Capítulo 2

Chapter 2
Thermodynamics of Separation Operations
§2.0 INSTRUCTIONAL OBJECTIVES

After completing this chapter, you should be able to:
Make energy, entropy, and availability balances around a separation process.
Explain phase equilibria in terms of Gibbs free energy, chemical potential, fugacity, fugacity coefficient, activity,
and activity coefficient.
Understand the usefulness of equilibrium ratios (K-values and partition coefficients) for liquid and vapor phases.
Derive K-value expressions in terms of fugacity coefficients and activity coefficients.
Explain how computer programs use equations of state (e.g., Soave–Redlich–Kwong or Peng–Robinson) to com-
pute thermodynamic properties of vapor and liquid mixtures, including K-values.
Explain how computer programs use liquid-phase activity-coefficient correlations (e.g., Wilson, NRTL,
UNIQUAC, or UNIFAC) to compute thermodynamic properties, including K-values.
For a given weak acid or base (including amino acids), calculate pH, pKa, degree of ionization, pI, and net charge.
Identify a buffer suited to maintain activity of a biological species at a target pH and evaluate effects of tempera-
ture, ionic strength, solvent and static charge on pH, and effects of pH on solubility.
Determine effects of electrolyte composition on electrostatic double-layer dimensions, energies of attraction, criti-
cal flocculation concentration, and structural stability of biocolloids.
Characterize forces that govern ligand–receptor–binding interactions and evaluate dissociation constants from free
energy changes or from batch solution or continuous sorption data.
Thermodynamic properties play a major role in separation liquid–liquid, and solid–liquid equilibrium—is the computer-
operations with respect to energy requirements, phase equili- ized Dortmund Data Bank (DDB) (www.ddbst.com), initi-
bria, biological activity, and equipment sizing. This chapter ated by Gmehling and Onken in 1973. It is updated annually
develops equations for energy balances, for entropy and and is widely used by industry and academic institutions. In
availability balances, and for determining densities and com- 2009, the DDB contained more than 3.9 million data points
positions for phases at equilibrium. The equations contain for 32,000 components from more than 64,000 references.
thermodynamic properties, including specific volume, Besides openly available data from journals, DDB contains a
enthalpy, entropy, availability, fugacities, and activities, all large percentage of data from non-English sources, chemical
as functions of temperature, pressure, and composition. Both industry, and MS and PhD theses.
ideal and nonideal mixtures are discussed. Equations to de-
termine ionization state, solubility, and interaction forces of §2.1 ENERGY, ENTROPY, AND
biomolecular species are introduced. However, this chapter is AVAILABILITY BALANCES
not a substitute for any of the excellent textbooks on
thermodynamics. Industrial separation operations utilize large quantities of
Experimental thermodynamic property data should be energy in the form of heat and/or shaft work. Distillation sep-
arations account for about 3% of the total U.S. energy con-
used, when available, to design and analyze the operation of
sumption (Mix et al. [1]). The distillation of crude oil into its
separation equipment. When not available, properties can of-
fractions is very energy-intensive, requiring about 40% of the
ten be estimated with reasonable accuracy. Many of these total energy used in crude-oil refining. Thus, it is important to
estimation methods are discussed in this chapter. The most know the energy consumption in a separation process, and to
comprehensive source of thermodynamic properties for pure what degree energy requirements can be reduced.
compounds and nonelectrolyte and electrolyte mixtures— Consider the continuous, steady-state, flow system for the
including excess volume, excess enthalpy, activity coeffi- separation process in Figure 2.1. One or more feed streams
cients at infinite dilution, azeotropes, and vapor–liquid, flowing into the system are separated into two or more
35
C02 09/29/2010 Page 36
36 Chapter 2 Thermodynamics of Separation Operations
Heat transfer in and out Table 2.1 Universal Thermodynamic Laws for a Continuous,
Qin, Ts Qout, Ts Steady-State, Flow System
⋅⋅⋅ ⋅⋅⋅ Energy balance:

⋅ X X
⋅ ð1Þ ðnh þ Q þ W s Þ ðnh þ Q þ W s Þ ¼ 0
Streams in ⋅
n, zi, T, P, h, s, b, υ ⋅
⋅ out of in to
Separation ⋅ system system
process ⋅
⋅ (system)
⋅ Entropy balance:
⋅
⋅ Streams out X Q
X Q

⋅ ΔSirr, LW n, zi, T, P, h, s, b, υ
ð 2Þ ns þ ns þ ¼ DSirr
⋅
⋅ out of
Ts in to
Ts
system system
⋅⋅⋅ ⋅⋅⋅
(surroundings) Availability balance:
X
To
(Ws)in (Ws)out T0
ð 3Þ nb þ Q 1 þ Ws
Shaft work in and out
in to
Ts
X
Figure 2.1 General separation system. system
T0
nb þ Q 1 þ W s ¼ LW
product streams. For each stream molar flow rates are denoted
out of
Ts
by n, the component mole fractions by zi, the temperature by system
T, the pressure by P, the molar enthalpies and entropies by h
Minimum work of separation:
and s, respectively, and the molar availabilities by b. If chem- X X
ical reactions occur in the process, enthalpies and entropies ð4Þ W min ¼ nb nb
are referred to the elements, as discussed by Felder and Rous- out of in to
seau [2]; otherwise they can be referred to the compounds. system system
Flows of heat in or out are denoted by Q, and shaft work Second-law efficiency:
crossing the boundary of the system by Ws. At steady state, if W min
kinetic, potential, and surface energy changes are neglected, ð 5Þ h ¼
LW þ W min
the first law of thermodynamics states that the sum of energy
where b ¼ h T0s ¼ availability function
flows into the system equals the sum of the energy flows LW ¼ T0 DSirr ¼ lost work
leaving the system.
In terms of symbols, the energy balance is given by
Eq. (1) in Table 2.1, where all flow-rate, heat-transfer, and be the average temperature of cooling water, air, or a nearby
shaft-work terms are positive. Molar enthalpies may be river, lake, or ocean. Heat transfer associated with this cool-
positive or negative, depending on the reference state. ant and transferred from (or to) the process is Q0. Thus, in
The first law of thermodynamics provides no information both (1) and (2) in Table 2.1, the Q and Q=Ts terms include
on energy efficiency, but the second law of thermodynamics, contributions from Q0 and Q0=T0.
given by Eq. (2) in Table 2.1, does. The derivation of (3) in Table 2.1 is made, as shown by
In the entropy balance, the heat sources and sinks in de Nevers and Seader [3], by combining (1) and (2) to elimi-
Figure 2.1 are at absolute temperatures, Ts. For example, if nate Q0. It is referred to as an availability (or exergy)
condensing steam at 150 C supplies heat, Q, to the reboiler balance, where availability means ‘‘available for complete
of a distillation column, Ts ¼ 150 þ 273 = 423 K. Unlike the conversion to shaft work.’’ The availability function, b, a
energy balance, which states that energy is conserved, the thermodynamic property like h and s, is defined by
entropy balance predicts the production of entropy, DSirr, b ¼ h T 0s ð2-1Þ
which is the irreversible increase in the entropy of the uni- and is a measure of the maximum amount of energy con-
verse. This term, which must be positive, is a measure of the verted into shaft work if the stream is taken to the reference
thermodynamic inefficiency. In the limit, as a reversible pro- state. It is similar to Gibbs free energy, g ¼ h Ts, but differs
cess is approached, DSirr tends to zero. Unfortunately, DSirr is in that the temperature, T0, appears in the definition instead
difficult to apply because it does not have the units of energy/ of T. Terms in (3) in Table 2.1 containing Q are multiplied by
unit time (power). (1 T0=Ts), which, as shown in Figure 2.2, is the reversible
A more useful measure of process inefficiency is lost Carnot heat-engine cycle efficiency, representing the maxi-
work, LW. It is derived by combining Eqs. (1) and (2) to ob- mum amount of shaft work producible from Q at Ts, where
tain a combined statement of the first and second laws, which the residual amount of energy (Q Ws) is transferred as heat
is given as Eq. (3) in Table 2.1. To perform this derivation, it to a sink at T0. Shaft work, Ws, remains at its full value in (3).
is first necessary to define an infinite source or sink available Thus, although Q and Ws have the same thermodynamic
for heat transfer at the absolute temperature, Ts ¼ T0, of the worth in (1) of Table 2.1, heat transfer has less worth in (3).
surroundings. This temperature, typically 300 K, represents Shaft work can be converted completely to heat, but heat can-
the largest source of coolant (heat sink) available. This might not be converted completely to shaft work.
C02 09/29/2010 Page 37
§2.1 Energy, Entropy, and Availability Balances 37
First law: T = Ts work of separation. The second-law efficiency, therefore, is

Q = Qin
Qin = Ws + Qout defined by (5) in Table 2.1.
Second law:
Qin Qout EXAMPLE 2.1 Use of Thermodynamic Laws.

= Reversible
Ts T0
heat For the propylene–propane separation of Figure 1.16, using the fol-
engine Ws
lowing thermodynamic properties and the relations given in Table
Combined first and (ΔSirr = 0) 2.1, compute in SI units: (a) the condenser duty, QC; (b) the reboiler
second laws (to duty, QR; (c) the irreversible entropy production, assuming 303 K
eliminate Qout):
for the condenser cooling-water sink and 378 K for the reboiler
Ws = [1 – (T0/Ts)] Qin steam source; (d) the lost work, assuming T0 ¼ 303 K; (e) the mini-
mum work of separation; and (f) the second-law efficiency.
T = T0
Q = Qout
Figure 2.2 Carnot heat-engine cycle for converting heat to shaft Phase Enthalpy (h), Entropy (s),
work. Stream Condition kJ/kmol kJ/kmol-K
Feed (F) Liquid 13,338 4.1683

Availability, like entropy, is not conserved in a real, Overhead vapor Vapor 24,400 24.2609
irreversible process. The total availability (i.e., ability to pro- (OV)
duce shaft work) into a system is always greater than the Distillate (D) and Liquid 12,243 13.8068
total availability leaving. Thus (3) in Table 2.1 is written reflux (R)
with the ‘‘in to system’’ terms first. The difference is the Bottoms (B) Liquid 14,687 2.3886
lost work, LW, also called the loss of availability (or exergy),
and is
LW ¼ T 0 DSirr ð2-2Þ Solution
Lost work is always positive. The greater its value, the Let QC and QR cross the boundary of the system. The following cal-
greater the energy inefficiency. In the lower limit, for a re- culations are made using the stream flow rates in Figure 1.16 and the
versible process, it is zero. The lost work has the units of properties above.
energy, thus making it easy to attach significance to its (a) From (1), Table 2.1, noting that the overhead-vapor molar
numerical value. flow rate is given by nOV ¼ nR þ nD and hR ¼ hD, the condenser
Lost work can be computed from Eq. (3) in Table 2.1. Its duty is
magnitude depends on process irreversibilities, which QC ¼ nOV ðhOV hR Þ
include fluid friction, heat transfer due to finite temperature- ¼ ð2;293 þ 159:2Þð24;400 12;243Þ
driving forces, mass transfer due to finite concentration- or ¼ 29;811;000 kJ/h
activity-driving forces, chemical reactions proceeding at
finite displacements from chemical equilibrium, mixing (b) An energy balance around the reboiler cannot be made because
streams of differing temperature, pressure, and/or composi- data are not given for the boilup rate. From (1), Table 2.1, an
tion, etc. To reduce lost work, driving forces for momentum, energy balance around the column is used instead:
heat, and mass transfer; and chemical reaction must be QR ¼ nD hD þ nB hB þ QC nF hF
reduced. Practical limits to reduction exist because, as driv- ¼ 159:2ð12;243Þ þ 113ð14;687Þ
ing forces decrease, equipment sizes increase, tending to þ 29;811;000 272:2ð13;338Þ
¼ 29;789;000 kJ/h
infinity as driving forces approach zero.
For a separation without chemical reaction, the summa- (c) Compute the production of entropy from an entropy balance
tion of the stream availability functions leaving the process is around the entire distillation system. From Eq. (2), Table 2.1,
usually greater than that for streams entering the process. In DSirr ¼ nD sD þ nB sB þ QC =T C nF sF QR =T R
the limit for a reversible process (LW ¼ 0), (3) of Table 2.1 ¼ 159:2ð13:8068Þ þ 113ð2:3886Þ
reduces to (4), where Wmin is the minimum shaft work for the þ 29;811;000=303 272:2ð4:1683Þ
separation and is equivalent to the difference in the heat- 29;789;000=378
transfer and shaft-work terms in (3). This minimum work is a ¼ 18;246 kJ/h-K
property independent of the nature (or path) of the separa-
(d) Compute lost work from its definition at the bottom of Table 2.1:
tion. The work of separation for an irreversible process is
greater than the minimum value from (4). LW ¼ T 0 DSirr
Equation (3) of Table 2.1 shows that as a process becomes ¼ 303ð18;246Þ ¼ 5;529;000 kJ/h
more irreversible, and thus more energy-inefficient, the Alternatively, compute lost work from an availability balance
increasing LW causes the required work of separation to around the system. From (3), Table 2.1, where the availability
increase. Thus, the equivalent work of separation for an function, b, is defined near the bottom of Table 2.1,
irreversible process is the sum of lost work and the minimum
C02 09/29/2010 Page 38
LW ¼ nF bF þ QR ð1 T 0 =T R Þ where superscript (p) refers to each of N phases. Conserva-

nD bD nB bB QC ð1 T 0 =T C Þ tion of moles of species, in the absence of chemical reaction,
¼ 272:2½13;338 ð303Þð4:1683Þ requires that
ð1Þ
XN
ðpÞ
þ 29;789;000ð1 303=378Þ dN i ¼ dN i ð2-5Þ
159:2½12;243 ð303Þð13:8068Þ p¼2
113½14;687 ð303Þð2:3886Þ
29;811;000ð1 303=303Þ
which, upon substitution into (2-4), gives
" #
¼ 5;529;000 kJ/h ðsame resultÞ XN XC
ðpÞ ð1Þ ðpÞ
mi mi dN i ¼0 ð2-6Þ
(e) Compute the minimum work of separation for the entire distilla- p¼2 i¼1
tion system. From (4), Table 2.1, ð1Þ ðpÞ
With dN i eliminated in (2-6), each dN i term can be varied
W min ¼ nD bD þ nB bB nF bF ðpÞ
independently of any other dN i term. But this requires that
¼ 159:2½12;243 ð303Þð13:8068Þ ðpÞ
each coefficient of dN i in (2-6) be zero. Therefore,
þ 113½14;687 ð303Þð2:3886Þ
ð1Þ ð2Þ ð3Þ ðNÞ
272:2½13;338 ð303Þð4:1683Þ mi ¼ mi ¼ mi ¼ ¼ mi ð2-7Þ
¼ 382;100 kJ=h
Thus, the chemical potential of a species in a multi-
(f) Compute the second-law efficiency for the entire distillation component system is identical in all phases at physical
system. From (5), Table 2.1, equilibrium.
W min
h¼
LW þ W min
§2.2.1 Fugacities and Activity Coefficients
382;100
¼
5; 529;000 þ 382;100 Chemical potential is not an absolute quantity, and the
¼ 0:0646 or 6:46% numerical values are difficult to relate to more easily under-
stood physical quantities. Furthermore, the chemical poten-
This low second-law efficiency is typical of a difficult distillation tial approaches an infinite negative value as pressure
separation, which in this case requires 150 theoretical stages with a approaches zero. Thus, the chemical potential is not favored
reflux ratio of almost 15 times the distillate rate. for phase-equilibria calculations. Instead, fugacity, invented
by G. N. Lewis in 1901, is employed as a surrogate.
The partial fugacity of species i in a mixture is like a
pseudo-pressure, defined in terms of the chemical potential
§2.2 PHASE EQUILIBRIA by

