postulates

the exi s t ence o f two s tates o f water mo lecules a t the hydrocarbon wa t er int erface, one with a high enthalpy and ent ropy s tate (s trong hyd rogen bonding at interface) and one wi th a lower entha lpy and entropy s t a t e , which d iffer very l i t t le in free energy ( 1 00 ) . An increase in

temp era ture would shift the equilib rium to the higher enthalpy s t a t e - resul t ing in the anomalous heat capaci ties observed .

4 . 4 Int eract ions and More

4 . 4 . 1 The Effect and Reve rsed Phas e HPLC

*

I t i s g ener al ly accepted that the hyd rophobic effect is respons ib le for the retention of nonpolar o r amphipathic so lut es on nonpolar supports when the mob ile phas e is aqueous ( 1 08-1 1 0 ) . The mobile phas es used in

reversed phase chromatography often contain mix tures of wa ter and polar organi c s o lvents e . g . methanol and acetonitril e . There is a diff iculty here since the hyd rophobic effect is applied only to compl etely aqueous solutions . To circumvent this d i f ficulty the ( 1 1 1 ) has been app lied to reversed-phase chroma tography by Melander and Horvath

( 1 09 , 1 4 6 ) . Sinanoglu originally used th e theory in order to explain the co i l to helix trans ition o f DNA in d i f f erent solvents ( 1 1 1 ) . He correlated the obs erved high s t ab i l i ty o f coiled DNA in aqueous s olution with the high cohes iveness of water and the dec reas e in solvent cavity

surfac e a rea caus ed by s t acking of the bas�s in the coiled conformation . Furthermo re an analys is of the thermodynamic cont ributions expected revealed tha t the mos t important c ont ribut ion to the coil to helix t rans i t io n was a negative entha lpy c aused by the decrease in solvent cavity area ( 1 1 1 ) . This is c ompa tib l e with the ob served d ecrease in s tab ility o f helical DNA with increas ed t emperatur e .

There is a concept ual point t o b e made her e . The s olvophob ic theory encomp as s es s olvents wh ich do no t c ontain wa ter at all , whe reas , hydro­ phobic ef fects are presumed to be c aused by the special properties of wat er . Therefo re inherent in the s o lvophob ic theory is the notion that

the special cohes ivenes s of wat er is merely an extreme in a cont inuum

of solvent cohes iveness ( 1 1 1 ) . This conc ept is supported by the approxima t e obed i enc e of many liquids including water to a l inear

* The mo re general t erm "hydrophob ic effect " is used here since it is unc lear whethe r the solute is completely part itioned into the nonpolar support a nd its adsorbed layers of nonpo lar mobile phase components