1

KINETIC STUDIES

Chemical kinetics deals with the rates of chemical reactions and with

how the rates depend on factors such as concentration and temperature. Such

studies are important in providing essential evidence as to the mechanisms of

chemical processes.

If Chemistry is making new substances out of old substances (i.e.,

chemical reactions), then there are two basic questions that must be answered:

1. Does the reaction want to go? This is the subject of chemical

thermodynamics.

2. If the reaction wants to go, how fast will it go? This is the subject of

chemical kinetics.

Kinetic studies constitute an important source of mechanistic

information on the reaction, as demonstrated by results referring to unsaturated

acids in both aqueous1,2

and non-aqueous media3.

The award of Nobel prize for the year 1992 to Prof. R. A. Marcus on the

“Electron Transfer Reactions” and 1999 Nobel prize to Prof. Ahmed Zewail for

discovely of “Femtochemistry” and 2001 Nobel prize to Profs. William

Knowles, K. Bary Sharpless and Royji Noyori for their work on “Chirally

Catalysed Hydrogenation Reactions” emphasize the importance of field of

reaction kinetics. Electron transfer reactions play a central role in physical,

chemical and biological processes. Because of the ubiquity of electron transfer

processes, the study of electron transfer reactions, perhaps more so than that of

2

any other area of chemistry is characterized by a strong interplay of theory and

experiment4, nonetheless the importance of electron transfer in transition metal

redox chemistry has been recognized5 and more recently it has become

increasingly obvious that many reactions in organic chemistry once thought to

be concerted in nature also occur via sequential one electron steps6.

The work of Henry Taube7 in redox systems unequivocally

demonstrated the transport of electron from reductant to oxidant. This

discovery certainly added many important features in the syntheses of

coordination complexes and organometallics. It is such a subject, which has

manifestations in almost all walks of life. As a result, oxidation-reduction

reaction needs at least two reactants, one capable of gaining electrons (oxidant)

and the other capable of losing electrons (reductant). Redox reactions are the

basis for numerous biochemical pathways and cellular chemistry, biosynthesis,

and regulation8.

Oxidation-reduction in inorganic reactions

Oxidation-reduction reaction may involve one or more electron

transfers. Depending upon the number of electrons transferred between oxidant

and reductant, the reaction may proceed in one or more steps. Electron transfer

reactions may occur by either of two mechanisms: outer-sphere mechanisms

and inner-sphere mechanisms9.

Considerations in an outer-sphere mechanism:

3

[Fe(CN)6] 4 -+ [Mo(CN)8] 3 -

[Fe(CN)6] 3 -+ [Mo(CN)8]4-

[Fe(CN)6] 4 - + [ Ir Cl 6] 2 - [ Fe(CN)6] 3- + [Ir Cl 6] 3-

1) reactants must get close together for tunneling to occur

2) bond lengthening and shortening must occur and

3) Franck-Condon principle must be obeyed

• electronic transitions (and electron transfer) occur on a far shorter time

scale than molecular vibrations (nuclear motion)

• this means that electron transfer will only occur when the complexes are

distorted to the appropriate geometry for the products – i.e., this imposes an

electronic barrier on the rate of electron transfer.

The coordination shells of the complexes or metal ion remains intact,

during this kind of electron transfer takes place. Such type of electron transfer

is called as tunneling effect. Outer sphere electron transfer is generally

enthalpically less favorable than inner sphere electron transfer because the

interaction through space between the redox centers in outersphere electron

transfer is weaker than the interaction through the chemical bridge present in

the inner sphere mechanism. By the same token, outer sphere electron transfer

is usually entropically more favorable than inner sphere electron transfer as the

two sites involved do not have to go through the ordering processes associated

with the formation of a bridge10

.

Such a mechanism is established when rapid electron transfer occurs

between two substitution-inert complexes.

