Gross R., Sidorenko A., Tagirov L. Nanoscale Devices

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Thermodynamic Principles of Artificial Nose

Based on Supramolecular Receptors

V. V. Gorbatchuk, M. A. Ziganshin

Kazan State University, A. M. Butlerov Institute of Chemistry, Kazan

420008, Russia

Abstract: The cooperative effects in the substrate vapor binding by solid

receptors and their relevance for structure-property relationships in

the odor sensor applications are discussed and reviewed.

Keywords: calixarenes, cyclodextrins, cross-linked hydrophilic polymers,

proteins, vapor binding cooperativity, molecular recognition, odor

sensors, headspace GC analysis, model sensor systems, structure-

property relationship.

Introduction

Application of supramolecular receptors such as calixarenes, cyclodextrins

and proteins in the odor recognition devices provides the enhanced vapor

binding selectivity [1, 2]. The answer on the question, why a given receptor

is more or less selective, is necessary for a design of the effective odor

sensors that can substitute for this purpose the living beings. In this review,

the effect of cooperativity in the substrate vapor binding by solid receptors

on the structure-property relationships of this process is discussed.

Cooperativity is one of the major factors defining the receptor selectivity.

However, this effect is often underestimated and even neglected in the

sensor applications.

In this review, we analyze two types

of the binding cooperativity. One

of them can be observed in binary systems. For another to be revealed, a

third component is necessary. These two types of cooperativity are of

thermodynamic nature (i.e. can be seen on sorption isotherms) and relate to

the

well-known cooperative effects of molecular biology and biochemistry.

R. Gross et al. (eds.), Nanoscale Devices - Fundamentals and Applications, 23–34.

24 V. V. Gorbatchuk, M. A. Ziganshin

The first was observed nearly a hundred years ago by Hill [3]. It is a

homotropic cooperative binding of oxygen by hemoglobin. The second is a

cooperative hydration effect on the enzyme activity [4]. The structural

requirements for synthetic supramolecular receptors (hosts) to mimic these

types of cooperativity are discussed in this paper.

Being cooperative, a substrate-receptor binding has a bundle of related

cooperative phenomena. These are the memory of the receptor preparation

history, the cooperative effect of the third component, and the temperature

effect on the binding threshold. Most of these effects are hard to be seen

using sensor devices. So, the data obtained for the model systems with

receptor powder, using headspace GC analysis, where these cooperative

effects can be controlled, are regarded here together with the corresponding

experimental approaches.

Because of the complicated interference of cooperative effects, they can

have a strong influence on the observed structure-property relationships.

Here several simple relationships of this kind are discussed, which were

obtained in standard conditions removing the memory effects, so that some

objective basis is provided for an aimed molecular design of sensitive

materials for “electronic nose” devices being capable to match the best

receptors of living nature.

Cooperative Binding in Binary Substrate-Receptor

Systems

Cooperative binding in the system with two relevant components: substrate

vapor and solid receptor, or vaporous guest and solid host, were observed in

a lot of works [5-11] for calixarenes and other clathrate forming

Fig. 1. A typical sorption isotherm of guest vapor by solid host in the binary

system.

Thermodynamic Principles of Artificial Nose 25

receptors. The typical shape of guest binding isotherm observed for

nitromethane vapor – solid tert-butylthiacalix[4]arene

is shown on Fig. 1.

This isotherm has a threshold of guest thermodynamic activity, or

relative vapor pressure, P/P

, below which no significant binding can be

seen. Above this threshold the guest-host binding capacity sharply increases

up to a saturation level, which corresponds to the formation of the saturated

clathrate.

The same shape of sorption isotherms was observed for the binding of

oxygen by hemoglobin in water solution [12]. While this cooperative effect

for a single hemoglobin molecule in solution is not very simple to explain,

mostly because the crystals of this protein, for which the structural X-ray

data were obtained, do not perform a significant binding cooperativity

[12, 13], for organic hosts like calixarenes a sigmoidal sorption isotherm

has rather trivial explanation. In terms of the Gibbs phase rule it is a result

of phase transition in solid host phase at the binding of the guest vapor that

gives a host-guest inclusion compound, or clathrate [5, 6, 9, 14, 15]. This

conclusion was confirmed by the comparison of the powder X-ray

diffractograms of the initial host and of the host saturated by guest [6, 16].

