Beruflich Dokumente
Kultur Dokumente
1 Preamble
2 Basic Concepts
3 Practicalities
4 Conclusion
References
1
1
10
20
20
PREAMBLE
feet, the field has been busy working towards phase two:
applying what it now knows to topics such as sensing,6
while simultaneously exploring many-bodied systems that
may or may not be at equilibrium; the latter in the short term
is fundamental to the development of systems chemistry7
and in the long term may contribute to the development of
synthetic complex systems (i.e., those possessing emergent
phenomena).811 Regardless of exactly how this second
phase evolves, the ability to measure equilibria will always
be a part of supramolecular chemistry, and hence a thorough
understanding of the underlying concepts and the practical
aspects of measuring equilibria is of fundamental importance. This chapter summarizes the important concepts,
techniques, and protocols in studying systems at equilibrium. We begin with the basic concepts, and, where appropriate, relate these to the common methods of determining the thermodynamics of complexation [NMR (nuclear
magnetic resonance), UVvis spectroscopy, and isothermal titration calorimetry (ITC)]. In the second section, we
examine practical aspects of determining this data using the
aforementioned techniques.
2
2.1
BASIC CONCEPTS
Association constants and Gibbs free energy
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Concepts
Gt
nA
(1)
where nA is the mole fraction of solute A. Chemical potential is analogous to potential energy, and thus assuming
there is no (kinetic) barrier of impediment, a system of
higher chemical potential will change so that a lower potential can be attained. Note that (1) relates how the free energy
of a system changes upon a change in its composition, that
is, Gt = A nA . Building on this, the total GFE (Gt ) of
the solution of A is the sum of the products of the mole
fraction and chemical potential of each of the constituents.
Thus in the case of solute A dissolved in solvent (S), we can
write (2), where nA and nS are the mole fractions of solute
and solvent, and A and S are their respective chemical
potentials:
Gt = nA A + nS S
(2)
A = A + RT ln nA
(3)
where A is the chemical potential of the standard (reference) state, R is the gas constant, T is the temperature, and
nA is, again, the mole fraction of A. However, most solutions do not behave ideally, and in these cases (3) can be
A = A + RT ln aA
(4)
(5)
(6)
= Grct
(7)
p,T
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G r < 0, reaction is
spontaneous
Grct = GB GA = 0B 0A
Gt
G r > 0, reverse
reaction is
spontaneous
Slope = G rct
B A = 0B 0A + RT (ln aB ln aA )
Grct =
nB = 1
Extent of reaction (z)
Grct
Grct
+ RT (ln aB ln aA )
aB
= Grct + RT ln
aA
(12)
(13)
(14)
(15)
Grct = Grct + RT ln
[A]
(8)
At any point of a reaction, the ratio of products to reactants,
in this case [B]/[A], is defined by the reaction quotient Q.
Formally, and more generally, we can define Q as
(9)
and hence
Grct = B A
(11)
G rct = 0
nB = 0
(10)
Q = J aJ J
(16)
where denotes the product of what follows it (as
denotes the sum), aJ is the activity of component J, and
J is the stoichiometric number. The reader will recall
that stoichiometry numbers are different from stoichiometry
coefficients, and are negative for the reagents and positive
for the products of a reaction. Thus, in the case at hand,
Q = aA1 aB1 = aB /aA . Hence, (14) can be written in the
more general form (17)
Grct = Grct + RT ln Q
(17)
Grct = RT ln K
(18)
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Concepts
(19)
(20)
(21)
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2.2
G = H TS
(22)
(Ssym
) entropy of mixing (Smix
). As a rule of thumb,
Svib
which can be mostly attributed to changes in internal
bond rotationsis usually an order of magnitude smaller.