Many separations are determined by the extent to which the f i ¼ C exp mi ð2-8Þ
species are distributed among two or more phases at equili- RT
brium at a specified T and P. The distribution is determined where C is a temperature-dependent constant. Regardless of
by application of the Gibbs free energy. For each phase in a the value of C, it is shown by Prausnitz, Lichtenthaler, and
multiphase, multicomponent system, the total Gibbs free de Azevedo [4] that (2-7) can be replaced with
energy is
f ð1Þ ¼ f ð2Þ ¼ f ð3Þ ¼ ¼ f ðNÞ ð2-9Þ
G ¼ GðT; P; N 1 ; N 2 ; . . . ; N C Þ i i i i
where Ni ¼ moles of species i. At equilibrium, the total G for Thus, at equilibrium, a given species has the same partial
all phases is a minimum, and methods for determining this fugacity in each phase. This equality, together with equality
are referred to as free-energy minimization techniques. Gibbs of phase temperatures and pressures,
free energy is also the starting point for the derivation of T ð1Þ ¼ T ð2Þ ¼ T ð3Þ ¼ ¼ T ðNÞ ð2-10Þ
commonly used equations for phase equilibria. From classi-
cal thermodynamics, the total differential of G is and Pð1Þ ¼ Pð2Þ ¼ Pð3Þ ¼ ¼ PðNÞ ð2-11Þ
X
C constitutes the conditions for phase equilibria. For a pure
dG ¼ S dT þ V dP þ mi dN i ð2-3Þ component, the partial fugacity, f i , becomes the pure-
i¼1
component fugacity, fi. For a pure, ideal gas, fugacity
where mi is the chemical potential or partial molar Gibbs free equals the total pressure, and for a component in an
energy of species i. For a closed system consisting of two or ideal-gas mixture, the partial fugacity equals its partial
more phases in equilibrium, where each phase is an open sys- pressure, pi ¼ y iP. Because of the close relationship
tem capable of mass transfer with another phase, between fugacity and pressure, it is convenient to define
" # their ratio for a pure substance as
X N X
C
ðpÞ ðpÞ
dGsystem ¼ mi dN i ð2-4Þ fi
p¼1 i¼1
fi ¼ ð2-12Þ
P;T P
C02 09/29/2010 Page 39
§2.2 Phase Equilibria 39
Table 2.2 Thermodynamic Quantities for Phase Equilibria
Limiting Value for Ideal Gas and

Thermodynamic Quantity Definition Physical Significance Ideal Solution

qG Partial molar free energy,
gi mi ¼
gi
Chemical potential mi
qN i P;T;N j

Partial fugacity fi C exp mi Thermodynamic pressure fiV ¼ yi P
RT fiL ¼ xi Ps
i
fi
Fugacity coefficient of a pure species fi Deviation to fugacity due to pressure fiV ¼ 1:0
P
Ps
fiL ¼ i
P

Partial fugacity coefficient of a iV fiV
f Deviations to fugacity due to pressure iV ¼ 1:0
f
species in a mixture yi P and composition s
iL ¼ Pi
f
iL f iL
f P
xi P
fi
Activity ai Relative thermodynamic pressure aiV ¼ yi
fi o
aiL ¼ xi
aiV
Activity coefficient giV Deviation to fugacity due to giV ¼ 1:0
yi
aiL composition giL ¼ 1:0
giL
xi
where fi is the pure-species fugacity coefficient, which is 1.0 For convenient reference, thermodynamic quantities use-
for an ideal gas. For a mixture, partial fugacity coefficients are ful in phase equilibria are summarized in Table 2.2.

iV f iV
f ð2-13Þ
yi P §2.2.2 K-Values
A phase-equilibrium ratio is the ratio of mole fractions
iL f iL
f ð2-14Þ
xi P of a species in two phases at equilibrium. For vapor–liquid
systems, the constant is referred to as the K-value or vapor–
such that as ideal-gas behavior is approached, f iV ! 1:0 and
liquid equilibrium ratio:
iL ! Ps =P, where Ps ¼ vapor pressure.
f i i
At a given temperature, the ratio of the partial fugacity of yi
a component to its fugacity in a standard state is termed the Ki ð2-19Þ
xi
activity. If the standard state is selected as the pure species at
the same pressure and phase as the mixture, then
For the liquid–liquid case, the ratio is a distribution or parti-
f tion coefficient, or liquid–liquid equilibrium ratio:
ai oi ð2-15Þ
fi
ð1Þ
Since at phase equilibrium, the value of f oi is the same for xi
K Di ð2Þ
ð2-20Þ
each phase, substitution of (2-15) into (2-9) gives another xi
alternative condition for phase equilibria,
ð1Þ ð2Þ ð3Þ ðNÞ For equilibrium-stage calculations, separation factors, like
ai ¼ ai ¼ ai ¼ ¼ ai ð2-16Þ (1-4), are defined by forming ratios of equilibrium ratios. For
For an ideal solution, aiV ¼ yi and aiL ¼ xi. the vapor–liquid case, relative volatility ai,j between compo-
To represent departure of activities from mole fractions nents i and j is given by
when solutions are nonideal, activity coefficients based on
concentrations in mole fractions are defined by Ki
aij ð2-21Þ
aiV Kj
giV ð2-17Þ
yi
Separations are easy for very large values of ai,j, but
aiL
giL ð2-18Þ become impractical for values close to 1.00.
xi Similarly for the liquid–liquid case, the relative selectivity
For ideal solutions, giV ¼ 1:0 and giL ¼ 1:0. bi,j is
C02 09/29/2010 Page 40
If (2-23) and (2-25) are used, a so-called activity co-

K Di efficient form of the K-value is obtained:
bij ð2-22Þ
K Dj
g fo g fiL
K i ¼ iL iL ¼ iL
iV ð2-27Þ
Equilibrium ratios can contain the quantities in Table 2.2 fiV P f
in a variety of formulations. The ones of practical interest are
formulated next. Since 1960, (2-27) has received some attention, with applica-
For vapor–liquid equilibrium, (2-9) becomes, for each tions to industrial systems presented by Chao and Seader
component, (C–S) [9], with a modification by Grayson and Streed [10].
fiV ¼ fiL Table 2.3 is a summary of formulations for vapor–liquid
equilibrium K-values. Included are the two rigorous expres-
To form an equilibrium ratio, partial fugacities are commonly sions (2-26) and (2-27) from which the other approximate
replaced by expressions involving mole fractions. From the formulations are derived. The Raoult’s law or ideal K-value
definitions in Table 2.2: is obtained from (2-27) by substituting, from Table 2.2, for
fiL ¼ giL xi f o an ideal gas and for ideal gas and liquid solutions, giL ¼
ð2-23Þ iV ¼ 1:0. The modified Raoult’s law
iL 1:0; fiL ¼ Psi =P and f
iL xi P
fiL ¼ f relaxes the assumption of an ideal liquid by including the liq-
or ð2-24Þ
uid-phase activity coefficient. The Poynting-correction form
iV yi P
fiV ¼ f for moderate pressures is obtained by approximating the
and ð2-25Þ
pure-component liquid fugacity coefficient in (2-27) by
Z P !
If (2-24) and (2-25) are used with (2-19), a so-called equa- s Pi
s
1
tion-of-state form of the K-value follows: fiL ¼ fiV exp yiL dP ð2-28Þ
P RT Psi

f where the exponential term is the Poynting correction. If the
K i ¼ iL ð2-26Þ liquid molar volume is reasonably constant over the pressure
fiV
range, the integral in (2-28) becomes yiL P Psi .
For a light gas species, whose critical temperature is less
Applications of (2-26) include the Starling modification of than the system temperature, the Henry’s law form for the
the Benedict, Webb, and Rubin (B–W–R–S) equation of state K-value is convenient, provided Hi, the Henry’s law co-
[5], the Soave modification of the Redlich–Kwong (S–R–K efficient, is available. This constant depends on composition,
or R–K–S) equation of state [6], the Peng–Robinson (P–R) temperature, and pressure. Included in Table 2.3 are recom-
equation of state [7], and the Pl€
ocker et al. modification of mendations for the application of each of the vapor–liquid K-
the Lee–Kesler (L–K–P) equation of state [8]. value expressions.
Table 2.3 Useful Expressions for Estimating K-Values for Vapor–Liquid Equilibria (Ki ¼ yi=xi)
Equation Recommended Application
Rigorous forms:

f
(1) Equation-of-state K i ¼ iL Hydrocarbon and light gas mixtures from cryogenic temperatures to
fiV the critical region
g fiL
(2) Activity coefficient K i ¼ iL
iV All mixtures from ambient to near-critical temperature
f
Approximate forms:
Psi
(3) Raoult’s law (ideal) Ki ¼ Ideal solutions at near-ambient pressure
P
giL Psi
(4) Modified Raoult’s law Ki ¼ Nonideal liquid solutions at near-ambient pressure
P
s Z P !
P 1
(5) Poynting correction K i ¼ giL fsiV i exp yiL dP Nonideal liquid solutions at moderate pressure and below the
P RT psi
critical temperature
Hi
(6) Henry’s law Ki ¼ Low-to-moderate pressures for species at supercritical temperature
P
C02 09/29/2010 Page 41
§2.3 Ideal-Gas, Ideal-Liquid-Solution Model 41
Regardless of which thermodynamic formulation is used Engineers’ Handbook, 6th ed., pp. 3-237 and 3-103, the vapor
for estimating K-values, their accuracy depends on the corre- pressure data for water and Henry’s law coefficients for CH4 are:
lations used for the thermodynamic properties (vapor pres-
sure, activity coefficient, and fugacity coefficients). For T, C Ps for H2O, atm H for CH4, atm
practical applications, the choice of K-value formulation is a
20 0.02307 3.76 104
compromise among accuracy, complexity, convenience, and 80 0.4673 6.82 104
past experience.
For liquid–liquid equilibria, (2-9) becomes
K-values for water and methane are estimated from (3) and (6),
f ð1Þ ¼ f ð2Þ ð2-29Þ respectively, in Table 2.3, using P = 2 atm, with the following
iL iL
results:
where superscripts (1) and (2) refer to the immiscible liquids.
A rigorous formulation for the distribution coefficient is T, C K H2 O K CH4 aM,W
obtained by combining (2-23) with (2-20) to obtain an 20 0.01154 18,800 1,629,000
expression involving only activity coefficients: 80 0.2337 34,100 146,000
ð1Þ ð2Þ oð2Þ ð2Þ

xi giL f iL giL These K-values confirm the assumptions of the phase distribution of
K Di ¼ ð2Þ
¼ ð1Þ oð1Þ
¼ ð1Þ
ð2-30Þ
xi giL f iL giL the two species. The K-values for H2O are low, but increase with
temperature. The K-values for methane are extremely high and do
For vapor–solid equilibria, if the solid phase consists of just not change rapidly with temperature.
one of the components of the vapor phase, combination of
(2-9) and (2-25) gives
iV yi P
fiS ¼ f ð2-31Þ §2.3 IDEAL-GAS, IDEAL-LIQUID-SOLUTION
MODEL
At low pressure, f iV ¼ 1:0 and the fugacity of the solid is
approximated by its vapor pressure. Thus for the vapor-phase Classical thermodynamics provides a means for obtaining
mole fraction of the component forming the solid phase: fluid properties in a consistent manner from P–y–T relation-
ships, which are equation-of-state models. The simplest
s
P model applies when both liquid and vapor phases are ideal
yi ¼ i solid ð2-32Þ solutions (all activity coefficients equal 1.0) and the vapor is
P
an ideal gas. Then the thermodynamic properties can be com-
For liquid–solid equilibria, if the solid phase is a pure puted from unary constants for each species using the equa-
component, the combination of (2-9) and (2-23) gives tions given in Table 2.4. These ideal equations apply only at
pressures up to about 50 psia (345 kPa), for components of
f iS ¼ giL xi f oiL ð2-33Þ similar molecular structure.
For the vapor, the molar volume, y, and mass density, r,
At low pressure, fugacity of a solid is approximated by vapor are computed from (1), the ideal-gas law in Table 2.4, which
pressure to give, for a component in the solid phase, requires the mixture molecular weight, M, and the gas con-
s stant, R. It assumes that Dalton’s law of additive partial pres-
P
xi ¼ i s solid ð2-34Þ sures and Amagat’s law of additive volumes apply.
giL Pi liquid The vapor enthalpy, hV, is computed from (2) by integrat-
ing an equation in temperature for the zero-pressure heat
capacity at constant pressure, CoPV , starting from a reference
(datum) temperature, T0, to the temperature of interest, and
EXAMPLE 2.2 K-Values from Raoult’s and Henry’s then summing the resulting species vapor enthalpies on a
Laws. mole-fraction basis. Typically, T0 is taken as 0 K or 25 C.
Pressure has no effect on the enthalpy of an ideal gas. A com-
Estimate the K-values and a of a vapor–liquid mixture of water (W)
mon empirical representation of the effect of temperature on
and methane (M) at P ¼ 2 atm, T ¼ 20 and 80 C. What is the effect
the zero-pressure vapor heat capacity of a component is the
of T on the component distribution?
fourth-degree polynomial:
Solution
C oPV ¼ a0 þ a1 T þ a2 T 2 þ a3 T 3 þ a4 T 4 R ð2-35Þ
At these conditions, water exists mainly in the liquid phase and will
follow Raoult’s law, as given in Table 2.3. Because methane has a where the constants depend on the species. Values of the con-
critical temperature of 82.5 C, well below the temperatures of
stants for hundreds of compounds, with T in K, are tabulated
interest, it will exist mainly in the vapor phase and follow Henry’s
law, in the form given in Table 2.3. From Perry’s Chemical
by Poling, Prausnitz, and O’Connell [11]. Because CP = dh/
dT, (2-35) can be integrated for each species to give the
C02 09/29/2010 Page 42
Table 2.4 Thermodynamic Properties for Ideal Mixtures The liquid molar volume and mass density are computed
from the pure species using (4) in Table 2.4 and assuming
Ideal gas and ideal-gas solution:
additive volumes (not densities). The effect of temperature
V M RT X
C on pure-component liquid density from the freezing point to
ð1Þ yV ¼ ¼ ¼ ; M¼ yi M i the critical region at saturation pressure is correlated well by
P
C rV P i¼1
Ni the two-constant equation of Rackett [12]:
i¼1
2=7
Z rL ¼ ABð1T=T c Þ ð2-38Þ
X
C T X
C
ð2Þ hV ¼ yi CoP iV
dT ¼ yi hoiv where values of the empirical constants A and B, and the crit-
i¼1 T0 i¼1 ical temperature, Tc, are tabulated for approximately 700
Z organic compounds by Yaws et al. [13].
X
C T C oP P X
C
ð 3Þ s V ¼ yi iV
dT R ln R yi ln yi The vapor pressure of a liquid species is well represented
i¼1 T0 T P0 i¼1 over temperatures from below the normal boiling point to the
critical region by an extended Antoine equation:
where the first term is soV
ln Ps ¼ k1 þ k2 =ðk3 þ T Þ þ k4 T þ k5 ln T þ k6 T k7 ð2-39Þ
Ideal-liquid solution:
where the constants kk depend on the species. Values of
V M X C X
C
these constants for hundreds of compounds are built into the
ð 4 Þ yL ¼ C ¼ ¼ xi yiL ; M¼ xi M i
P rL i¼1 i¼1
physical-property libraries of all process simulation pro-
Ni
i¼1
grams. Constants for other vapor-pressure equations are
tabulated by Poling et al. [11]. At low pressures, the
X
C enthalpy of vaporization is given in terms of vapor pressure
ð5Þ hL ¼ xi hoiV DH vap
i by classical thermodynamics:
i¼1 s