A structural illustration of the phase transition at the formation of inclusion

compound with solid host is shown on Figure 2.

Fig. 2. A structural illustration of the phase transition at the formation of inclusion

compound with solid host.

For description of sigmoidal sorption isotherms the Hill equation can be

used:

A = SC(P/P

)

/ (1 + C(P/P

)

), (1)

where S – inclusion stoichiometry, C – sorption constant, N – cooperativity

constant, A – experimentally determined solid phase composition (mol of

guest per mol of host). The fitting of the sigmoidal sorption isotherms with

the Hill equation (1) gives two stable solutions: the stoichiometry S and the

ratio (lnC)/N. The last value directly relates to the threshold activity of the

guest at the half saturation of host A = 0.5S:

0.5S

= exp(-(lnC)/N). (2)

26 V. V. Gorbatchuk, M. A. Ziganshin

The Gibbs energy of the guest inclusion can be calculated by the

integration of the sorption isotherms having a saturation part:

SOc

aRTdYPPRTG

5.0

ln)/ln(

∫

==∆ .

(3)

Here, Y = A/S is the host saturation extent. The inclusion free energy

∆

the free energy of transfer of 1 mole of guest from the standard state of pure

liquid to the saturated solid phase (inclusion compound). The right part of

equation (3) is valid if the ln(P/P

) value is given by equation (1) as a

function of Y.

The problem is that no sorption isotherms, obtained up-to-date using thin

layer of solid receptors on QCM sensors, have a shape shown on Figure 1.

The initial part of these isotherms have rather Langmuir [1, 17-19] or the

linear [1, 20] shape, Figure 3. For the same toluene vapor – solid tert-

butylcalix[6]arene pair the thin layer of this host on QCM sensor gives a

BET isotherm [17], while its powder gives a sigmoidal isotherm [21].

Fig. 3. Typical isotherms of the guest vapor sorption by the host thin layer on QCM

sensor with linear and BET shape.

The reason for that may be the different history of the host samples. The

low-temperature decomposition of clathrates, which occurs on the surface

of QCM sensors, may produce the zeolite-like material with empty cavities

in the host keeping the packing of clathrate. Such transition was observed

using X-ray method [22]. The zeolites with the fixed surface of gas–solid

interface have the sorption isotherms with the Langmuir shape like shown

on Figure 3 [23]. The host polymorphism as a function of thermal history

was also observed in the other studies [24-26]. The sigmoidal isotherms

(Figure 1) were observed for the host powder, where the clathrate memory

effect was removed by heating [5 ,6 ,9 ,14 ,15].

Thermodynamic Principles of Artificial Nose 27

Cooperative Hydration Effect on the Substrate Vapor

Binding

The molecular design of biomimetic receptors for the sensor applications is

often confined to the synthesis of molecularly imprinted polymers (MIP)

with the binding sites similar to those of antibodies and enzymes [27]. For a

MIP to be a genuine analogue of antibodies, it should have also a

biomimetic hydration effect on a substrate binding [28]. Hydration is a

crucial factor for the protein receptor properties. It cooperatively enhances

the rates of enzymatic reactions in low water conditions [4]. Proteins in

contact with some water-organic mixtures show a cooperative increase both

in water uptake [29, 30] and uptake of hydrophobic organic components

[31, 32] above a certain hydration threshold. Antibodies also need a

sufficient hydration to bind antigens [2]. The typical sigmoidal sorption

isotherm, where the partition coefficient A/(P/P

) between the pure liquid

sorbate and solid protein phase is plotted against the protein hydration, is

shown on Figure 4.

Fig. 4. The hydration effect on the binding affinity of cross-linked poly(N-6-

aminohexylacrylamide) (data from Ref. [28]) and human serum albumin (data from

Ref. [31]) for benzene and cyclohexane.