4

[CoCl (NH3)5] 2+ + [ Cr(H2O)6 ] 2+ [Co(NH3)5 (H2O)] 2+ + [CrCl (H2O)5] 2+

[ Co(NH3)5Cl] 2++ Cr(H2O) 6] 2+ + 5 H2O [Co(H2O)6] 2+ + [Cr(H2O)5 Cl] 2+

+ 5 NH3

The inner-sphere mechanism should obey three distinct steps:

1) substitution to form a bridge between oxidant and reductant

2) actual electron transfer and

3) separation of the products (often with transfer of the bridge ligand)

An inner-sphere mechanism is one in which the reactant and oxidant

share a ligand transitorily in their inner or primary co-ordination spheres

forming a bridged intermediate activated complex. The discoverer of the inner-

sphere mechanism was Henry Taube, who was awarded the Nobel Prize in

Chemistry in 1983 for his pioneering studies. A particularly historic finding is

summarized in the abstract of the seminal publication11

.

Taube’s classical 1953 experiment (Nobel Prize 1983):

The electron being transferred across a bridging group. An example is

given below

Oxidation –reduction in organic reactions

In Organic Chemistry, oxidations and reductions are different from

ordinary redox reactions because many reactions carry the name but do not

actually involve electron transfer in the electrochemical sense of the word.

Covalent bond fission is an essential feature of organic reactions and it

can be affected by two different pathways12

, viz., “Homolytic reactions” in

which electron pairs are symmetrically disrupted and “Heterolytic reactions”

in which electron pairs are transferred from one molecule to another as an

5

undivided entity. Electron removal by these two pathways has clearly

distinguishable characterstics.

Homolytic fission is chemical bond dissociation of a neutral molecule

generating two free radicals. That is, two electrons that are involved in the

bond are distributed one by one to the two species. In homolytic reaction

electrons are removed singly from organic molecules forming free radicals

leading to chain reactions, dimerisations or disproportionations13

. All

heterolytic organic chemistry reactions can be described by a sequence of

fundamental mechanistic subtypes. The elementary mechanistic subtypes

taught in introductory organic chemistry are SN1, SN2, E1, E2, addition and

addition-elimination. Using arrow pushing, each of these mechanistic subtypes

can be described. On the contrary in heterolytic reactions oxidants attack

exposed electron pairs or loosely held π-electrons yield stable molecular or

ionic products in one or at most two consecutive stages and very seldom lead to

chain reactions.

Probable ways of electron transfer reactions

There are two types of electron transfer reactions14,15

first one is

“Complementary reactions” and the second one is “Non-complementary

reactions”.

Complementary reactions

The oxidant and reluctant change their oxidation state by an equal

number of units. These are termed as complementary electron transfer

reactions16

.

6

Ce(III) + Co(III) Ce(IV) + Co(II)

U(IV) + Tl(III) U(VI) + Tl(I)

Sn(II) + Hg(II) Sn(IV) + Hg(0)

(A) Cr(V) + Fe(II) Cr(IV) + Fe(III) slow

Cr(IV) + Fe(II) Cr(III) + Fe(III) rapid

(B) Cr(V) + Fe(II) Cr(III) + Fe(IV) slow

Fe(IV) + Fe(II) 2Fe(III) rapid

(i) One equivalent – One equivalent reactions:

These are the electron reactions in which there occurs the transfer of one

electron from one species to the other. These simple reactions serve as models

for more complicated systems and their study has proved invaluable in

developing and understanding of the electron transfer in solution17

. e.g.,

(ii) Two-equivalent –Two-equivalent reactions17, 18

:

A large number of complementary reactions have been explained by

assuming the formation of bridged activated complexes between the oxidant

and the reductant for the facile transfer of electron through the bridging ligand.

Non-complementary reactions

The oxidant and the reductant change their oxidation states by a different

number of units. These are termed as non-complementary electron transfer

reactions 19

. Most of the non-complementary reactions proceed via elementary

steps each involving one electron transfers. The most commonly observed

kinetic scheme 19

is

Subsequently, chromium(V) reacts with ferrous ion in a rate determining step

by one of the following schemes.

Cr(VI) + Fe(II) Cr(V) + Fe(III)

7

According to Tong and King, mechanism (A) is more appropriate

because, the slowest step corresponds to the change in the coordination number

four of chromium(V) to six of chromium(III).

Multi equivalent reactions

Oxidising agents such as Cr(VI) and Mn(VII) undergo net changes of 3

and 5 units in oxidation number respectively during their reactions in acidic

solution20

. For the most part, these reactions occur by one or two electron

steps, with the necessary intervention of unstable intermediate oxidation states

of Cr or Mn. The reactions of Cr(VI) with transition metal complexes

generally proceed by sequential one-electron step21

, but with post transition

metal ions and with non-metallic compounds, two electron steps appear to be

preferred.