2 d ln P
Z DH ¼ RT
vap
ð2-40Þ
X
C T dT
ðCoP ÞiV DH vap
i
ð6Þ sL ¼ xi dT
i¼1 T0 T T If (2-39) is used for the vapor pressure, (2-40) becomes
X C " #
P k k
R ln R xi ln xi DH vap ¼ RT 2
2
þ k4 þ þ k7 k6 T k7 1 ð2-41Þ
5
P0 i¼1 ðk3 þ T Þ2 T
Vapor–liquid equilibria: The enthalpy of an ideal-liquid mixture is obtained by

Psi subtracting the enthalpy of vaporization from the ideal vapor
ð 7Þ K i ¼ enthalpy for each species, as given by (2-36), and summing,
P
as shown by (5) in Table 2.4. The entropy of the ideal-liquid
Reference conditions (datum): h, ideal gas at T0 and zero pressure; s, ideal mixture, given by (6), is obtained in a similar manner from
gas at T0 and 1 atm pressure.
the ideal-gas entropy by subtracting the molar entropy of
Refer to elements if chemical reactions occur; otherwise refer to
components. vaporization, given by DHvap=T.
The final equation in Table 2.4 gives the expression for the
ideal-gas species molar enthalpy: ideal K-value, previously included in Table 2.3. It is the K-
Z T
X 5
ak1 T k T k0 R value based on Raoult’s law, given as
o o
hV ¼ C PV dT ¼ ð2-36Þ
T0 k¼1
k pi ¼ xi Psi ð2-42Þ
The vapor entropy is computed from (3) in Table 2.4 by where the assumption of Dalton’s law is also required:
integrating C oPV =T from T0 to T for each species; summing
on a mole-fraction basis; adding a term for the effect of pres- pi ¼ y i P ð2-43Þ
sure referenced to a datum pressure, P0, which is generally Combination of (2-42) and (2-43) gives the Raoult’s law K-
taken to be 1 atm (101.3 kPa); and adding a term for the value:
entropy change of mixing. Unlike the ideal vapor enthalpy,
the ideal vapor entropy includes terms for the effects of pres- yi Psi
sure and mixing. The reference pressure is not zero, because Ki ¼ ð2-44Þ
xi P
the entropy is infinity at zero pressure. If (2-35) is used for
the heat capacity,
" # The extended Antoine equation, (2-39), can be used to
Z T o X
C PV T 4
ak T k T k0 estimate vapor pressure. The ideal K-value is independent of
dT ¼ a0 ln þ R ð2-37Þ
T0 T T0 k¼1
k compositions, but exponentially dependent on temperature
because of the vapor pressure, and inversely proportional to
C02 09/29/2010 Page 43
§2.3 Ideal-Gas, Ideal-Liquid-Solution Model 43
pressure. From (2-21), the relative volatility using (2-44) is From (1), Table 2.4,
pressure independent. MV ¼ ð0:5559Þð106:168Þ þ ð0:4441Þð104:152Þ ¼ 105:27
ML ¼ ð0:4848Þð106:168Þ þ ð0:5152Þð104:152Þ ¼ 105:13
Vapor molar volume and density: From (1), Table 2.4,
EXAMPLE 2.3 Thermodynamic Properties of an Ideal-
Gas Mixture. RT ð8:314Þð350:65Þ
yV ¼ ¼ ¼ 219:2 m3 /kmol
P ð13:332Þ
Styrene is manufactured by catalytic dehydrogenation of ethylben-
M V 105:27
zene, followed by vacuum distillation to separate styrene from rV ¼ ¼ ¼ 0:4802 kg/m3
yV 219:2
unreacted ethylbenzene [14]. Typical conditions for the feed are
77.5 C (350.6 K) and 100 torr (13.33 kPa), with the following vapor Vapor molar enthalpy (datum = ideal gas at 298.15 K and
and liquid flows at equilibrium: 0 kPa):
From (2-36) for ethylbenzene,
n, kmol/h hoEBV ¼ 43098:9ð350:65 298:15Þ

Component Vapor Liquid 707:151
þ 350:652 298:152
2
Ethylbenzene (EB) 76.51 27.31
0:481063
Styrene (S) 61.12 29.03 350:653 298:153
3

1:30084 104
Based on the property constants given, and assuming that the ideal- þ 350:654 298:154
gas, ideal-liquid-solution model of Table 2.4 is suitable at this low 4
pressure, estimate values of yV, rV, hV, sV, yL, rL, hL, and sL in SI ¼ 7;351;900 J=kmol
units, and the K-values and relative volatility, a.
Similarly, hoSV ¼ 6;957;700 J=kmol
Property Constants for (2-35), (2-38), (2-39) (In all cases, T is in K) From (2), Table 2.4, for the mixture,
P o
Ethylbenzene Styrene hV ¼ yi hiV ¼ ð0:5559Þð7;351;900Þ
þð0:4441Þð6;957;100Þ ¼ 7;176;800 J=kmol
M, kg/kmol 106.168 104.152
C oPV , J/kmol-K: Vapor molar entropy (datum = pure components as vapor at
a0R 43,098.9 28,248.3 298.15 K, 101.3 kPa):
a1R 707.151 615.878 From (2-37), for each component,
a2R 0.481063 0.40231 Z T o
C PV
a3R 1.30084 104 9.93528 105 dT ¼ 22;662 J/kmol-K for ethylbenzene
T0 T
a4R 0 0 and 21;450 J/kmol-K for styrene
Ps, Pa:
k1 86.5008 130.542 From (3), Table 2.4, for the mixture,
k2 7,440.61 9,141.07
sV ¼ ½ð0:5559Þð22;662:4Þ þ ð0:4441Þð21;450:3Þ
k3 0 0
k4 0.00623121 0.0143369 13:332
8;314 ln 8;314½ð0:5559Þ ln ð0:5559Þ
k5 9.87052 17.0918 101:3
k6 4.13065 1018 1.8375 1018
k7 6 6 þ ð0:4441Þ ln ð0:4441Þ ¼ 44;695 J/kmol-K
rL, kg/m3: Note that the pressure effect and the mixing effect are significant.
A 289.8 299.2 Liquid molar volume and density:
B 0.268 0.264 From (2-38), for ethylbenzene,
Tc, K 617.9 617.1 2=7
R ¼ 8.314 kJ/kmol-K or kPa-m3/kmol-K ¼ 8,314 J/kmol-K rEBL ¼ ð289:8Þð0:268Þð1350:65=617:9Þ ¼ 816:9 kg/m3
M EB
yEBL ¼ ¼ 0:1300 m3 /kmol
rEBL
Solution
Similarly, rSL ¼ 853:0 kg/m3
Phase mole-fraction compositions and average molecular
weights: ySL ¼ 0:1221 m3 /kmol
From yi ¼ ðniV Þ=nV ;xi ¼ ðniL Þ=nL ; From (4), Table 2.4, for the mixture,
yL ¼ ð0:4848Þð0:1300Þ þ ð0:5152Þð0:1221Þ ¼ 0:1259 m3 /kmol

Ethylbenzene Styrene
M L 105:13
rL ¼ ¼ ¼ 835:0 kg/m3
y 0.5559 0.4441 yL 0:1259
x 0.4848 0.5152
C02 09/29/2010 Page 44
§2.4 GRAPHICAL CORRELATIONS OF

Liquid molar enthalpy (datum = ideal gas at 298.15 K): THERMODYNAMIC PROPERTIES
Use (5) in Table 2.4 for the mixture. For the enthalpy of vapor-
Plots of thermodynamic properties are useful not only for the
ization of ethylbenzene, from (2-41),
data they contain, but also for the pictoral representation,
"
ð7;440:61Þ
which permits the user to make general observations, estab-
DH vap
EB ¼ 8;314ð350:65Þ 2
þ 0:00623121 lish correlations, and make extrapolations. All process simu-
ð0 þ 350:65Þ2
lators that contain modules that calculate thermodynamic
#
ð9:87052Þ properties also contain programs that allow the user to make
þ þ 6 4:13065 1018 ð350:65Þ5 plots of the computed variables. Handbooks and all thermo-
ð350:65Þ
dynamic textbooks contain generalized plots of thermo-
¼ 39;589;800 J/kmol dynamic properties as a function of temperature and
DH vap pressure. A typical plot is Figure 2.3, which shows vapor
Similarly, S ¼ 40;886;700 J/kmol
pressures of common chemicals for temperatures from below
Then, applying (5), Table 2.4, using hoEBV and hoSV from above, the normal boiling point to the critical temperature where the
vapor pressure curves terminate. These curves fit the
hL ¼ ½ð0:4848Þð7;351;900 39;589;800Þ þ ð0:5152Þð6;957;700 extended Antoine equation (2-39) reasonably well and are
40;886;700Þ ¼ 33;109;000 J/kmol useful in establishing the phase of a pure species and for esti-
mating Raoult’s law K-values.
Liquid molar entropy (datum = pure components as vapor at
Nomographs for determining effects of temperature and
298.15 K and 101.3 kPa):
pressure on K-values of hydrocarbons and light gases are pre-
From (6), Table 2.4 for the mixture, using values for
RT o sented in Figures 2.4 and 2.5, which are taken from Hadden
T0 C PV =T dT and DHvap of EB and S from above, and Grayson [15]. In both charts, all K-values collapse to 1.0
at a pressure of 5,000 psia (34.5 MPa). This convergence
39;589;800
sL ¼ ð0:4848Þ 22;662 pressure depends on the boiling range of the components in
350:65
the mixture. In Figure 2.6 the components (N2 to nC10) cover
40;886;700 a wide boiling-point range, resulting in a convergence pres-
þ ð0:5152Þ 21;450
350:65 sure of close to 2,500 psia. For narrow-boiling mixtures such

13:332 as ethane and propane, the convergence pressure is generally
8;314 ln
101:3 less than 1,000 psia. The K-value charts of Figures 2.4 and
2.5 apply to a convergence pressure of 5,000 psia. A proce-
8;314½0:4848 ln ð0:4848Þ þ 0:5152 ln ð0:5152Þ
dure for correcting for the convergence pressure is given by
¼ 70;150 J/kmol-K Hadden and Grayson [15]. Use of the nomographs is illus-
trated in Exercise 2.4.
K-values: Because (7), Table 2.4, will be used to compute the
K-values, first estimate the vapor pressures using (2-39). For ethyl- No simple charts are available for estimating liquid–liquid
benzene, distribution coefficients because of the pronounced effect of
composition. However, for ternary systems that are dilute in
s 7;440:61
ln PEB ¼ 86:5008 þ the solute and contain almost immiscible solvents, a tabula-
0 þ 350:65
tion of distribution (partition) coefficients for the solute is
þ 0:00623121ð350:65Þ þ ð9:87052Þ ln ð350:65Þ given by Robbins [16].
þ 4:13065 1018 ð350:65Þ6
¼ 9:63481 EXAMPLE 2.4 K-Values from a Nomograph.
PsEB ¼ expð9:63481Þ ¼ 15;288 Pa ¼ 15:288 kPa Petroleum refining begins with distillation of crude oil into different
boiling-range fractions. The fraction boiling from 0 to 100 C is light
naphtha, a blending stock for gasoline. The fraction boiling from
Similarly, PsS ¼ 11:492 kPa 100 to 200 C, the heavy naphtha, undergoes subsequent processing.
One such process is steam cracking, which produces a gas contain-
From (7), Table 2.4, ing ethylene, propylene, and other compounds including benzene
and toluene. This gas is sent to a distillation train to separate the
15:288 mixture into a dozen or more products. In the first column, hydrogen
K EB ¼ ¼ 1:147
13:332 and methane are removed by distillation at 3.2 MPa (464 psia). At a
11:492 tray in the column where the temperature is 40 F, use Figure 2.4 to
KS ¼ ¼ 0:862 estimate K-values for H2, CH4, C2H4, and C3H6.
13:332
Relative volatility: From (2-21),
Solution
K EB 1:147
aEB;S ¼ ¼ ¼ 1:331 The K-value of hydrogen depends on the other compounds in the
KS 0:862 mixture. Because benzene and toluene are present, locate a point A
C02 09/29/2010 Page 45
§2.5 Nonideal Thermodynamic Property Models 45
10,000
6,000
4,000
2,000 er
e at
Critical points xid W
1,000 io
rd
Carbon dioxide lfu
600 Su ol
th an
400 Me
Triple point lene
200 E t hy
Vapor pressure, lb/sq in.
100 ne
Etha
60
40 )
d CO 2
oli ide
20 (S
ch lor
ne
opa t hyl
Pr Me
10
A
ide
m
6 lor
er
ch
th
4 l
thy
w
E ne
Do
ne ta id
2 ta p Ac
i -Bu ne He ic
ry
e to n- et
cu
ne e Ac ol Ac
1 tan e
er
ta n n
-Bu -Pe ha en
M
ne
n i Et
z
0.6 en
ze
ne yl b
en
e
0.4 ne ne ne e yle
an
e
ob
n a e e n op
nta ex nz lu
ec
a
ct o-X -Pr
itr
e
n-H Be To
D
0.2 n-P n
N
O
n-
0.1
–100 –75 –50 –25 0 25 50 75 100 150 200 250 300 350 400 500 600 700 800
Temperature, °F
Figure 2.3 Vapor pressure as a function of temperature.