It should be noted that of these three, only translational
entropy is concentration dependent. The additional entropy
and Smix
are generally quite small. Thus, the
factors Ssym
entropy of symmetry is defined by Ssym = R ln , where
is the symmetry number characteristic of the point group
of the molecule. For molecules of low symmetry (e.g.,
the C1 point group) = 1, whereas for higher symmetry molecules, for example, dodecahedrane (Ih point group)
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Concepts
Guest 5
H (kcal mol1)
ln Ka =
+ve
(23)
Guest 4
Guest 3
ve
+ve
Guest 2
Guest 1
ve
S (kcal mol1 T1)
2.3
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k1
k1
HG
(24)
ka
kb
Bound
(25)
The rate constants for both the forward and reverse processes are those of unimolecular processes (units s1 ), and
it is the slowest of these two processes that we must compare with the rate at which the system is interrogated. For
spectroscopic determinations, the timescale of the analytical
technique is dictated by the Heisenburg uncertainty principle. The energy gap (E) between the two states connected
by the absorption is related to the time difference t by (26)
E t = 2
(26)
B0
2
(27)
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Concepts
s TMS
Operating Frequency (MHz) 106
(28)
2.4
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The host, guest, and hostguest complex each has a particular solvation shell, and the change in solvation in forming
the complex plays a large part in the overall thermodynamics of binding. A much more accurate equation would therefore account for the hydrating water molecules. Regardless
of our poor understanding of these hydration shells, a comparison of many hostguest complexes reveals that the
complexation of most organic molecules receives a thermodynamic boost from the hydrophobic effect. That said,
because of the shielding properties of highly polar water,
noncovalent interactions that primarily involve electrostatic
forces cannot be relied upon to the same extent as they
can be in organic solvents. Hence, although the strongest of
noncovalent interactionsmetal coordinationhas proven
to be effective drivers of complexation (and assembly) in
water, hydrogen bonding has proven so far to be of limited
utility. However, more often than not, the thermodynamic
boost from the hydrophobic effect more than compensates
for any loss of attractive electrostatic interactions between
molecules and, as a result, binding constants in water tend
to be at least 12 orders of magnitude larger. That this is
true is perhaps not so interesting in its own right. After
all, there are many situations where strong binding is not
a requirement, and many systems where strong binding
is a detriment. However, that binding is usually stronger
means that by and large any particular host is able to
bind a wider range of potential guests; and if selectivity is required, it is always easier to prevent binding than
create it.
In addition to stronger binding, the desolvation of surfaces on the host and guest as they form a complex also
leads to a characteristic decrease in the heat capacity of
the solution. The standard heat capacity of a substance at
constant pressure (Cp ), is the amount of energy a substance
absorbs per unit change in temperature (29):
Cp =
H
T
(29)
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10
Concepts
H = H + Cp
(30)
A similar equation (31) can be derived for the relationship between the standard entropy change (S ) and the
standard heat capacity change:
S = S + Cp ln T
(31)
PRACTICALITIES
Beyond the basic thermodynamics that we have just discussed, there are many considerations regarding how we
actually perform experiments to determine Ka , G , H ,
S , and Cp of complexation in 1 : 1 hostguest systems
(19). In determining thermodynamic data for a complexation event, there are, as there are with any physical chemistry problem, two goals. The first goal is to define the
system mathematically with a basic mathematical model;
the second is to fit the obtained data to the mathematical
model. The first goal is, of course, independent of the analytical technique we are going to use, whereas the second
is very much dependent on it. Irrespective of the technique
used, the overall aim is to quantify the formation of the
hostguest complex for a given initial concentration of host
and guest. This can be accomplished by directly measuring
the amount of hostguest complex, or indirectly by measuring the remaining free host or guest and using mass balance
equations to calculate the concentration of the complex.
Many analytical techniques are available to the experimentalist for this task, but we focus here on the most widely
used techniques, NMR, UV, and fluorescence spectroscopy,
and ITC, and give a succinct account on how to conduct
such experiments with these techniques. For more detailed
descriptions of the individual techniques, as well as details
of other techniques used, the reader is directed to some of
the many excellent reviews available in the literature.5, 3841
Each technique has its advantages and limitations, and our
intent here is to provide enough information to allow the
experimentalist to choose the most suitable technique for
his/her particular research.