The protein hydration is favorable for the binding of hydrophobic

compounds, like benzene, but only above a threshold value of water

contents. Above this threshold the protein binding affinity for a sorbate

(substrate) goes up to the saturation level that is approximately equal to the

28 V. V. Gorbatchuk, M. A. Ziganshin

value observed for the same protein-substrate pair in water solutions

[31, 32]. For this favorable hydration effect to be seen, a synthetic polymer

should be hydrophilic to let water penetrate inside its bulk phase and have a

rather rigid structure preventing the sorption of hydrophobic or large

substrates without hydration [28]. The cross-linked poly(N-6-

aminohexylacrylamide) (PNAHAA), studied in [28], fits rather well to

these requirements. The sorption isotherm of benzene on this polymer has

almost the same shape as for human serum albumin, Figure 4.

Cooperative phenomena in binary protein-water systems were

described as a result of protein microheterogeneous structure [33].

The

clathrates of water were observed around hydrophobic groups of amino acid

residues [34]

and bound hydrophobic compounds [35, 36]

in protein

crystals.

Since the same cooperative hydration effect is observed for the

binding of hydrophobic compounds by an amorphous non-protein

macromolecular material, like PNAHAA [28], and proteins that do not

perform significant cooperativity at the binding of organic vapors in

absence of water [31, 32],

one can conclude that a source of protein

hydration cooperativity may be rather the properties of bound water itself

than the special protein structure.

Water bound by hydrophilic macromolecular receptor contributes

much to its binding selectivity. The hydration of PNAHAA increases its

selectivity for the pair benzene-cyclohexane up to almost that of liquid

water [28]. But this polymer as well as proteins [31, 32] becomes much less

selective for the pairs of more hydrophilic sorbates when hydrated. Strong

dependence of the substrate binding selectivity on the receptor hydration

can be a powerful tool in the applications of the odor recognition devices.

A further justification of the clathrate nature of the cooperative

hydration effect and the role of hydration in the substrate binding by

hydrophilic receptors comes from the sorption studies for beta-cyclodextrin

(BCD) [37]. Dry beta-cyclodextrin does not bind monofunctional

compounds larger than ethanol. Hence, being hydrophilic, it fits to the

above-mentioned requirement for the receptor to have the biomimetic

hydration effect. BCD does bind benzene up to hydration of 0.06 g H

O/g

BCD and benzene activity P/P

=0.8 as shown in Figure 5. But when BCD

is almost completely hydrated, it forms 1:1.3 clathrate with benzene [37]

(see Figure 5). The shape of benzene sorption isotherm on BCD hydrated to

0.172 g H

O/g BCD has the same shape as for the guest vapor binding by

solid hydrophobic hosts as shown by Figure 1.

Thermodynamic Principles of Artificial Nose 29

Fig. 5. The hydration effect on the sorption of benzene by beta-cyclodextrin

(BCD). Data taken from ref. [37].

Secondary Cooperative Effects for the Substrate Vapor

Binding

The main two types of cooperative effects described above define the odor

sensing technique based on the substrate-receptor (host-guest) binding with

the formation of clathrates, or inclusion compounds, in the binary systems

with the homogeneous initial host, where the memory effects are removed,

and in ternary systems, where the change of receptor hydration is a

dominating factor. Generally, in the sensor applications more complex

systems and/or conditions may be used. In these cases, the secondary

cooperative effects may be observed, which, in essence, relate to the main

two, but may significantly change the substrate-receptor affinity and

binding selectivity, or even mask the system cooperativity as it is observed

in the systems with memory effects (Figure 3).

The cooperative effect of the third component (second guest) on the

guest binding by solid host is one of such secondary effects. This effect can

reduce the inclusion threshold by the guest activity so that the sorption

isotherm acquires a Langmuir shape (Figure 6) due to the addition of a

small amount of the third component [8]. This change may occur when

30 V. V. Gorbatchuk, M. A. Ziganshin

Fig. 6. The cooperative effect of third component (0.1 mol toluene/mol host) on the

sorption of acetonitrile by tert-butylcalix[4]arene at 298 K. Data from ref. [8].

both guests included can coexist in a single crystal [5]. Otherwise, the

threshold activity of the guest binding increases a little [8], probably

because of the competition between two guests for the binding sites in solid

host phase.

Formally, the reduction of the guest threshold activity in the presence of

a small amount of the third component (Figure 6) corresponds to the

increase of the host-guest binding affinity below the host saturation level.