[Adapted from A.S. Faust, L.A. Wenzel, C.W. Clump, L. Maus, and L.B. Andersen, Principles of Unit Operations, John Wiley & Sons, New York (1960).]
midway between the points for ‘‘H2 in benzene’’ and ‘‘H2 in tolu- Not included in Table 2.5 is the van der Waals equation,
ene.’’ Next, locate a point B at 40 F and 464 psia on the T-P grid. P ¼ RT/(y b) a=y2, where a and b are species-dependent
Connect points A and B with a straight line and read K ¼ 100 where constants. The van der Waals equation was the first success-
the line intersects the K scale. With the same location for point B, ful formulation of an equation of state for a nonideal gas. It is
read K ¼ 11 for methane. For ethylene (ethene) and propylene (pro- rarely used anymore because of its narrow range of applica-
pene), the point A is located on the normal boiling-point scale; the
tion. However, its development suggested that all species
same point is used for B. Resulting K-values are 1.5 and 0.32,
respectively.
have equal reduced molar volumes, yr ¼ y=yc, at the same
reduced temperature, Tr ¼ T=Tc, and reduced pressure, Pr ¼
P=Pc. This finding, referred to as the law of corresponding
states, was utilized to develop (2) in Table 2.5 and defines
the compressibility factor, Z, which is a function of Pr, Tr,
§2.5 NONIDEAL THERMODYNAMIC
and the critical compressibility factor, Zc, or the acentric fac-
PROPERTY MODELS
tor, v. This was introduced by Pitzer et al. [17] to account for
Two types of models are used: (1) P–y–T equation-of-state differences in molecular shape and is determined from the
models and (2) activity coefficient or free-energy models. vapor pressure curve by:
Their applicability depends on the nature of the components " s #
P
in the mixture and the reliability of the equation constants. v ¼ log 1:000 ð2-45Þ
Pc T r ¼0:7
The value for v is zero for symmetric molecules. Some typi-
§2.5.1 P–y–T Equation-of-State Models
cal values of v are 0.264, 0.490, and 0.649 for toluene, n-
A relationship between molar volume, temperature, and pres- decane, and ethyl alcohol, respectively, as taken from the
sure is a P–y–T equation of state. Numerous such equations extensive tabulation of Poling et al. [11].
have been proposed. The simplest is the ideal-gas law, which In 1949, Redlich and Kwong [18] published an equation
applies only at low pressures or high temperatures because it of state that, like the van der Waals equation, contains only
neglects the volume occupied by the molecules and the inter- two constants, both of which can be determined from Tc and
molecular forces. All other equations of state attempt to cor- Pc, by applying the critical conditions
rect for these two deficiencies. The most widely used 2
equations of state are listed in Table 2.5. These and other qP q P
¼ 0 and ¼0
such equations are discussed by Poling et al. [11]. qy T c qy2 T c
C02 09/29/2010 Page 46
Figure 2.4 Vapor–liquid equilibria, 40 to 800 F.

[From S.T. Hadden and H.G. Grayson, Hydrocarbon Proc. and Petrol. Refiner, 40, 207 (Sept. 1961), with permission.]
C02 09/29/2010 Page 47
Figure 2.5 Vapor–liquid equilibria, 260 to 100 F.

[From S.T. Hadden and H.G. Grayson, Hydrocarbon Proc. and Petrol. Refiner, 40, 207 (Sept. 1961), with permission.]
The R–K equation, given as (3) in Table 2.5, is an improve- containing many more constants. Furthermore, the R–K
ment over the van der Waals equation. Shah and Thodos [19] equation can approximate the liquid-phase region.
showed that the R–K equation, when applied to nonpolar If the R–K equation is expanded to obtain a common
compounds, has accuracy comparable with that of equations denominator, a cubic equation in y results. Alternatively, (2)
C02 09/29/2010 Page 48
100 aP
where A¼ ð2-47Þ
Experimental data
R2 T 2
of Yarborough
bP
N2 S–R–K correlation B¼ ð2-48Þ
Temperature 250°F
RT
C1 Equation (2-46), a cubic in Z, can be solved analytically

10 CO2 for three roots (e.g., see Perry’s Handbook, 8th ed., p. 3-10).
At supercritical temperatures, where only one phase exists,
C2 one real root and a complex conjugate pair of roots are
H 2S
obtained. Below the critical temperature, where vapor and/or
liquid phases can exist, three real roots are obtained, with the
largest value of Z applying to the vapor and the smallest root
C3
corresponding to the liquid (ZV and ZL).
K-value
1.0 The intermediate value of Z is discarded.

To apply the R–K equation to mixtures, mixing rules are
used to average the constants a and b for each component.
nC5 The recommended rules for vapor mixtures of C components
are
" #
XC X
C 0:5
a¼ y i y j ai aj ð2-49Þ
nC7
.1 i¼1 j¼1
Toluene
X
C
nC10 b¼ y i bi ð2-50Þ
i¼1
.01
100 1000 10,000
Pressure, psia
Figure 2.6 Comparison of experimental K-value data and S–R–K EXAMPLE 2.5 Specific Volume of a Mixture from
correlation. the R–K Equation.
Use the R–K equation to estimate the specific volume of a vapor
and (3) in Table 2.5 can be combined to eliminate y to give mixture containing 26.92 wt% propane at 400 F (477.6 K) and a
the compressibility factor, Z, form of the equation: saturation pressure of 410.3 psia (2,829 kPa). Compare the results
with the experimental data of Glanville et al. [20].
Z 3 Z 2 þ A B B2 Z AB ¼ 0 ð2-46Þ
Table 2.5 Useful Equations of State
Name Equation Equation Constants and Functions

RT
(1) Ideal-gas law P¼ None
y
ZRT
(2) Generalized P¼ Z ¼ Z fPr ; T r ; Z c or vg as derived from data
y
RT a b ¼ 0:08664RT c =Pc
(3) Redlich–Kwong (R–K) P¼ 2
y b y þ by a ¼ 0:42748R2 T 2:5
c =Pc T
0:5
b ¼ 0:08664RT c =Pc
RT a 2
(4) Soave–Redlich–Kwong (S–R–K or R–K–S) P¼ 2 a ¼ 0:42748R2 T 2c 1 þ f v 1 T 0:5
r =Pc
y b y þ by
f v ¼ 0:48 þ 1:574v 0:176v2
b ¼ 0:07780RT c =Pc
RT a 2
(5) Peng–Robinson (P–R) P¼ a ¼ 0:45724R2 T 2c 1 þ f v 1 T 0:5
r =Pc
y b y2 þ 2by b2
f v ¼ 0:37464 þ 1:54226v 0:26992v2
C02 09/29/2010 Page 49
Solution Following the work of Wilson [21], Soave [6] added a

third parameter, the acentric factor, v, to the R–K equation.
Let propane be denoted by P and benzene by B. The mole fractions
The resulting Soave–Redlich–Kwong (S–R–K) or Redlich–
are
Kwong–Soave (R–K–S) equation, given as (4) in Table 2.5,
0:2692=44:097 was accepted for application to mixtures of hydrocarbons
yP ¼ ¼ 0:3949
ð0:2692=44:097Þ þ ð0:7308=78:114Þ because of its simplicity and accuracy. It makes the parame-
yB ¼ 1 0:3949 ¼ 0:6051 ter a a function of v and T, thus achieving a good fit to vapor
The critical constants are given by Poling et al. [11]: pressure data and thereby improving the ability of the equa-
tion to predict liquid-phase properties.
Propane Benzene Four years after the introduction of the S–R–K equation,
Peng and Robinson [7] presented a modification of the R–K
Tc, K 369.8 562.2 and S–R–K equations to achieve improved agreement in the
Pc, kPa 4,250 4,890 critical region and for liquid molar volume. The Peng–
Robinson (P–R) equation of state is (5) in Table 2.5. The
From Table 2.5, b and a for propane in the R–K equation, in SI units, S–R–K and P–R equations of state are widely applied in cal-
are: culations for saturated vapors and liquids. For mixtures of
hydrocarbons and/or light gases, the mixing rules are given
0:08664ð8:3144Þð369:8Þ
bP ¼ ¼ 0:06268 m3 /kmol by (2-49) and (2-50), except that (2-49) is often modified to
4;250
include a binary interaction coefficient, kij:
0:42748ð8:3144Þ2 ð369:8Þ2:5 " #
aP ¼ XC XC 0:5
ð4;250Þð477:59Þ0:5 a¼ y i y j ai aj 1 kij ð2-51Þ
i¼1 j¼1
¼ 836:7 kPa-m6 /kmol2
Similarly, for benzene, bB ¼ 0.08263 m3/kmol and aB ¼ 2,072 kPa- Values of kij from experimental data have been published for
m6/kmol2. both the S–R–K and P–R equations, e.g., Knapp et al. [22].
From (2-50), Generally kij is zero for hydrocarbons paired with hydrogen
or other hydrocarbons.
b ¼ ð0:3949Þð0:06268Þ þ ð0:6051Þð0:08263Þ ¼ 0:07475 m3 /kmol
Although the S–R–K and P–R equations were not
From (2-49), intended to be used for mixtures containing polar organic
compounds, they are applied by employing large values of kij
a ¼ y2P aP þ 2yP yB ðaP aB Þ0:5 þ y2B aB in the vicinity of 0.5, as back-calculated from data. However,
¼ ð0:3949Þ2 ð836:7Þ þ 2ð0:3949Þð0:6051Þ½ð836:7Þð2;072Þ0:5 a preferred procedure for polar organics is to use a mixing
rule such as that of Wong and Sandler, which is discussed in
þ ð0:6051Þ2 ð2;072Þ ¼ 1;518 kPa-m6 /kmol2
Chapter 11 and which bridges the gap between a cubic equa-
From (2-47) and (2-48) using SI units, tion of state and an activity-coefficient equation.
ð1;518Þð2;829Þ Another model for polar and nonpolar substances is the
A¼ ¼ 0:2724 virial equation of state due to Thiesen [23] and Onnes [24].
ð8:314Þ2 ð477:59Þ2
A common representation is a power series in 1=y for Z:
ð0:07475Þð2;829Þ
B¼ ¼ 0:05326 B C
ð8:314Þð477:59Þ2 Z ¼1þ þ þ ð2-52Þ
y y2
From (2-46), the cubic Z form of the R–K equation is obtained:
A modification of the virial equation is the Starling form [5] of
Z 3 Z 2 þ 0:2163Z 0:01451 ¼ 0
the Benedict–Webb–Rubin (B–W–R) equation for hydrocar-
This equation gives one real root and a pair of complex roots: bons and light gases. Walas [25] presents a discussion of B–
Z ¼ 0:7314; 0:1314 þ 0:04243i; 0:1314 0:04243i W–R-type equations, which—because of the large number of
terms and species constants (at least 8)—is not widely used
The one real root is assumed to be that for the vapor phase. except for pure substances at cryogenic temperatures. A more
From (2) of Table 2.5, the molar volume is useful modification of the B–W–R equation is a generalized
ZRT ð0:7314Þð8:314Þð477:59Þ corresponding-states form developed by Lee and Kesler [26]
y¼ ¼ ¼ 1:027 m3 /kmol
P 2;829 with an extension to mixtures by Pl€ocker et al. [8]. All of the
constants in the L–K–P equation are given in terms of the acen-
The average molecular weight of the mixture is 64.68 kg/kmol. The
specific volume is
tric factor and reduced temperature and pressure, as developed
from P–y–T data for three simple fluids (v ¼ 0), methane,
y 1:027 argon, and krypton, and a reference fluid (v ¼ 0.398), n-
¼ ¼ 0:01588 m3 /kg ¼ 0:2543 ft3 /lb
M 64:68 octane. The equations, constants, and mixing rules are given by
Glanville et al. report experimental values of Z ¼ 0.7128 and y=M ¼ Walas [25]. The L–K–P equation describes vapor and liquid
0.2478 ft3/lb, which are within 3% of the estimated values. mixtures of hydrocarbons and/or light gases over wide ranges
of T and P.
C02 09/29/2010 Page 50
§2.5.2 Derived Thermodynamic Properties "

from P–y–T Models iV ¼ exp ðZ V 1Þ Bi lnðZ V BÞ
f ð2-56Þ
B
If a temperature-dependent, ideal-gas heat capacity or rffiffiffiffiffi ! #
enthalpy equation such as (2-35) or (2-36) is available, along A Ai Bi B
2 ln 1 þ
with an equation of state, all other vapor- and liquid-phase B A B ZV
properties can be derived from the integral equations in Table
2.6. These equations, in the form of departure from the ideal- The results for the liquid phase are identical if yi and ZV
gas equations of Table 2.4, apply to vapor or liquid. (but not hoiV ) are replaced by xi and ZL, respectively. The liq-
When the ideal-gas law, P ¼ RT=y, is substituted into Eqs. uid-phase forms of (2-53) and (2-54) account for the enthalpy
(1) to (4) of Table 2.6, the results for the vapor are and entropy of vaporization. This is because the R–K equa-
tion of state, as well as the S–R–K and P–R equations, are
ðh hoV Þ ¼ 0; f ¼ 1
continuous functions through the vapor and liquid regions, as
ðs soV Þ ¼ 0; f ¼ 1 shown for enthalpy in Figure 2.7. Thus, the liquid enthalpy is
determined by accounting for four effects, at a temperature
When the R–K equation is substituted into the equations of below the critical. From (1), Table 2.6, and Figure 2.7:
Table 2.6, the results for the vapor phase are:
Z y" #
XC
3A B o qP
hV ¼ yi hoiV þ RT Z V 1 ln 1 þ ð2-53Þ hL ¼ hV þ Py RT PT dy
2B ZV 1 qT y
i¼1
¼ hoV
X C
P |{z}
o
sV ¼ yi siV R ln o ð2-54Þ ð1Þ Vapor at zero pressure
i¼1
P Z " ! #
yV s
X C qP
þ ðPyÞV s RT PT dy
R ðyi ln yi Þ þ R ln ðZ V BÞ 1 qT
y
i¼1 |fflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflffl{zfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflffl}
ð2Þ Pressure correction for vapor to saturation pressure
A B
fV ¼ exp Z V 1 ln ðZ V BÞ ln 1 þ
B ZV qP
T ðyV s yLs Þ
ð2-55Þ qT
|fflfflfflfflfflfflfflfflfflfflfflfflfflfflfflsffl{zfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflffl}
ð3Þ Latent heat of vaporization
h i Z yL
qP
Table 2.6 Integral Departure Equations of Thermodynamics þ ðPyÞL ðPyÞL PT dy
s
yLs qT y
At a given temperature and composition, the following equations |fflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflffl{zfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflffl}
give the effect of pressure above that for an ideal gas. ð4Þ Correction to liquid for pressure in excess of saturation pressure
Mixture enthalpy: ð2-57Þ

Z
y
qP where the subscript s refers to the saturation pressure.
(1) h hoV ¼ Py RT PT dy The fugacity coefficient, f, of a pure species from the
1 qT y
Mixture entropy: R–K equation, as given by (2-55), applies to the vapor for
Z Z P < Psi . For P > Psi, f is the liquid fugacity coefficient. Satu-
y
qP y
R ration pressure corresponds to the condition of fV ¼ fL.
ð 2Þ s soV ¼ dy dy
1 qT y 1 y Thus, at a temperature T < Tc, the vapor pressure, Ps, can be
Pure-component fugacity coefficient:

P=0
Z
P 1
1 RT h°V
(3) fiV ¼ exp y dP 2
RT 0 P
Molar enthalpy, H
r
Vapo
Z 1 P=P
1 RT
¼ exp P dy ln Z þ ðZ 1Þ 0
3
RT y y
Partial fugacity coefficient: hL

( Z " # ) 4
1
iV 1 qP RT
(4) f ¼ exp dV ln Z Liqu
id
RT V qN i T;V;N j V
X
C
T
where V ¼ y N i
i¼1 Temperature, T
Figure 2.7 Contributions to enthalpy.
C02 09/29/2010 Page 51
1.0 10
9
8
100°F
7
n-Decane
6
n-Heptane
Reduced vapor pressure Ps/Pc
5
Benzene
Cy
Ethane K-value
cl
4
oh
Redlich–Kwong
ex
n-Butane
an
equation
e
3 Propylene
0.1
i-Butane
Methane 2 Propane
Ethyl alcohol
n-Decane
Toluene
1
100 200 300 400 500 600 800 1,000
0.01 Pressure, psia
0.5 0.6 0.7 0.8 0.9 1.0
Curves represent experimental data of:
Reduced temperature, T/Tc Kay et al. (Ohio State Univ.) Robinson et al. (Univ. Alberta)
Sage et al. (Calif. Inst. Tech.) Thodos (Northwestern)
Figure 2.8 Reduced vapor pressure.
Figure 2.9 K-values of ethane in binary hydrocarbon mixtures at 100 F.
estimated from the R–K equation of state by setting (2-55) and 780 psia (4.964 MPa to 5.378 MPa). At the convergence
for the vapor equal to (2-55) for the liquid and solving for P, pressure, separation by distillation is impossible because K-
which equals Ps. values become 1.0. Figure 2.9 shows that at 100 F, ethane
The results of Edmister [27] are plotted in Figure 2.8. The does not form ideal solutions with all the other components
R–K vapor-pressure curve does not satisfactorily represent because the K-values depend on the other component, even
data for a wide range of molecular shapes, as witnessed by for paraffin homologs. For example, at 300 psia, the K-value
the data for methane, toluene, n-decane, and ethyl alcohol. of ethane in benzene is 80% higher than the K-value of
This failure represents a shortcoming of the R–K equation ethane in propane.
and is why Soave [6] modified the R–K equation by introduc- The ability of equations of state, such as S–R–K, P–R, and
ing the acentric factor, v. Thus, while the critical constants Tc L–K–P equations, to predict the effects of composition, tem-
and Pc are insufficient to generalize thermodynamic behav- perature, and pressure on K-values of mixtures of hydrocar-
ior, a substantial improvement results by incorporating a bons and light gases is shown in Figure 2.6. The mixture
third parameter that represents the generic differences in the contains 10 species ranging in volatility from nitrogen to n-
reduced-vapor-pressure curves. decane. The experimental data points, covering almost a 10-
As seen in (2-56), partial fugacity coefficients depend on fold range of pressure at 250 F, are those of Yarborough [28].
pure-species properties, Ai and Bi, and mixture properties, A Agreement with the S–R–K equation is very good.
and B. Once f iL are computed from (2-56), a K-value
iV and f
can be estimated from (2-26).
The most widely used P–y–T equations of state are the S–
R–K, P–R, and L–K–P. These are combined with the integral
departure equations of Table 2.6 to obtain equations for esti- EXAMPLE 2.6 Effect of EOS on Calculations.
mating enthalpy, entropy, fugacity coefficients, partial fugac- In the thermal hydrodealkylation of toluene to benzene (C7H8 þ H2
ity coefficients, and K-values. The results of the integrations ! C6H6 + CH4), excess hydrogen minimizes cracking of aromatics
are complex and unsuitable for manual calculations. How- to light gases. In practice, conversion of toluene per pass through the
ever, the calculations are readily made by computer programs reactor is only 70%. To separate and recycle hydrogen, hot reactor-
incorporated into all process simulation programs. effluent vapor of 5,597 kmol/h at 500 psia (3,448 kPa) and 275 F
Ideal K-values as determined from Eq. (7) in Table 2.4 (408.2 K) is partially condensed to 120 F (322 K), with phases sepa-
rated in a flash drum. If the composition of the reactor effluent is as
depend only on temperature and pressure. Most frequently,
given below and the flash pressure is 485 psia (3,344 kPa), calculate
they are suitable for mixtures of nonpolar compounds such
equilibrium compositions and flow rates of vapor and liquid leaving
as paraffins and olefins. Figure 2.9 shows experimental the drum and the amount of heat transferred, using a process simula-
K-value curves for ethane in binary mixtures with other, less tion program for each of the equation-of-state models discussed
volatile hydrocarbons at 100 F (310.93 K), which is close to above. Compare the results, including K-values and enthalpy and
ethane’s critical temperature of 305.6 K, for pressures from entropy changes.
100 psia (689.5 kPa) to convergence pressures between 720
C02 09/29/2010 Page 52
Note that the material balances are always precisely satisfied.

Component Mole Fraction Users of simulation programs should never take this as an indication
Hydrogen (H) 0.3177 that the results are correct but instead should always verify results in
all possible ways.
Methane (M) 0.5894
Benzene (B) 0.0715
Toluene (T) 0.0214
1.0000 §2.6 LIQUID ACTIVITY-COEFFICIENT
MODELS
Solution
Predictions of liquid properties based on Gibbs free-energy
The computations were made using the S–R–K, P–R, and L–K–P models for predicting liquid-phase activity coefficients, and
equations of state. The results at 120 F and 485 psia are: other excess functions such as volume and enthalpy of mixing,
are developed in this section. Regular-solution theory, which
Equation of State describes mixtures of nonpolar compounds using only con-
stants for the pure components, is presented first, followed by
S–R–K P–R L–K–P
models useful for mixtures containing polar compounds, which
Vapor flows, kmol/h: require experimentally determined binary interaction parame-
Hydrogen 1,777.1 1,774.9 1,777.8 ters. If these are not available, group-contribution methods can
Methane 3,271.0 3,278.5 3,281.4 be used to make estimates. All models can predict vapor–liquid
Benzene 55.1 61.9 56.0 equilibria; and some can estimate liquid–liquid and even solid–
Toluene 6.4 7.4 7.0 liquid and polymer–liquid equilibria.
Total 5,109.6 5,122.7 5,122.2 For polar compounds, dependency of K-values on compo-
Liquid flows, kmol/h: sition is due to nonideal behavior in the liquid phase. For
Hydrogen 1.0 3.3 0.4 hydrocarbons, Prausnitz, Edmister, and Chao [29] showed
Methane 27.9 20.4 17.5 that the relatively simple regular-solution theory of Scatch-
Benzene 345.1 338.2 344.1 ard and Hildebrand [30] can be used to estimate deviations
Toluene 113.4 112.4 112.8 due to nonideal behavior. They expressed K-values in terms
Total 487.4 474.3 474.8 of (2-27), K i ¼ giL fiL =f iV . Chao and Seader [9] simplified
K-values: and extended application of this equation to hydrocarbons
Hydrogen 164.95 50.50 466.45 and light gases in the form of a compact set of equations.
Methane 11.19 14.88 17.40 These were widely used before the availability of the S–R–K
Benzene 0.01524 0.01695 0.01507 and P–R equations.
Toluene 0.00537 0.00610 0.00575 For hydrocarbon mixtures, regular-solution theory is
Enthalpy change, 35.267 34.592 35.173 based on the premise that nonideality is due to differences in
GJ/h van der Waals forces of attraction among the molecules pres-
Entropy change, 95.2559 93.4262 95.0287 ent. Regular solutions have an endothermic heat of mixing,
MJ/h-K and activity coefficients are greater than 1. These solutions
Percent of benzene 88.2 86.7 87.9 are regular in that molecules are assumed to be randomly dis-
and toluene persed. Unequal attractive forces between like and unlike
condensed molecule pairs cause segregation of molecules. However, for
regular solutions the species concentrations on a molecular
Because the reactor effluent is mostly hydrogen and methane, the level are identical to overall solution concentrations. There-
effluent at 275 F and 500 psia, and the equilibrium vapor at 120 F fore, excess entropy due to segregation is zero and entropy of
and 485 psia, are nearly ideal gases (0.98 < Z < 1.00), despite the regular solutions is identical to that of ideal solutions, where
moderately high pressures. Thus, the enthalpy and entropy changes the molecules are randomly dispersed.
are dominated by vapor heat capacity and latent heat effects, which
are independent of which equation of state is used. Consequently,
the enthalpy and entropy changes differ by less than 2%. §2.6.1 Activity Coefficients from Gibbs Free Energy
Significant differences exist for the K-values of H2 and CH4.
Activity-coefficient equations are often based on Gibbs free-
However, because the values are large, the effect on the amount of
equilibrium vapor is small. Reasonable K-values for H2 and CH4, energy models. The molar Gibbs free energy, g, is the sum of
based on experimental data, are 100 and 13, respectively. K-values the molar free energy of an ideal solution and an excess
for benzene and toluene differ among the three equations of state by molar free energy gE for nonideal effects. For a liquid
as much as 11% and 14%, respectively, which, however, causes less X
C X
C
than a 2% difference in the percentage of benzene and toluene con- g ¼ xi gi þ RT xi ln xi þ gE
densed. Raoult’s law K-values for benzene and toluene are 0.01032 i¼1 i¼1
and 0.00350, which are considerably lower than the values com- ð2-58Þ
X
C
puted from the three equations of state because deviations to fugaci- ¼ xi gi þ RT ln xi þ gEi

ties due to pressure are important. i¼1
C02 09/29/2010 Page 53
§2.6 Liquid Activity-Coefficient Models 53
where g ¼ h Ts and excess molar free energy is the sum of X

C
Fi
the partial excess molar free energies, which are related to gE ¼ RT xi ln ð2-65Þ
i¼1
xi
the liquid-phase activity coefficients by

gEi
qðN t gE =RT Þ Substitution of (2-65) into (2-59) gives
¼ ln gi ¼
RT qN i P;T;N j yiL yiL
ð2-59Þ ln giL ¼ ln þ1 ð2-66Þ
g E X E
qðg =RT Þ yL yL
¼ xk
RT k
qxk P;T;xr Thus, the activity coefficient of a species in a regular solu-
tion, including the Flory–Huggins correction, is
where j 6¼ i; r 6¼ k; k 6¼ i, and r 6¼ i. 2 3
!2
The relationship between excess molar free energy and PC
excess molar enthalpy and entropy is 6yiL di Fj dj 7
6 yiL yiL 7
6 j¼1 7
XC
E
giL ¼ exp 6 þ ln þ1 7
gE ¼ hE TsE ¼ xi hi TsEi ð2-60Þ 6 RT yL yL 7
4 5
i¼1
ð2-67Þ
§2.6.2 Regular-Solution Model
For a regular liquid solution, the excess molar free energy is
based on nonideality due to differences in molecular size and
intermolecular forces. The former are expressed in terms of EXAMPLE 2.7 Activity Coefficients from Regular-
liquid molar volume, and the latter in terms of the enthalpy Solution Theory.
of vaporization. The resulting model is Yerazunis et al. [31] measured liquid-phase activity coefficients for
" # the n-heptane/toluene system at 1 atm (101.3 kPa). Estimate activity
XC
1X C X C
E 2
g ¼ ðxi yiL Þ Fi Fj di dj ð2-61Þ coefficients using regular-solution theory both with and without the
i¼1
2 i¼1 j¼1 Flory–Huggins correction. Compare estimated values with experi-
mental data.
where F is the volume fraction assuming additive molar vol-
umes, given by Solution
xi yiL xi yiL
Fi ¼ C ¼ ð2-62Þ Experimental liquid-phase compositions and temperatures for 7 of
P yL
xj yjL 19 points are as follows, where H denotes heptane and T denotes
j¼1 toluene:
and d is the solubility parameter, which is defined in terms of

T, C xH xT
the volumetric internal energy of vaporization as
vap 1=2 98.41 1.0000 0.0000
DEi
di ¼ ð2-63Þ 98.70 0.9154 0.0846
yiL 99.58 0.7479 0.2521
101.47 0.5096 0.4904
Combining (2-59) with (2-61) yields an expression for the
104.52 0.2681 0.7319
activity coefficient in a regular solution:
107.57 0.1087 0.8913
!2
PC 110.60 0.0000 1.0000
yiL di F j dj
j¼1
ln giL ¼ ð2-64Þ At 25 C, liquid molar volumes are yHL ¼ 147:5 cm3 /mol and
RT
yTL ¼ 106:8 cm3 /mol. Solubility parameters are 7.43 and 8.914
Because ln giL varies almost inversely with absolute tem- (cal/cm3)1/2, respectively, for H and T. As an example, consider
perature, yiL and dj are taken as constants at a reference tem- 104.52 C. From (2-62), volume fractions are
perature, such as 25 C. Thus, the estimation of gL by regular- 0:2681ð147:5Þ
solution theory requires only the pure-species constants yL FH ¼ ¼ 0:3359
0:2681ð147:5Þ þ 0:7319ð106:8Þ
and d. The latter parameter is often treated as an empirical
FT ¼ 1 FH ¼ 1 0:3359 ¼ 0:6641
constant determined by back-calculation from experimental
data. For species with a critical temperature below 25 C, yL Substitution of these values, together with the solubility parameters,
and d at 25 C are hypothetical. However, they can be eval- into (2-64) gives
( )
uated by back-calculation from data. 147:5½7:430 0:3359ð7:430Þ 0:6641ð8:914Þ2
When molecular-size differences—as reflected by liquid gH ¼ exp
1:987ð377:67Þ
molar volumes—are appreciable, the Flory–Huggins size
correction given below can be added to the regular-solution ¼ 1:212
free-energy contribution:
C02 09/29/2010 Page 54
§2.6.3 Nonideal Liquid Solutions