Electron transfer reactions are found to be governed by two classical

principles

(a) Michaelis principle of compulsory univalent oxidation steps22

(b) Shaffer’s principle of equivalent change23

Michaelis hypothesis involves the principle that an oxidation-reduction

reaction takes place in one or more successive single electron transfer steps.

This principle evolved from a considerations of restricted field of redox

reactions, of which the oxidation of hydroquinones to quinones through

semiquinone intermediate is typical and is now generally recognised as being

without universal validity. Apart from the reactions involving metal ions,

many two equivalent redox reactions are now known which proceed in one step

through the transfer of hydride ion or an oxygen atom24

. e. g. ,

NO2 + OCl-- NO3 + Cl

--

8

The second principle23

refers to the observation that non-complementary

reactions are often slow compared with complementary one’s. Examples are

the slow reduction of Tl(III) by Fe(II)25

or Ce(IV) by Tl(I)26

as compared to the

rapid reduction of Tl(III) by Sn(II)27

and Ce(IV) by Fe(II)28

.

The observations expressed by Shaffer, for non-complementary

reactions, are based on the low probability of termolecular mechanisms as one

possibility or the formation of the unstable valence states as the other

possibility14

.

Product isolation and purification

Product isolation is the removal of those components whose properties

vary markedly from that of the desired product. For most products, water is the

chief impurity and isolation steps are designed to remove most of it, reducing

the volume of material to be handled and concentrating the product. Solvent

extraction, adsorption, ultrafiltration, and precipitation are some of the unit

operations involved.Isolation and identification of products formed during a

reaction is very essential before attempting to formulate a mechanism of the

reaction. Various techniques like IR, NMR, mass spectroscopy, gas-liquid

chromatography etc., are presently available for isolation and characterization

of reaction products29

.

Active species

The species which is involved in a slow step, will influence the reaction.

The reaction condition will determine the nature of the active species.

The diperiodatoargentate(III) complex is diamagnetic and exhibits

square planar configuration with dsp2 hybrid bonds

30. Periodate acts as a

bidentate ligand and contributes to the stabilization of Ag(III). The structure

9

and cell dimensions of DPA compound resemble those of

diperiodatocuprate(III). Monoperiodatoargentate(III) is considered the active

species of the diperiodatoargentate(III). The Ag(III) periodate complex ion can

be represented as [Ag(H2O)(IO6)2]7-

and in solution it can be considered as

hydroaquodiperiodatoargentate(III). To formulate the reaction rate as a

function of species concentration, therefore, requires knowledge of the

existence of such equilibria and generally speaking, the knowledge of

determination of one or more equilibrium constants.

Unstable oxidation states

The formation of unstable oxidation states during the course of non

complementary reactions has been now anticipated in a number of such

reactions with sufficient proofs. For example, the reductions of Tl(III) by

Fe(II)25

, V(III) or V(IV)31,32

and Cr(VI) by Tl(I)33

can only be explained

through the formation of unstable oxidation states have been observed in other

studies. The inter conversions between Cr(III) and Cr(VI) always appear to

involve the unstable states, Cr(IV) and Cr(V).

Five main components of a kinetic investigations are:

1) Product and intermediate detection

2) Concentration determination of all species present

3) deciding on a method of following the rate

4) The kinetic analysis

5) Determination of the mechanism

10

INTERACTION STUDY OF BIOACTIVE DRUGS WITH HUMAN

SERUM ALBUMIN AND BOVINE SERUM ALBUMIN

During the past 20 years there has been a remarkable growth in the use

of fluorescence in the biological sciences. Fluorescence spectroscopy and time

resolved are considered to be primarily research tools in biochemistry and

biophysics. Fluorescence technology is used by scientist from many

disciplines.

Serum albumins

Serum albumin is the major transport protein for unesterified fatty acids,

but is also capable of binding an extraordinarily diverse range of metabolites,

drugs and organic compounds. Since the overall distribution, metabolism and

efficacy of many drugs in the body are correlated with their affinities towards

serum albumin34

, the investigation of pharmaceuticals with respect to albumin–

drug binding is important. They also play a leading role in drug disposition and

efficacy. Furthermore, albumins are the principal biomacromolecules that are

involved in the maintenance of colloid blood pressure and are implicated in the

facilitated transfer of many substances across organ–circulatory interfaces such

as liver, intestine, kidney and brain35

. These studies may provide information of

the structural features that determine the therapeutic effectiveness of drugs, and

have become an important research field in the life sciences, chemistry and

clinical medicine.