This section begins with highlights of how the timeframe
of a technique and the concentration of a sample have
important practical ramifications. Subsequently, we discuss
the base mathematical model for 1 : 1 complexations before
looking at how this model is tailored to each analytical
technique. Finally, we discuss a common approach sometimes used to confirm 1 : 1 binding, as well as very briefly
highlight higher stoichiometry systems.
3.1
Timeframe of analysis
We have discussed the importance of timeframe of analysis with regard to both the timeframe by which equilibrium
in a system is attained and the timeframe of the exchange
process of the complexation under investigation. Practical
aspects of the former simply involve double-checking that
equilibrium has in fact been attained. Practical aspects of
the latter are a little bit more complex. As we have discussed, different techniques operate at different timeframes,
and it is important to appreciate how this relates to the
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3.2
Concentration range
11
1E 03
Concentration (M)
1E 03
8E 04
6E 04
4E 04
2E 04
0E +00
1E + 01
1E + 02
1E +03
1E +04
1E +05
1E + 06
1E + 07
1E + 08
K a (M1)
Figure 3 Graph of the concentration of host [H ] (blue), guest [G] (red), and hostguest complex [HG] (green) against equilibrium
constant (Ka ) where the total (initial) concentration of host and guest (Ht = Gt ) = 1 mM.
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12
Concepts
100
% complexation
80
60
40
20
0
1E + 00
1E 01
1E 02
1E04
G t (M)
1E 03
1E 05
1E 06
1E 07
Figure 4 Graph of the percentage complexation against total guest concentration (Gt = Ht ) where the equilibrium constant (Ka ) is
set to 1 103 M1 .
3.3
With the exception of just one scenario, all of the techniques commonly utilized by supramolecular chemists to
determine thermodynamic data yield too many unknowns
if just a single host/guest ratio is studied. The exception,
slow exchanging systems studied by NMR, allows the direct
measurement of the individual components of the mixture (see below) from just one Ht : Gt ratio. For the other
approaches, we must carry out a titration in which the
Ht : Gt ratio is varied systematically and construct a mathematical model based on the mass balance equations for
the equilibrium and (20). The corresponding mass balance
equations are (33) and (34):
Ht = [H ] + [HG]
(33)
Gt = [G] + [HG]
(34)
(35)
(1 Ka Gt + Ka Ht )
(1 Ka Gt + Ka Ht )2 + 4Ka Gt
2Ka
(36)
3.4
NMR spectroscopy
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(37)
13
(38)
max Ka [G]
1 + Ka [G]
(39)
max
1
Ka [G]
+1
(40)
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14
Concepts
obs =
2
+1
Ka Gt Ka Ht 1 + (1 Ka Gt + Ka Ht )2 + 4Ka Gt
(41)
0.20
d (ppm)
0.15
0.10
0.05
0.00
0
0.002
0.004
0.006
0.008
G t (M)
0.01
0.012
0.014
0.016
Figure 5 Three theoretical binding isotherms for 1 mM host titrated with guests of association constants, Ka = 50 ( ), 1000 ( ), and
104 M1 ( ).
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3.5
(43)
= HG H G
(42)
(44)
Equation (44) actually pertains to a relatively rare system, because in most cases we select the absorption to
monitor so that one of the species does not absorb. In
rare cases where all species do absorb at the wavelength
examined, it is necessary to determine G and H in a
separate experiment to reduce the number of unknowns.