1 atm With dissimilar polar species that can form or break hydro-
Experimental data for toluene
gen bonds, the ideal-liquid-solution assumption is invalid
1.6 and regular-solution theory is also not applicable. Ewell,
and n-heptane, respectively
Regular solution theory Harrison, and Berg [33] provide a classification based on the
Regular solution theory potential for association or solvation due to hydrogen-bond
Liquid-phase activity coefficient
1.5 with Flory–Huggins correction

formation. If a molecule contains a hydrogen atom attached
to a donor atom (O, N, F, and in certain cases C), the active
1.4 hydrogen atom can form a bond with another molecule con-
γ n-heptane taining a donor atom. The classification in Table 2.7 permits
qualitative estimates of deviations from Raoult’s law for
1.3 γ toluene
binary pairs when used in conjunction with Table 2.8.
Positive deviations correspond to values of giL > 1. Noni-
deality results in variations of giL with composition, as shown
1.2 in Figure 2.11 for several binary systems, where the Roman
numerals refer to classification in Tables 2.7 and 2.8. Starting
with Figure 2.11a, the following explanations for the non-
1.1
idealities are offered: n-heptane (V) breaks ethanol (II)
hydrogen bonds, causing strong positive deviations. In Figure
1.0 2.11b, similar, but less positive, deviations occur when
0 0.2 0.4 0.6 0.8 1.0 acetone (III) is added to formamide (I). Hydrogen bonds are
Mole fraction of n-heptane broken and formed with chloroform (IV) and methanol (II) in
Figure 2.10 Liquid-phase activity coefficients for n-heptane/ Figure 2.11c, resulting in an unusual deviation curve for
toluene system at 1 atm. chloroform that passes through a maximum. In Figure 2.11d,
chloroform (IV) provides active hydrogen atoms that form
Values of gH and gT computed in this manner for all seven liquid-
phase conditions are plotted in Figure 2.10.
hydrogen bonds with oxygen atoms of acetone (III), thus
Applying (2-67) at 104.52 C with the Flory–Huggins correction causing negative deviations. For water (I) and n-butanol (II)
gives in Figure 2.11e, hydrogen bonds of both molecules are
broken, and nonideality is sufficiently strong to cause forma-
147:5 147:5
gH ¼ exp 0:1923 þ ln þ1 ¼ 1:179 tion of two immiscible liquid phases.
117:73 117:73
Nonideal-solution effects can be incorporated into
Values of the computed gH and gT are included in Figure 2.10. K-value formulations by the use of the partial fugacity
Deviations from experimental data are not greater than 12% for coefficient, F i , in conjunction with an equation of state and
regular-solution theory and not greater than 6% with the Flory– adequate mixing rules. This method is most frequently used
Huggins correction. Unfortunately, good agreement is not always for handling nonidealities in the vapor phase. However, F iV
obtained for nonpolar hydrocarbon solutions, as shown, for exam- reflects the combined effects of a nonideal gas and a nonideal
ple, by Hermsen and Prausnitz [32], who studied the cyclopentane/
gas solution. At low pressures, both effects are negligible. At
benzene system.
moderate pressures, a vapor solution may still be ideal even
Table 2.7 Classification of Molecules Based on Potential for Forming Hydrogen Bonds
Class Description Example
I Molecules capable of forming three-dimensional networks of Water, glycols, glycerol, amino alcohols, hydroxylamines,
strong H-bonds hydroxyacids, polyphenols, and amides
II Other molecules containing both active hydrogen atoms and Alcohols, acids, phenols, primary and secondary amines, oximes,
donor atoms (O, N, and F) nitro and nitrile compounds with a-hydrogen atoms, ammonia,
hydrazine, hydrogen fluoride, and hydrogen cyanide
III Molecules containing donor atoms but no active hydrogen Ethers, ketones, aldehydes, esters, tertiary amines (including
atoms pyridine type), and nitro and nitrile compounds without a-
hydrogen atoms
IV Molecules containing active hydrogen atoms but no donor CHCl3, CH2Cl2, CH3CHCl2, CH2ClCH2Cl, CH2ClCHClCH2Cl,
atoms that have two or three chlorine atoms on the same and CH2ClCHCl2
carbon as a hydrogen or one chlorine on the carbon atom
and one or more chlorine atoms on adjacent carbon atoms
V All other molecules having neither active hydrogen atoms nor Hydrocarbons, carbon disulfide, sulfides, mercaptans, and
donor atoms halohydrocarbons not in class IV
C02 09/29/2010 Page 55
Table 2.8 Molecule Interactions Causing Deviations from Raoult’s Law
Type of Deviation Classes Effect on Hydrogen Bonding
Always negative III þ IV H-bonds formed only

Quasi-ideal; always positive or ideal III þ III No H-bonds involved
III þ V
IV þ IV
IV þ V
VþV
Usually positive, but some negative IþI H-bonds broken and formed
I þ II
I þ III
II þ II
II þ III
Always positive I þ IV H-bonds broken and formed, but dissociation of
(frequently limited solubility) Class I or II is more important effect
II þ IV
Always positive IþV H-bonds broken only
II þ V
though the gas mixture does not follow the ideal-gas law. volume of 106.3 cm3/mol. By contrast, excess liquid enthalpy
Nonidealities in the liquid phase, however, can be severe and excess liquid entropy may not be small. Once the partial
even at low pressures. When polar species are present, mix- molar excess functions for enthalpy and entropy are estimated
ing rules can be modified to include binary interaction for each species, the excess functions for the mixture are com-
parameters, kij, as in (2-51). The other technique for handling puted from the mole fraction sums.
iV in the K-value formula-
solution nonidealities is to retain f

tion but replace fiL by the product of giL and fiL, where the
§2.6.4 Margules Equations
former accounts for deviations from nonideal solutions.
Equation (2-26) then becomes Equations (1) and (2) in Table 2.9 date back to 1895, yet the
g fiL two-constant form is still in use because of its simplicity.
K i ¼ iL
iV ð2-68Þ These equations result from power-series expansions for gEi
f
and conversion to activity coefficients by (2-59). The one-
which was derived previously as (2-27). At low pressures, constant form is equivalent to symmetrical activity-
iV ¼ 1:0, so (2-68) reduces
from Table 2.2, fiL ¼ Psi =P and f coefficient curves, which are rarely observed.
to a modified Raoult’s law K-value, which differs from (2-44)
in the added giL term: §2.6.5 van Laar Equation
g Ps
K i ¼ iL i ð2-69Þ Because of its flexibility, simplicity, and ability to fit many
P systems well, the van Laar equation is widely used. It was
At moderate pressures, (5) of Table 2.3 is preferred. derived from the van der Waals equation of state, but the con-
Regular-solution theory is useful only for estimating values stants, shown as A12 and A21 in (3) of Table 2.9, are, in theory,
of giL for mixtures of nonpolar species. Many semitheoretical constant only for a particular binary pair at a given tempera-
equations exist for estimating activity coefficients of binary ture. In practice, the constants are best back-calculated from
mixtures containing polar species. These contain binary inter- isobaric data covering a range of temperatures. The van Laar
action parameters back-calculated from experimental data. Six theory expresses the temperature dependence of Aij as
of the more useful equations are listed in Table 2.9 in binary- 0
pair form. For a given activity-coefficient correlation, the equa- A ij
Aij ¼ ð2-70Þ
tions of Table 2.10 can be used to determine excess volume, RT
excess enthalpy, and excess entropy. However, unless the de- Regular-solution theory and the van Laar equation are
pendency on pressure is known, excess liquid volumes cannot equivalent for a binary solution if
be determined directly from (1) of Table 2.10. Fortunately, the
yiL 2
contribution of excess volume to total volume is small for solu- Aij ¼ d i dj ð2-71Þ
tions of nonelectrolytes. For example, a 50 mol% solution of RT
ethanol in n-heptane at 25 C is shown in Figure 2.11a to be a The van Laar equation can fit activity coefficient–compo-
nonideal but miscible liquid mixture. From the data of Van sition curves corresponding to both positive and negative
Ness, Soczek, and Kochar [34], excess volume is only 0.465 deviations from Raoult’s law, but cannot fit curves that
cm3/mol, compared to an estimated ideal-solution molar exhibit minima or maxima such as those in Figure 2.11c.
C02 09/29/2010 Page 56
20
8.0
10
Activity coefficient, γ
8.0
6.0 4.0
Formamide
4.0 Ethanol
Acetone
3.0 N-Heptane
2.0
2.0
1.0 1.0
0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0
Mole fraction ethanol in liquid phase Mole fraction acetone in liquid phase
(a) (b)
10.0
8.0
6.0 1.0
0.9
4.0 Methanol 0.8
0.7 Acetone
0.6
Chloroform Chloroform
2.0 0.5
0.4
1.0 0.3
0 0.2 0.4 0.6 0.8 1.0 0 0.2 0.4 0.6 0.8 1.0
Mole fraction chloroform Mole fraction of acetone
in liquid phase in liquid phase
(c) (d)
30.0
20.0 γ2 B b
15.0
10.0 Phase A +
Phase A
8.0
6.0 Phase B
5.0 Water γ 1 Phase B
4.0
3.0
a γ 2A
2.0 Butanol γ 2 a γ 1A
γ1 B b
1.0
0 0.2 0.4 0.6 0.8 1.0
Mole fraction water in liquid phase
(e)
Figure 2.11 Typical variations of activity coefficients with composition in binary liquid systems: (a) ethanol(II)/n-heptane(V); (b) acetone
(III)/formamide(I); (c) chloroform(IV)/methanol(II); (d) acetone(III)/chloroform(IV); (e) water(I)/n-butanol(II).
When data are isothermal or isobaric over only a narrow It is important that the van Laar equation predict azeotrope
range of temperature, determination of van Laar constants is formation, where xi ¼ yi and Ki ¼ 1.0. If activity coefficients
conducted in a straightforward manner. The most accurate are known or can be computed at the azeotropic composition
procedure is a nonlinear regression to obtain the best fit to say, from (2-69) (giL ¼ P=Psi , since Ki ¼ 1.0), these coeffi-
the data over the entire range of binary composition, subject cients can be used to determine the van Laar constants by
to minimization of some objective function. A less accurate, solving (2-73) and (2-74), which describe activity-coefficient
but extremely rapid, manual-calculation procedure can be data at any single composition:
used when experimental data can be extrapolated to infinite-
dilution conditions. Modern experimental techniques are
x2 ln g2 2
available for accurately and rapidly determining activity A12 ¼ ln g1 1 þ ð2-73Þ
coefficients at infinite dilution. Applying (3) of Table 2.9 to x1 ln g1
the conditions xi ¼ 0 and then xj ¼ 0,
Aij ¼ ln g1
i ; xi ¼ 0 x1 ln g1 2
A21 ¼ ln g2 1 þ ð2-74Þ
x2 ln g2
and Aji ¼ ln g1
j ; xj ¼ 0 ð2-72Þ
C02 09/29/2010 Page 57
Table 2.9 Empirical and Semitheoretical Equations for Correlating Liquid-Phase Activity Coefficients of Binary Pairs
Name Equation for Species 1 Equation for Species 2
(1) Margules logg1 ¼ Ax22 logg2 ¼ Ax21
(2) Margules (two-constant) 12 þ 2x1 ðA

log g1 ¼ x22 ½A 12 Þ
21 A 21 þ 2x2 ðA
log g2 ¼ x21 ½A 21 Þ
12 A
A12 A21
(3) van Laar (two-constant) ln g1 ¼ ln g2 ¼
½1 þ ðx1 A12 Þ=ðx2 A21 Þ2 ½1 þ ðx2 A21 Þ=ðx1 A12 Þ2
(4) Wilson (two-constant) lng1 ¼ lnðx1 þ L12 x2 Þ ln g2 ¼ ln ðx2 þ L21 x1 Þ

L12 L21 L12 L21
þx2 x1
x1 þ L12 x2 x2 þ L21 x1 x1 þ L12 x2 x2 þ L21 x1
x22 t21 G221 x21 t12 G12 x21 t12 G212 x22 t21 G21
(5) NRTL (three-constant) ln g1 ¼ 2
þ 2
ln g2 ¼ 2
þ
ðx1 þ x2 G21 Þ ðx2 þ x1 G12 Þ ðx2 þ x1 G12 Þ ðx1 þ x2 G21 Þ2

Gij ¼ exp aij tij Gij ¼ exp aij tij
C1 Z u1 C2 Z u2
(6) UNIQUAC (two-constant) ln g1 ¼ ln þ q ln ln g2 ¼ ln þ q ln
x1 2 1 C1 x2 2 2 C2

r1 r2
þ C2 l 1 l 2 q1 ln ðu1 þ u2 T 21 Þ þ C1 l 2 l 1 q2 ln ðu2 þ u1 T 12 Þ
r2 r1

T 21 T 12 T 12 T 21
þ u2 q1 þ u1 q2
u1 þ u2 T 21 u2 þ u1 T 12 u2 þ u1 T 12 u1 þ u2 T 21
Mixtures of self-associated polar molecules (class II in §2.6.6 Local-Composition Concept

Table 2.7) with nonpolar molecules (class V) can exhibit and the Wilson Model
strong nonideality of the positive-deviation type shown in
Following its publication in 1964, the Wilson equation [37],
Figure 2.11a. Figure 2.12 shows experimental data of Sinor
and Weber [35] for ethanol (1)=n-hexane (2), a system of this in Table 2.9 as (4), received wide attention because of
its ability to fit strongly nonideal, but miscible systems.
type, at 101.3 kPa. These data were correlated with the van
As shown in Figure 2.12, the Wilson equation, with binary
Laar equation by Orye and Prausnitz [36] to give A12 ¼
2.409 and A21 ¼ 1.970. From x1 ¼ 0.1 to 0.9, the data fit to 30
the van Laar equation is good; in the dilute regions, however, 1 atm
deviations are quite severe and the predicted activity coeffi-
cients for ethanol are low. An even more serious problem 20
Experimental data
with highly nonideal mixtures is that the van Laar equation van Laar equation
Wilson equation
may erroneously predict phase splitting (formation of two
liquid phases) when values of activity coefficients exceed
approximately 7. 10
9
8
7
γ 6
Table 2.10 Partial Molar Excess Functions
5
Excess volume:
4
γ ethanol γn-hexane
q ln giL
ð 1Þ iL y
y ID
iL EiL ¼ RT
y 3
qP T;x
Excess enthalpy:
2
ID E 2 q ln giL
ð 2Þ hiL hiL hiL ¼ RT
qT P;x
Excess entropy:
" #
q lngiL
ð 3Þ siL siL siL ¼ R T
ID E
þ ln giL 1.0 2.0 4.0 6.0 8.0 1.0
qT P;x
xethanol
Figure 2.12 Activity coefficients for ethanol/n-hexane.