11

There is evidence of conformational changes in bovine serum albumin

induced by its interaction with low molecular weight drugs. These changes

appear to affect the secondary and tertiary structure of albumin36

. Serum

albumins most important property is the ability to serve as a depot protein and

as a transport protein for a variety of endogenous and exogenous compounds

such as fatty acids, hormones, bilirubin, drugs, and a large diversity of

metabolites37-39

.

The HSA and BSA consist of amino acids chains forming a single

polypeptide with well-known sequence40

. The BSA shows 76% sequence

identity with the HSA41

. From the spectroscopic point of view, one of the main

differences between the two proteins is that BSA has two tryptophan residues

(W131 and W214), while HSA has only one (W214). The fluorescence of HSA

and BSA comes from the tryptophan, tyrosine, and phenylalanine residues39

.

Actually, the intrinsic fluorescence of HSA and BSA is almost exclusively

contributed by tryptophan alone when excited at 282 nm, because

phenylalanine has a very low quantum yield and the fluorescence of tyrosine is

almost totally quenched if it is ionized or is near an amino group, a carboxyl

group, or a tryptophan. This viewpoint was supported by the experimental

observation of Sulkowska42

. That is, the changes in intrinsic fluorescence

intensity of HSA and BSA are those in tryptophan residues when small

molecular substances are bound to HSA and BSA. . BSA has two tryptophan

residues embedded in two different domains: Trp 134, located in proximity of

the protein surface but buried in hydrophobic pocket of domain I and Trp 214

12

located in an internal part of domain II43

. It consists of a single chain 582

amino acid globular nonglycoprotein cross linked with 17 cystine residues (8

disulphide bonds and 1 free thiol). BSA is divided into three linearly arranged,

structurally distinct and evolutionarily related domains (I - III); each domain is

composed of two subdomains (A and B)44,45

.

Studies on drug HSA or drug BSA interactions can reveal properties of

drug-protein complex by providing useful information on the structure features

that govern the therapeutic effectiveness of drugs. Insight into interaction

mechanisms between drugs and plasma proteins is of crucial importance in

understanding pharmacodynamics and pharmacokinetics of a drug. Drug

binding influences the distribution, excretion, metabolism, and interaction with

the target tissues. This is why the drug/protein interaction has become an

important research field in life science, chemistry, and clinical medicine41,46

.

Quenching of fluorescence

Fluorescence quenching refers to any process which decreases the

fluorescence intensity of a sample. A variety of molecular interactions can

result in quenching. These include excited state reactions, molecular

rearrangements, energy transfer, ground state complex formation and

collisional quenching47

.

Proteins are by no means rigid, but engage in internal motions of many

kinds48-51

. The amplitude and time scale of internal protein motions may be

decipherable from the rates at which agents of varying molecular sue can reach

tryptophan side chains and quench their fluorescence or phosphorescence. Such

13

encounters may reflect a deep penetration of the quencher into the protein

matrix, a protein unfolding reaction that transiently exposes the tryptophan, or

more simply some degree of tryptophan exposure to solvent in the native

protein. The latter possibility is especially suggested by the fact that very few

protein tryptophans are fully inaccessible to solvent52,53

.

Quenching measurements of albumin fluorescence is an important

method to study the interactions of compounds with proteins54,55

. It can reveal

accessibility of quenchers to albumins fluorophores, help to understand

albumin binding mechanisms to compounds and provide clues to the nature of

the binding phenomenon56,57

.

Fluorescence quenching studies are quit useful to understand the

mechanism of interaction between proteins and drugs. The decrease of

quantum yield of fluorescence from a fluorophore induced by a variety of

molecular interaction with quencher molecule is called fluorescence quencher.

The fluroscence intensity of a compound can be decreased by a variety of

molecular interactions viz, excited state reactions, molecular rearrangements,

energy transfer, ground state complex formation and collisional quenching.

Quenching is divided into Static quenching and Dynamic quenching.