Hiroses excellent practical guide on binding constant
determinations describes the methods to treat the collected data (Aobs vs Gt ) of this more complex regression
analyses.39
For the majority of cases where only one species
absorbs at the observed wavelength (H or G = 0), we
can write simplified equations (45 and 46). In the case of
these equations, we assume it is the guest that does not
absorb:
Aobs = AH + AHG
(45)
= HG H
(46)
(47)
(48)
Aobs = AH + AG + AHG
15
Ka Ht [G]
1 + K[G]
(49)
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Concepts
Aobs =
Ht
2
+1
Ka Gt Ka Ht 1 + (1 Ka Gt + Ka Ht )2 + 4Ka Gt
(50)
3.6
The development of sensitive isothermal titration calorimeters first impacted the biological sciences. However, over
the last decade or so the technique has become increasingly utilized within supramolecular chemistry. One of the
major reasons behind its proven popularity is the fact that
Ka , G , H , and S are obtained in a single automated experiment. In a typical ITC titration, small aliquots
of a concentrated solution of the guest are added to a solution of the host in the ITC cell. Upon each addition, a
measured amount of heat is given off, and this decreases
during the titration and reaches zero upon saturation of
the host. The total heat liberated in this titration yields
the enthalpy change, while the shape of the curve for
heat release as a function of host/guest ratio provides the
equilibrium constant and hence the free energy of binding. As a result, the entropy change for complexation can
be directly calculated. This more direct approach to garnering thermodynamic data has much smaller associated
errors, particularly for H , and avoids the issues associated with vant Hoff plots such as the possibility that H
varies with temperature, or whether the obtained data has
chemical roots or is simply artifactual. ITC also allows
a more direct and accurate determination of heat capacity
changes. For straightforward cases of 1 : 1 complex formation, there is a linear relationship between H and T ,
the gradient of which is the Cp associated with binding. Thus, a series of five or more experiments run at
different temperatures accurately yields any heat capacity
change.
An ITC titration yields an amount of heat released or
absorbed (Q) for each aliquot of added guest solution.
The sum of these heats (Q) can be defined by (51):
(51)
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Q = Gt V0 H V0 H
(1 Ka Gt + Ka Ht )
(1 Ka Gt + Ka Ht )2 + 4Ka Gt
2Ka
17
(52)
3.7
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18
3.8
Concepts
3.9
Arbitrary units
3E 05
2E 05
2E 05
1E 05
5E 06
Competition experiments
ka(A)
HGA
(53)
H + GB
ka(B)
HGB
(54)
where Ka(A) > Ka(B) and the latter is known. The mass balance equations then become: Ht = [H ] + [HGA ] + [HGB ],
GAt = [GA ] + [HGA ], and GBt = [GB ] + [HGB ], where Ht
is the total host and GAt and GBt are the totals of GA
and GB , respectively. If we take the example of slow
exchanging system by NMR, the determination of Ka(A)
is accomplished using these mass balance equations, the
relative integration of HGA and HGB , and the following
equation (55):
[HGA ][GB ]
Ka(A)
=
Ka(B)
[HGB ][GA ]
(55)
0E + 00
0.0
0.2
0.4
0.6
Mole ratio
0.8
1.0
Figure 6 Continuous variation method (Job Plot) for a hypothetical 1 : 1 complex formation.
3.10
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(56)
19
even for a simple ternary complex, the exact (or closedform) solution of the required cubic equation is relatively
involved.
As just mentioned, in a host with two binding sites, the
nature of the binding sites, whether there is cooperativity
in binding, and whether there is an order to guest complexation, all modify the base mathematical model. The nature
of the recognition sites is straightforward; they can either
be identical or different. Regarding cooperativity in the system, there are three possibilities: (i) the two binding pockets
are independent of one another and there is no cooperativity; (ii) the net free energy change of binding for the
overall process is more negative than the sum of the individual free energy changes arising from binding each single
guest: in other words the system displays positive cooperativity; (iii) the system is negatively cooperative system,
that is, the net free energy change for the overall process
is less negative than the sum of the free energy changes
of the individual binding events. Finally, binding can occur
randomly or sequentially. The simplest combination of all
these variations is where the two binding sites are identical and independent of each other, in which case the exact
solution base model simplifies to a quadratic equation. If
the binding sites are different, and/or there is cooperativity
involved, and/or there is an order to complexation, then the
base mathematical models are generally cubic equations. As
with 1 : 1 complexations, the next step after a base model
has been chosen is to modify it in order for the model to fit
the chosen analytical technique. Software that models the
different systems arising from combinations of these factors is available in modern ITC instruments, and a number
of researchers have provided their own in-house software
for those techniques such as NMR that are not specifically
designed for binding constant determinations.46, 47
As alluded to above, an alternative to closed solutions of
higher polynomials is to use an open, or iterative, approach.