[Data from J.E. Sinor and J.H. Weber, J. Chem. Eng. Data, 5, 243–247
ID = ideal mixture; E = excess because of nonideality.
(1960).]
C02 09/29/2010 Page 58
15 of type 1 also, but the variation is small compared to the effect of tem-
15 of type 2 perature on the exponential terms in (2-76) and (2-77).
The Wilson equation is extended to multicomponent mix-
Overall mole fractions: x1 = x2 = 1/2
Local mole fractions: tures by neglecting ternary and higher interactions and assum-
x21 =
Molecules of 2 about a central molecule 1 ing a pseudo-binary mixture. The following multicomponent
Total molecules about a central molecule 1 Wilson equation involves only binary interaction constants:
x21 + x11 = 1, as shown
0 1
x12 + x22 = 1 ! xi Lik
x11 3/8 XC XB
C
C
@ P x L A ð2-79Þ
C
x21 5/8 ln gk ¼ 1 ln xj Lkj
j ij
j¼1 i¼1 j¼1
Figure 2.13 The concept of local compositions.
[From P.M. Cukor and J.M. Prausnitz, Int. Chem. Eng. Symp. Ser. No. 32, 3,
88 (1969).] where Lii ¼ Ljj ¼ Lkk ¼ 1.
For highly nonideal, but still miscible, mixtures, the Wil-
interaction parameters L12 ¼ 0.0952 and L21 ¼ 0.2713 from son equation is markedly superior to the Margules and van
Orye and Prausnitz [36], fits experimental data well even in Laar equations. It is consistently superior for multi-
dilute regions where the variation of g1 becomes exponential. component solutions. The constants in the Wilson equation
Corresponding infinite-dilution activity coefficients com- for many binary systems are tabulated in the DECHEMA
puted from the Wilson equation are g1 1 ¼ 21:72 and
collection of Gmehling and Onken [39] and the Dortmund
g12 ¼ 9:104. Data Bank. Two limitations of the Wilson equation are its
The Wilson equation accounts for differences in both inability to predict immiscibility, as in Figure 2.11e, and
molecular size and intermolecular forces, consistent with the maxima and minima in activity-coefficient–mole fraction
Flory–Huggins relation (2-65). Overall solution volume frac- relationships, as in Figure 2.11c.
tions (Fi ¼ xiyiL=yL) are replaced by local-volume fractions, When insufficient data are available to determine binary
F i , related to local-molecule segregations caused by differing parameters from a best fit of activity coefficients, infinite-
energies of interaction between pairs of molecules. The con- dilution or single-point values can be used. At infinite
cept of local compositions that differ from overall composi- dilution, the Wilson equation in Table 2.9 becomes
tions is illustrated for an overall, equimolar, binary solution in ln g1
1 ¼ 1 ln L12 L21 ð2-80Þ
Figure 2.13, from Cukor and Prausnitz [38]. About a central
molecule of type 1, the local mole fraction of type 2 mole- ln g1
2 ¼ 1 ln L21 L12 ð2-81Þ
cules is shown to be 5/8, while the overall composition is 1/2.
For local-volume fraction, Wilson proposed If temperatures corresponding to g1 1
1 and g2 are not close or
equal, (2-76) and (2-77) should be substituted into (2-80) and
i ¼ yiL xi expðlii =RT Þ
F ð2-75Þ (2-81)—with values of (l12 l11) and (l12 l22) deter-
PC mined from estimates of pure-component liquid molar vol-
yjL xj exp lij =RT
j¼1 umes—to estimate L12 and L21.
When the data of Sinor and Weber [35] for n-hexane/etha-
where energies of interaction lij ¼ lji , but lii 6¼ ljj . Follow- nol, shown in Figure 2.12, are plotted as a y–x diagram in
ing Orye and Prausnitz [36], substitution of the binary form ethanol (Figure 2.14), the equilibrium curve crosses the 45
of (2-75) into (2-65) and defining the binary interaction line at x ¼ 0.332. The temperature corresponding to this
parameters as composition is 58 C. Ethanol has a normal boiling point
of 78.33 C, which is higher than the boiling point of 68.75 C
y2L ðl12 l11 Þ
L12 ¼ exp ð2-76Þ
y1L RT
1.0

y1L ðl12 l22 Þ
L21 ¼ exp ð2-77Þ 1 atm
y2L RT 0.8
leads to an equation for a binary system:

yethyl alcohol
gE
0.6 45° line
¼ x1 ln ðx1 þ L12 x2 Þ x2 ln ðx2 þ L21 x1 Þ ð2-78Þ
RT Equilibrium
0.4
The Wilson equation is effective for dilute compositions
where entropy effects dominate over enthalpy effects. The
Orye–Prausnitz form for activity coefficient, in Table 2.9, 0.2
follows from combining (2-59) with (2-78). Values of Lij < 1
correspond to positive deviations from Raoult’s law, while
0
values > 1 signify negative deviations. Ideal solutions result 0 0.2 0.4 0.6 0.8 1.0
xethyl alcohol
when Lij ¼ 1. Studies indicate that lii and lij are tempera-
ture-dependent. Values of yiL/yjL depend on temperature Figure 2.14 Equilibrium curve for n-hexane/ethanol.
C02 09/29/2010 Page 59
for n-hexane. Nevertheless, ethanol is more volatile than n- 14:696

hexane up to an ethanol mole fraction of x ¼ 0.322, the mini- gE ¼ ¼ 2:348
6:26
mum-boiling azeotrope. This occurs because of the close
14:696
boiling points of the two species and the high activity coeffi- gH ¼ ¼ 1:430
10:28
cients for ethanol at low concentrations. At the azeotropic
composition, yi ¼ xi; therefore, Ki ¼ 1.0. Applying (2-69) to Substituting these values together with the above corresponding val-
both species, ues of xi into the binary form of the Wilson equation in Table 2.9 gives
ln 2:348 ¼ lnð0:332 þ 0:668LEH Þ
g1 Ps1 ¼ g2 Ps2 ð2-82Þ
LEH LHE
þ0:668
0:332 þ 0:668LEH 0:332LHE þ 0:668
If pure species 2 is more volatile Ps2 > Ps1 , the criteria for
ln 1:430 ¼ ln ð0:668 þ 0:332LHE Þ
formation of a minimum-boiling azeotrope are
LEH LHE
g1 1 ð2-83Þ 0:332
0:332 þ 0:668LEH 0:332LHE þ 0:668
g2 1 ð2-84Þ Solving these two nonlinear equations simultaneously, LEH ¼ 0.041
and LHE ¼ 0.281. From these constants, the activity-coefficient
g1 Ps2 curves can be predicted if the temperature variations of LEH and LHE
and < ð2-85Þ
g2 Ps1 are ignored. The results are plotted in Figure 2.15. The fit of experi-
mental data is good except, perhaps, for near-infinite-dilution condi-
for x1 less than the azeotropic composition. These criteria tions, where g1 1
E ¼ 49:82 and gH ¼ 9:28. The former is considerably
are most readily applied at x1 ¼ 0. For example, for the greater than the value of 21.72 obtained by Orye and Prausnitz [36]
n-hexane (2)/ethanol (1) system at 1 atm when the liquid- from a fit of all data points. A comparison of Figures 2.12 and 2.15
phase mole fraction of ethanol approaches zero, the tem- shows that widely differing g1 E values have little effect on g in the
region xE ¼ 0.15 to 1.00, where the Wilson curves are almost identi-
perature approaches 68.75 C (155.75 F), the boiling point
cal. For accuracy over the entire composition range, data for at least
of pure n-hexane. At this temperature, Ps1 ¼ 10 psia (68.9
three liquid compositions per binary are preferred.
kPa) and Ps2 ¼ 14:7 psia (101.3 kPa). Also from Figure
2.12, g1 1
1 ¼ 21:72 when g2 ¼ 1.0. Thus, g1 =g2 ¼ 21:72,
s s
but P2 =P1 ¼ 1:47. Therefore, a minimum-boiling azeotrope The Wilson equation can be extended to liquid–liquid or
will occur. vapor–liquid–liquid systems by multiplying the right-hand
Maximum-boiling azeotropes are less common. They side of (2-78) by a third binary-pair constant evaluated from
occur for close-boiling mixtures when negative deviations experimental data [37]. However, for multicomponent sys-
from Raoult’s law arise, giving gi < 1.0. Criteria are derived tems of three or more species, the third binary-pair constants
in a manner similar to that for minimum-boiling azeotropes. must be the same for all binary pairs. Furthermore, as shown
At x1 ¼ 1, where species 2 is more volatile, by Hiranuma [40], representation of ternary systems
g1 ¼ 1:0 ð2-86Þ
g1
2 < 1:0 ð2-87Þ 40
g1 Ps 1 atm
and 2
< 1s ð2-88Þ 30
g1 P2 Experimental data
20 Wilson equation
For azeotropic binary systems, interaction parameters L12 (constants from
and L21 can be determined by solving (4) of Table 2.9 at the azeotropic condition)
azeotropic composition, as shown in the following example.
10
9
8
γ 7
6
EXAMPLE 2.8 Wilson Constants from 5
γ ethanol γ n-hexane
Azeotropic Data. 4
From measurements by Sinor and Weber [35] of the azeotropic con- 3

dition for the ethanol (E)/n-hexane (H) system at 1 atm (101.3 kPa,
14.696 psia), calculate L12 and L21. 2
Solution
The azeotrope occurs at xE ¼ 0.332, xH ¼ 0.668, and T ¼ 58 C 1.0
0 0.2 0.4 0.6 0.8 1.0
(331.15 K). At 1 atm, (2-69) can be used to approximate K-values. xethanol
Thus, at azeotropic conditions, gi ¼ P=Psi . The vapor pressures at
Figure 2.15 Liquid-phase activity coefficients for ethanol/n-hexane
58 C are PsE ¼ 6:26 psia and PsH ¼ 10:28 psia. Therefore,
system.
C02 09/29/2010 Page 60
involving only one partially miscible binary pair can be 3. aji ¼ 0.40 for saturated hydrocarbons and homolog
extremely sensitive to the third binary-pair Wilson constant. perfluorocarbons (e.g., n-hexane/perfluoro-n-hexane).
For these reasons, the Wilson equation is not favored for 4. aji ¼ 0.47 for alcohols or other strongly self-associated
liquid–liquid systems. species with nonpolar species (e.g., ethanol/benzene);
carbon tetrachloride with either acetonitrile or nitro-
§2.6.7 NRTL Model methane; water with either butyl glycol or pyridine.
The nonrandom, two-liquid (NRTL) equation developed by
Renon and Prausnitz [41, 42], given in Table 2.9, represents §2.6.8 UNIQUAC Model
an extension of Wilson’s concept to multicomponent liquid–
liquid, and vapor–liquid–liquid systems. It is widely used for In an attempt to place calculations of activity coefficients on
liquid–liquid extraction. For multicomponent vapor–liquid a more theoretical basis, Abrams and Prausnitz [43] used sta-
systems, only binary-pair constants from binary-pair experi- tistical mechanics to derive an expression for excess free
mental data are required. For a multicomponent system, the energy. Their model, UNIQUAC (universal quasichemical),
NRTL expression is generalizes an analysis by Guggenheim and extends it to
molecules that differ in size and shape. As in the Wilson and
2 0 13
P
C P
C NRTL equations, local concentrations are used. However,
tji Gji xj
C 6 B x t G
k kj kj C7
j¼1 X 6 xj Gij B k¼1 C7
rather than local volume fractions or local mole fractions,
ln gi ¼ C þ 6C Btij C C7 UNIQUAC uses local area fraction uij as the primary concen-
P j¼1
4 P @ P A5
Gki xk Gkj xk Gkj xk tration variable.
k¼1 k¼1 k¼1 The local area fraction is determined by representing a
ð2-89Þ molecule by a set of bonded segments. Each molecule is
characterized by two structural parameters determined rela-

where Gji ¼ exp aji tji ð2-90Þ tive to a standard segment, taken as an equivalent sphere of a
unit of a linear, infinite-length, polymethylene molecule. The
The coefficients t are given by two structural parameters are the relative number of seg-
ments per molecule, r (volume parameter), and the relative
gij gjj surface area, q (surface parameter). These parameters, com-
tij ¼ ð2-91Þ
RT puted from bond angles and bond distances, are given for
many species by Abrams and Prausnitz [43–45] and Gmeh-
gji gii ling and Onken [39]. Values can also be estimated by the
tji ¼ ð2-92Þ
RT group-contribution method of Fredenslund et al. [46].
For a multicomponent liquid mixture, the UNIQUAC
where the double-subscripted g values are energies of model gives the excess free energy as
interaction for molecule pairs. In the equations, Gji ¼6 Gij, tij
gE X C
Ci Z XC
ui
¼
6 tji, Gii ¼ Gjj ¼ 1, and tii ¼ tjj ¼ 0. Often (gij gjj) and ¼ xi ln þ qi xi ln
other constants are linear in temperature. For ideal solutions, RT i¼1
x i 2 i¼1
C i
t ji ¼ 0. ! ð2-93Þ
X C XC
The parameter aji characterizes the tendency of species qi xi ln ui T ji
j and i to be distributed nonrandomly. When aji ¼ 0, local i¼1 j¼1
mole fractions equal overall solution mole fractions. Generally, The first two terms on the right-hand side account for combi-
aji is independent of temperature and depends on molecule natorial effects due to differences in size and shape; the last
properties similar to the classifications in Tables 2.7 and 2.8. term provides a residual contribution due to differences in
Values of aji usually lie between 0.2 and 0.47. When intermolecular forces, where
aji > 0.426, phase immiscibility is predicted. Although aji can x i ri
be treated as an adjustable parameter determined from experi- Ci ¼ C ¼ segment fraction ð2-94Þ
P
mental binary-pair data, commonly aji is set according to the x i ri
i¼1
following rules, which are occasionally ambiguous:
x i qi
1. aji ¼ 0.20 for hydrocarbons and polar, nonassociated u¼ ¼ area fraction ð2-95Þ
P
C
species (e.g., n-heptane/acetone). xi qi
i¼1
2. aji ¼ 0.30 for nonpolar compounds (e.g., benzene/ where Z ¼ lattice coordination number set equal to 10, and
n-heptane), except fluorocarbons and paraffins; non- u u
ji ii
polar and polar, nonassociated species (e.g., benzene/ T ji ¼ exp ð2-96Þ
acetone); polar species that exhibit negative deviations RT
from Raoult’s law (e.g., acetone/chloroform) and mod- Equation (2-93) contains two adjustable parameters for each
erate positive deviations (e.g., ethanol/water); mixtures binary pair, (uji uii) and (uij ujj). Abrams and Prausnitz
of water and polar nonassociated species (e.g., water/ show that uji ¼ uij and Tii ¼ Tjj ¼ 1. In general, (uji uii) and
acetone). (uij ujj) are linear functions of absolute temperature.
C02 09/29/2010 Page 61
If (2-59) is combined with (2-93), the activity coefficient groups; (4) predictions can be made over a temperature range
for a species in a multicomponent mixture becomes: of 275–425 K and for pressures to a few atmospheres; and
C R (5) extensive comparisons with experimental data are availa-
lngi ¼ ln gi þ ln gi
X C ble. All components must be condensable at near-ambient
¼ ln Ci =xi þ Z=2 qi ln ui =Ci þ l i Ci =xi xj l j conditions.
j¼1 The UNIFAC method is based on the UNIQUAC equation
|fflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflffl{zfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflffl}
C; combinatorial
(2-97), wherein the molecular volume and area parameters
2 0 13 are replaced by
X ðiÞ
6 ! r ¼ v k Rk ð2-99Þ
C B C7 i
6 X C X B uj T ij C7 k
þ qi 6 61 ln uj T ji B
BX C
C7
C7 X ðiÞ
4 j¼1 j¼1 @ A5 qi ¼ vk Qk ð2-100Þ
uk T kj k
k¼1 ðiÞ
|fflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflffl{zfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflffl} where vk is the number of functional groups of type k in
R; residual
molecule i, and Rk and Qk are the volume and area parame-
ð2-97Þ ters, respectively, for the type-k functional group.
The residual term in (2-97), which is represented by ln gRi ,
Z is replaced by the expression
where lj ¼ rj aj rj 1 ð2-98Þ X ðiÞ
2 ðiÞ
ln gRi ¼ vk ln Gk ln Gk ð2-101Þ
For a mixture of species 1 and 2, (2-97) reduces to (6) in k
|fflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflffl{zfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflfflffl}
Table 2.9 for Z ¼ 10. all functional groups in mixture
where Gk is the residual activity coefficient of group k, and