Static and dynamic quenching can be distinguished by their dependence

on temperature58

. Higher temperature results in faster diffusion and hence

larger amount of collisional quenching. On the other hand , higher temperature

will typically result in the dissociation of weakly bound complexes and hence

smaller amount of static quenching.

14

Energy transfer

Fluorescence energy transfer is the transfer of the excited state energy

from a donor (d) to an acceptor(a). This transfer occurs without the appearance

of a photon , and is primarily a result of dipole-dipole interactions between the

donor and the acceptor. The rate of energy transfer depends upon the extent of

overlap of the emission spectrum of the donor with the absorption spectrum of

the acceptor, the relative oriatation of the donor and acceptor transition dipoles,

and the distance between these molecules59

. Measurement of the rate of energy

transfer permits the distance between the donor and the acceptor to be

calculated, a procedure widely used in biochemical research. The experimental

results of Wu and Stryer59

provide an excellent illustration of the use of

fluorescence energy transfer to determine the distances between various

binding sites on a protein60

.

Förster resonance energy transfer, also known as fluorescence resonance

energy transfer, resonance energy transfer (RET) or electronic energy transfer

(EET), is a mechanism describing energy transfer between two chromophores.

A donor chromophore, initially in its electronic excited state, may transfer

energy to an acceptor chromophore (in proximity, typically less than 10 nm)

through nonradiative dipole–dipole coupling. This mechanism is termed

"Förster resonance energy transfer" and is named after the German scientist

Theodor Förster61

.

15

SUMMARY OF THE PRESENT WORK

The thesis is divided into seven chapters including general introduction

and summary of the present work. Chapter two to seven have been divided

into two parts as: Part-A: Kinetic studies and Part-B: Interaction study of

bioactive drugs with human serum albumin and bovine serum albumin.

I General introduction and summary of the present work

This chapter introduces about the principles and applications of kinetic studies

and drug protein interaction by spectroscopic methods, including the summary

of the present work .

PART -A : KINETIC STUDIES

II Oxidation of 6-aminopenicillanic acid by diperiodatoargantate(III) in

aqueous alkaline medium ― A kinetic and mechanistic study

Many pharmaceutical compounds and metabolites are being found in

surface and ground waters, indicating their ineffective removal by conventional

waste water treatment technologies. Advanced oxidation processes for the

transformation of 6-aminopenicillanic acid in water are alternatives to

traditional water treatment. Therefore the kinetics of oxidation of 6-

aminopenicillanic acid by diperiodatoargentate(III) in alkaline medium at a

constant ionic strength of 0.04 mol dm-3

was studied spectrophotometrically at

25 oC. The oxidation products, 2-formyl-5,5-dimethyl thiazolidine 4-carboxylic

acid and Ag(I), were identified by LC-ESI-MS and IR spectral studies. The

reaction between 6-aminopenicillanic acid and diperiodatoargentate(III) in

alkaline medium exhibits 1:1 stoichiometry. The reaction shows first order with

respect to diperiodatoargentate(III) concentration. The order with respect to

16

6-aminopenicillanic acid and alkali concentrations is less than unity. The rate

goes on decreasing with the increase in the concentration of periodate.

Monoperiodatoargentate(III) is considered as the active species of the

diperiodatoargentate(III). A possible mechanism is proposed. The reaction

constants involved in the different steps of the mechanisms are determined. The

activation parameters with respect to slow step of the mechanism are calculated

and discussed. The thermodynamic quantities are also determined.

III Oxidation of acyclovir by cuprate(III) periodate complex in aqueous

alkaline medium: A kinetic and mechanistic approach

The oxidation of acyclovir by diperiodatocuprate(III) in aqueous

alkaline medium at a constant ionic strength of 0.01 mol dm-3

was studied

spectrophotometrically at 25 0C. The reaction between acyclovir and DPC in

alkaline medium exhibits 1:4 stoichiometry (acyclovir : diperiodatocuprate

(III)). The main oxidation products were identified by the spot test, Infra Red

and liquid chromatography mass spectral studies. The reaction is of first order

in diperiodatocuprate(III) and has less than unit order in acyclovir

concentration and negative fractional order in periodate and alkali

concentrations. Intervention of free radical was observed in the reaction. The

oxidation reaction in alkaline medium has been shown to proceed via a

diperiodatocuprate(III)-acyclovir complex, which decomposes slowly in a rate

determining step followed by other fast steps to give the products. A suitable

mechanism is proposed. The reaction constants involved in the different steps

of the mechanism were calculated. The activation parameters with respect to

slow step of the mechanism and thermodynamic quantities were determined

and discussed.