This more general strategy to parsing out the thermodynamic data for each microscopic binding event within
higher order systems requires that each equilibrium constant expression and corresponding mass balance equation
be identified. From this, the concentration of each species at
set Ka values can be formulated by iteration, and this process layered on top of the normal iteration process that
fits the species distribution to the experimentally obtained
data.48 The advantage of an open solution approach is that
it can be readily expanded for higher stoichiometric systems that are too difficult, if not impossible, to analyze
via closed-form solutions. It is worth noting that many
researchers make available in-house software for these calculations.4951 A significant disadvantage of this approach,
however, is that this dual iterative approach requires an
initial estimate of the association constants at each microscopic step; and the more complicated the system is, the
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20
Concepts
more the accuracy required for these estimations. The reason for this increased accuracy requirement is that different
initial Ka estimates can lead to different final Ka values. It
is therefore prudent to begin with a good estimate of the
Ka values and make sure that the final Ka values represent
a global minimum by changing the starting point to see
if this affects the outcome. It is also prudent to use chemical intuition when considering the final data. For example,
the garnering of four association constants from a binding isotherm possessing only one inflection point should be
treated with considerable suspicion. Likewise, if the magnitude of the obtained data seems overtly high or low relative
to published data, the practitioner should be cautious.
Of the numerous practical issues that can arise in
studying higher order systems, perhaps the most important
is the strength of cooperativity. The degree or strength of
cooperativity can be determined using the Hill equation.12
For practical purposes, however, we simply need to be
mindful of cases where binding is strongly cooperative
because this will affect our ability to observe selected
intermediates. For example, if it is strongly positively
cooperative (Ka2 Ka1 ), then the addition of host to guest
may not allow the observation of the intermediate HG
because the excess guest present will promote the full
conversion of HG to HG2 . In cases where exchange is
slow on the NMR timescale, this would mean that no
peaks corresponding to HG would be apparent; whereas
if exchange is fast on the NMR timescale (or we are
using UVvis or ITC), no inflection point corresponding
to this complex would be apparent in the binding isotherm.
If this is the case, then only the overall (macroscopic)
thermodynamic data can be obtained. One possible way to
obtain the microscopic data is to perform a reverse titration
of guest into host, but only if the positive cooperativity is
not too strong. Similarly, if strong negative cooperativity is
observed, it may not be possible to observe the formation
of HG2 even if the host is titrated into excess guest. These
influences of cooperativity mean that it is often instructive
to perform both a forward and a reverse titration when
studying higher order systems.49
CONCLUSION
also allowed researchers to identify previously underappreciated noncovalent forces, and how they can play a role in
the properties of molecules. As a result, en masse, these
studies have been responsible for defining and uniting the
field of supramolecular chemistry. As the field moves forward and begins to address new challenges of a second
phase, it is likely that binding constant determinations will
continue to play a significant role. That role may change,
but the need to quantify thermodynamic parameters of association is of such importance in both synthetic and biological contexts that a good grounding will always be essential.
With that in mind, we hope that readers have found this
introduction to the topic useful.
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Supramolecular Chemistry: From Molecules to Nanomaterials, Online 2012 John Wiley & Sons, Ltd.
This article is 2012 John Wiley & Sons, Ltd.
This article was published in the Supramolecular Chemistry: From Molecules to Nanomaterials in 2012 by John Wiley & Sons, Ltd.
DOI: 10.1002/9780470661345.smc005