Nearly the same effect was observed for hydrated beta-lactoglobulin, which

in the presence of 1.2 % of lipids shows more than a double binding affinity

for decane and terpenes than the defatted preparation [32]. Lipids behave as

included in the protein solid phase, because the combined effect of lipids

and hydration perform an apparent synergism.

The cooperative effect of the third component may have a profound

effect on the structure-energy relationships of the host-guest binding,

making the host selectivity in ternary systems with the binary mixtures of

guest vapors much different from the value calculated from the binding

Gibbs energies in binary “guest vapor – solid host” systems.

Another significant secondary cooperative effect is a temperature effect

on the receptor hydration threshold. It was observed for beta-lactoglobulin,

which shows a reduction of the hydration threshold value on almost 0.1 g

O/g BLG at relatively small temperature increase from 298 to 309.5 K

(Figure 7) [32].

Thermodynamic Principles of Artificial Nose 31

Fig. 7. The temperature effect on the hydration threshold of alpha-terpinene

Besides, the value of the protein hydration threshold depends on the

protein hydration history: preliminary hydration pushes the hydration

threshold of hydrophobic sorbate (substrate) binding to the higher values, as

compared with the value of threshold hydration observed when protein is

hydrated in situ – in the presence of the hydrophobic sorbate [31]. Such

hydration history or memory effects were observed in studies of enzymatic

reactions with enzymes suspended in organic solvents [38].

The described secondary cooperative effects can give a larger variety of

structure-affinity relationships for the same set of receptors prepared or

used in different conditions, so that a more specific “fingerprint” can be

obtained for a given organic component or a complex organic vapor

mixture than in the case, when liquid sensitive material is used.

Structure-Energy Relationship

The secondary effects, especially the receptor memory of previous

treatment and clathrate structure are detrimental for the predictability of the

receptor behavior in the odor sensor applications. Moreover, the apparent

structure-energy relationship depends much

on the choice of substrate

(guest) standard state or concentration scale in the estimations of the sensor

effect or selectivity. When the substrate vapor with a certain pressure or

concentration is chosen as a standard state, the difference in Gibbs energies

of the substrate vapor condensation is often a major contribution in the

observed sensor selectivity, no much matter what is the nature of the

receptor used [39]. In this case, the sensor selectivity for organic vapors

follows the selectivity of their solvation in liquid solvents, like

sorption by initially dried defatted beta-lactoglobulin. Data taken from Ref. 32.

32 V. V. Gorbatchuk, M. A. Ziganshin

(Linear Solvation Energy Relationship) approach, which may be used for

the characterization of unknown vapors by array of polymer-coated sensors

[40].

Fig. 8. Nonlinear influence of the guest molecular size on the excessive Gibbs

energy of guest inclusion by solid host from the infinitely dilute solution in model

liquid solvent.

Still the supramolecular receptors (hosts) exist that are able to bind a very

restricted number of guests, when the host memory of the former clathrate

structure is removed by heating [7, 10]. This phenomenon corresponds to

the essentially nonlinear structure-energy relationship for clathrate

formation. A scheme of such relationship for the case, where only guest

(substrate) size is important, is given on Figure 8. This scheme describes

the guest size effect on the inclusion Gibbs energy ∆G

trans

determined for

the standard state: an infinitely dilute liquid solution of the guest in a model

solvent having the same energy of pair-wise molecular interactions with the

guest as the host cavity interior. This approach allows extracting a pure

contribution of supramolecular effect in inclusion Gibbs energy ∆G

calculated using equation (3) from the sorption data.

The minimum on the V-like dependence corresponds to the guest size

such that its further infinitely small increase gives the same cavity energy

costs in the host phase as in the model solvent. Above this point an ordinary

size exclusion effect should be observed. It was found as a linear structure-

energy relationship for the binding of organic vapors by 2,2’-bis(9-

hydroxy-9-fluorenyl)biphenyl [7] and tert-butylthiacalix[4]arene [10]

powders with toluene chosen as a model solvent, and the guest molar

refraction MR

used as a guest molecular size parameter.

hexadecane. The last process can be easily quantified in terms of LSER

Gross R., Sidorenko A., Tagirov L. Nanoscale Devices - Fundamentals and Applications

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