17

IV Kinetics and mechanism of methocarbamol by alkaline permanganate

The kinetics of oxidation of methocarbamol by permanganate in alkaline

medium at a constant ionic strength of 0.17 mol dm-3

was studied

spectrophotometrically using rapid kinetic accessory. The reaction between

permanganate and methocarbamol exhibited 1:4 stoichiometry (methocarbamol

:permanganate). The reaction was of first order in permanganate and has less

than unit order in both methocarbamol and alkali concentrations. A decrease in

the dielectric constant of the medium decreased the rate of reaction. The

oxidation reaction in alkaline medium has been shown to proceed via a

permanganate- methocarbamol complex which decomposes slowly in a rate

determining step followed by other fast steps to give the products. A suitable

mechanism is proposed. The reaction constants involved in the different steps

of the mechanism were derived. The activation parameters with respect to the

slow step of the mechanism were computed and discussed and thermodynamic

quantities were also determined.

PART-B: INTERACTION STUDY OF BIOACTIVE DRUGS WITH

HUMAN SERUM ALBUMIN AND BOVINE SERUM ALBUMIN

V Interaction between a antiretroviral drug – navirapine with bovine serum

albumin : A fluorescence quenching and fourier transformation infrared

spectroscopy study

The interaction between nevirapine to bovine serum albumin has been

studied by spectroscopic methods. The experimental results revealed a static

quenching mechanism in the interaction of nevirapine with BSA. The number

of binding sites close to unity for nevirapine–BSA indicated the presence of

18

single class of binding site for the drug in protein. The binding constant values

of nevirapine–BSA were observed to be 1.98x10-4

, 1.74 x10-4

, and 1.38 x10-4

at

288K, 298K and 308K respectively. Thermodynamic parameters indicated that

the hydrophobic forces played the major role in the binding of nevirapine to

BSA. The distance of separation between the serum albumin and nevirapine

was obtained from the Förster’s theory of non-radioactive energy transfer. The

metal ions viz., Ca2+

, Co2+

, Cu2+

, Ni2+

and Zn2+

were found to influence the

binding of the drug to protein. The fluorescence spectra, UV absorption spectra

and FT-IR spectral results revealed the changes in the secondary structure of

protein upon interaction with nevirapine.

VI Binding of the bioactive component venlafexine hydrochloride to bovine

serum albumin

The binding of vanlafexine hydrochloride (VEN HCL) to bovine serum

albumin (BSA) was investigated by spectroscopic methods viz., fluorescence,

FT-IR and UV–vis absorption techniques. The binding parameters have been

evaluated by fluorescence quenching method., and the thermodynamic

parameters, ΔH0, ΔS

0 and ΔG

0 were calculated. Based on the Forster’s theory

of non-radiation energy transfer, the binding average distance, r, between the

donor (BSA) and acceptor (VEN HCL) was evaluated . Spectral results showed

the binding of VEN HCL to BSA induced conformational changes in BSA. The

effect of common ions was also tested on the binding of VEN HCL to BSA.

19

VII A study on the interaction between navirapine and human serum albumin

using fluorescence quenching method

Present work was designed to study the interaction between navirapine

and human serum albumin (HSA) under simulative physiological conditions

using fluorescence spectroscopy. Static quenching was suggested by the

fluorescence measurement. The binding constants (K) were calculated

according to the relevant fluorescence data at different conditions including

temperature. The number of binding sites n was obtained at various

temperatures. The distance, r, between donor (HSA) and acceptor (NAVP) was

evaluated according to Föster energy transfer theory.The results of

fluorescence spectra, FT – IR and UV–vis absorption techniques showed that

the conformation of human serum albumin has been changed in the presence of

navirapine. The thermodynamic parameters, enthalpy change (∆H0) and

entropy change (∆S0) were calculated to be -18.06 kJ mol

-1 and 21.42 J mol

-1

K-1

respectively according to vant Hoff equation. The effect of common ions

was tested on the binding of navirapine to human serum albumin.

20

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