ðiÞ
Gk is the same quantity but in a reference mixture that con-
§2.6.9 UNIFAC Model
tains only molecules of type i. The latter quantity is required
ðiÞ
Liquid-phase activity coefficients are required for design pur- so that gRi ! 1:0 as xi ! 1.0. Both Gk and Gk have the same
poses even when experimental equilibria data are not availa- form as the residual term in (2-97). Thus,
ble and the assumption of regular solutions is not valid 2 ! 3
because polar compounds are present. For such situations, X X um T mk
ln Gk ¼ Qk 41 ln um T mk P 5 ð2-102Þ
Wilson and Deal [47], and then Derr and Deal [48], in the m m
un T nm
1960s presented estimation methods based on functional n
groups instead of molecules. In a solution of toluene and ace- where um is the area fraction of group m, given by an equa-
tone, the contributions might be 5 aromatic CH groups, 1 aro- tion similar to (2-95),
matic C group, and 1 CH3 group from toluene; and 2 CH3
Xm Q
groups plus 1 CO carbonyl group from acetone. Alterna- um ¼ P m ð2-103Þ
tively, larger groups might be employed to give 5 aromatic X n Qm
n
CH groups and 1 CCH3 group from toluene; and 1 CH3 group where Xm is the mole fraction of group m in the solution,
and 1 CH3CO group from acetone. As larger functional
P ðjÞ
groups are used, the accuracy increases, but the advantage of vm xj
the group-contribution method decreases because more j
Xm ¼ P P ð2-104Þ
ðjÞ
groups are required. In practice, about 50 functional groups vn xj
represent thousands of multicomponent liquid mixtures. j n
For partial molar excess free energies, gEi , and activity
and Tmk is a group interaction parameter given by an equa-
coefficients, size parameters for each functional group and
tion similar to (2-96),
interaction parameters for each pair are required. Size param- a
mk
eters can be calculated from theory. Interaction parameters T mk ¼ exp ð2-105Þ
are back-calculated from existing phase-equilibria data and T
used with the size parameters to predict properties of mix- where amk 6¼ akm. When m ¼ k, then amk ¼ 0 and Tmk ¼ 1.0.
ðiÞ
tures for which data are unavailable. For Gk , (2-102) also applies, where u terms correspond to
The UNIFAC (UNIQUAC Functional-group Activity the pure component i. Although Rk and Qk differ for each
Coefficients) group-contribution method—first presented by functional group, values of amk are equal for all subgroups
Fredenslund, Jones, and Prausnitz [49] and further developed within a main group. For example, main group CH2 consists
by Fredenslund, Gmehling, and Rasmussen [50], Gmehling, of subgroups CH3, CH2, CH, and C. Accordingly,
Rasmussen, and Fredenslund [51], and Larsen, Rasmussen, aCH3 ;CHO ¼ aCH2 ;CHO ¼ aCH;CHO ¼ aC;CHO
and Fredenslund [52]—has advantages over other methods in
that: (1) it is theoretically based; (2) the parameters are Thus, the experimental data required to obtain values of amk
essentially independent of temperature; (3) size and binary and akm and the size of the corresponding bank of data for
interaction parameters are available for a range of functional these parameters are not as great as might be expected.
C02 09/29/2010 Page 62
The group-contribution method was improved by the liquid phases. Single liquid phases can exist only for cyclo-
introduction of a modified UNIFAC method by Gmehling hexane-rich mixtures of x1 ¼ 0.8248 to 1.0 and for metha-
et al. [51], referred to as UNIFAC (Dortmund). For mixtures nol-rich mixtures of x1 ¼ 0.0 to 0.1291. Because a coexisting
having a range of molecular sizes, they modified the combi- vapor phase exhibits one composition, two coexisting liquid
natorial part of (2-97). For temperature dependence they phases prevail at opposite ends of the dashed line in Figure
replaced (2-105) with a three-coefficient equation. These 2.16. The liquid phases represent solubility limits of metha-
changes permit reliable predictions of activity coefficients nol in cyclohexane and cyclohexane in methanol.
ð1Þ ð1Þ ð2Þ ð2Þ
(including dilute solutions and multiple liquid phases), heats For two coexisting liquid phases, giL xi ¼ giL xi must
of mixing, and azeotropic compositions. Values of UNIFAC hold. This permits determination of the two-phase region in
(Dortmund) parameters for 51 groups have been available in Figure 2.16 from the van Laar or other suitable activity-co-
publications starting in 1993 with Gmehling, Li, and Schiller efficient equation for which the constants are known. Also
[53] and more recently with Wittig, Lohmann, and Gmehling shown in Figure 2.16 is an equilibrium curve for the binary
[54], Gmehling et al. [92], and Jakob et al. [93]. mixture at 55 C, based on data of Strubl et al. [56]. At this
higher temperature, methanol and cyclohexane are miscible.
The data of Kiser, Johnson, and Shetlar [57] show that phase
§2.6.10 Liquid–Liquid Equilibria
instability ceases to exist at 45.75 C, the critical solution
When species are notably dissimilar and activity coefficients temperature. Rigorous methods for determining phase
are large, two or more liquid phases may coexist. Consider instability and, thus, existence of two liquid phases are based
the binary system methanol (1) and cyclohexane (2) at 25 C. on free-energy calculations, as discussed by Prausnitz et al.
From measurements of Takeuchi, Nitta, and Katayama [55], [4]. Most of the semitheoretical equations for the liquid-
van Laar constants are A12 ¼ 2.61 and A21 ¼ 2.34, corre- phase activity coefficient listed in Table 2.9 apply to liquid–
sponding, respectively, to infinite-dilution activity coeffi- liquid systems. The Wilson equation is a notable exception.
cients of 13.6 and 10.4 from (2-72). Parameters A12 and A21 The NRTL equation is the most widely used.
can be used to construct an equilibrium plot of y1 against x1
assuming 25 C. Combining (2-69), where Ki ¼ yi /xi, with
§2.7 DIFFICULT MIXTURES
XC
P¼ xi giL Psi ð2-106Þ The equation-of-state and activity-coefficient models in §2.5
i¼1 and §2.6 are inadequate for estimating K-values of mixtures
gives the following for computing yi from xi: containing: (1) polar and supercritical (light-gas) compo-
x1 g1 Ps1 nents, (2) electrolytes, (3) polymers and solvents, and (4) bio-
y1 ¼ ð2-107Þ macromolecules. For these difficult mixtures, special models
x1 g1 Ps1 þ x2 g2 Ps2
are briefly described in the following subsections. Detailed
Vapor pressures at 25 C are Ps1 ¼ 2:452 psia (16.9 kPa) and discussions are given by Prausnitz, Lichtenthaler, and de
Ps2 ¼ 1:886 psia (13.0 kPa). Activity coefficients can be com- Azevedo [4].
puted from the van Laar equation in Table 2.9. The resulting
equilibrium is shown in Figure 2.16, where over much of
§2.7.1 Predictive Soave–Redlich–Kwong (PSRK)
the liquid-phase region, three values of x1 exist for a given
y1. This indicates phase instability with the formation of two
Model
Equation-of-state models are useful for mixtures of nonpolar
1.0 and slightly polar compounds. Gibbs free-energy activity-
coefficient models are suitable for liquid subcritical nonpolar
y1, mole fraction methanol in vapor
and polar compounds. When a mixture contains both polar

0.8
compounds and supercritical gases, neither method applies.
To describe vapor–liquid equilibria for such mixtures, more
55°C
0.6 theoretically based mixing rules for use with the S–R–K and
P–R equations of state have been developed. To broaden the
25°C range of applications of these models, Holderbaum and
0.4 Gmehling [58] formulated a group-contribution equation of
state called the predictive Soave–Redlich–Kwong (PSRK)
model, which combines the S–R–K equation of state with
0.2
UNIFAC. To improve the ability of the S–R–K equation to
predict vapor pressure of polar compounds, they make the
0
pure-component parameter, a, in Table 2.5 temperature de-
0 0.2 0.4 0.6 0.8 1.0 pendent.To handle mixtures of nonpolar, polar, and super-
x1, mole fraction methanol in liquid critical components, they use a mixing rule for a that
Figure 2.16 Equilibrium curves for methanol/cyclohexane. includes the UNIFAC model for nonideal effects. Pure-com-
[Data from K. Strubl, V. Svoboda, R. Holub, and J. Pick, Collect. Czech. ponent and group-interaction parameters for use in the PSRK
Chem. Commun., 35, 3004–3019 (1970).] model are provided by Fischer and Gmehling [59]. In
C02 09/29/2010 Page 63
§2.8 Selecting an Appropriate Model 63
particular, [58] and [59] provide parameters for nine light of water and two polymers [e.g., polyethylene glycol (PEG)
gases in addition to UNIFAC parameters for 50 groups. and dextran] or one polymer (e.g., PEG) and a salt (e.g.,
K2SO4, Na2SO4, and KCl). At equilibrium, the aqueous top
phase is enriched in PEG and depleted in dextran or salt,
§2.7.2 Electrolyte Solution Models
while the aqueous bottom phase is depleted in PEG and
Solutions of electrolytes are common in the chemical and enriched in dextran or a salt. When an ATPS is dilute in bio-
biochemical industries. For example, sour water, found in chemical solutes, they partition between the two aqueous
many petroleum plants, consists of water and five dissolved phases, leaving the phase equilibria for the ATPS essentially
gases: CO, CO2, CH4, H2S, and NH3. Because of dissocia- unaltered. Therefore, the design of an ATPE separation
tion, the aqueous solution includes ionic as well as molecular requires a phase diagram for the ATPS and partition coeffi-
species. For sour water, the ionic species include Hþ, OH, cients for the biochemical solutes. As discussed in §8.6, ter-
HCO3, CO3=, HS, S=, NH4þ, and NH2COO, with the nary phase diagrams, similar to Figure 8.44, for over 100
positive and negative ions subject to electroneutrality. For ATPSs have been published. Also, partition coefficients have
example, while the apparent concentration of NH3 in the been measured for a number of biomolecules in several
solution might be 2.46 moles per kg of water, the molality is ATPSs, e.g., Madeira et al. [89]. When the ternary phase dia-
0.97 when dissociation is taken into account, with NH4þ hav- gram and/or the partition coefficients are not available, they
ing a molality of 1.49. All eight ionic species are nonvolatile, may be estimated by methods developed by King et al. [90]
while all six molecular species are volatile to some extent. and Haynes et al. [91].
Calculations of vapor–liquid equilibrium for multicomponent
electrolyte solutions must consider both chemical and physi-
§2.8 SELECTING AN APPROPRIATE MODEL
cal equilibrium, both of which involve liquid-phase activity
coefficients. Design or analysis of a separation process requires a suitable
Models have been developed for predicting activity coeffi- thermodynamic model. This section presents recommenda-
cients in multicomponent systems of electrolytes. Of particu- tions for making at least a preliminary selection.
lar note are those of Pitzer [60] and Chen and associates The procedure includes a few models not covered in this
[61, 62, 63] , both of which are included in process simula- chapter but for which a literature reference is given. The pro-
tion programs. Both models can handle dilute to concentrated cedure begins by characterizing the mixture by chemical
solutions, but only the model of Chen and associates, which types: Light gases (LG), Hydrocarbons (HC), Polar organic
is a substantial modification of the NRTL model, can handle compounds (PC), and Aqueous solutions (A), with or without
mixed-solvent systems. Electrolytes (E) or biomacromolecules (B).
If the mixture is (A) with no (PC), and if electrolytes are
present, select the modified NRTL equation. Otherwise,
§2.7.3 Polymer Solution Models
select a special model, such as one for sour water (containing
Polymer processing commonly involves solutions of solvent, NH3, H2S, CO2, etc.) or aqueous amine solutions.
monomer, and soluble polymer, thus requiring vapor–liquid If the mixture contains (HC), with or without (LG), for a
and, sometimes, liquid–liquid phase-equilibria calculations, wide boiling range, choose the corresponding-states method
for which activity coefficients of all components are needed. of Lee–Kesler–Pl€ocker [8, 65]. If the HC boiling range is
In general, the polymer is nonvolatile, but the solvent and not wide, selection depends on the pressure and tempera-
monomer are volatile. When the solution is dilute in the poly- ture. The Peng–Robinson equation is suitable for all tem-
mer, activity-coefficient methods of §2.6, such as the NRTL peratures and pressures. For all pressures and noncryogenic
method, are suitable. Of more interest are mixtures with temperatures, the Soave–Redlich–Kwong equation is appli-
appreciable concentrations of polymer, for which the meth- cable. For all temperatures, but not pressures in the critical
ods of §2.5 and §2.6 are inadequate, so, special-purpose region, the Benedict–Webb–Rubin–Starling [5, 66, 67]
models have been developed. One method, which is available method is viable.
in process simulation programs, is the modified NRTL model If the mixture contains (PC), selection depends on
of Chen [64], which combines a modification of the Flory– whether (LG) are present. If they are, the PSRK method is
Huggins equation (2-65) for widely differing molecular size recommended. If not, then a liquid-phase activity-coefficient
with the NRTL concept of local composition. Because Chen method should be chosen. If the binary interaction coeffi-
represents the polymer with segments, solvent–solvent, sol- cients are not available, select the UNIFAC method, which
vent–segment, and segment–segment binary interaction should be considered as only a first approximation. If the
parameters are required. These are available from the litera- binary interaction coefficients are available and splitting into
ture and may be assumed to be independent of temperature, two liquid phases will not occur, select the Wilson or NRTL
polymer chain length, and polymer concentration. equation. Otherwise, if phase splitting is probable, select the
Aqueous two-phase extraction (ATPE) is a nondenaturing NRTL or UNIQUAC equation.
and nondegrading method for recovering and separating large All process simulators have expert systems that chose
biomolecules such as cells, cell organelles, enzymes, lipids, what the program designers believe to be the optimal thermo-
proteins, and viruses from fermentation broths and solutions dynamic package for the chemical species involved. How-
of lysed cells. An aqueous two-phase system (ATPS) consists ever, since temperature, composition, and pressure in the
C02 09/29/2010 Page 64
various processing units vary, care must be taken to use the which can vary with temperature and ionic strength; (2)
expert system correctly. charge(s)—positive or negative; (3) interactions with solu-
tion components such as metal ions or chelating agents; (4)
solubility and expense; and (5) interference with analytical
§2.9 THERMODYNAMIC ACTIVITY OF
methods.
BIOLOGICAL SPECIES Simple monovalent (n ¼ 1) buffers in aqueous solution
Effective bioseparations economically and reliably recover yield an uncharged form of weak acid, HA, after proton addi-
active biological product. Common petrochemical separation [69,70]:
tions (e.g., distillation) occur by creating or adding a second H2 O þ HA À H3 Oþ þ A ð2-108Þ
phase, often a vapor. This is seldom possible with bioproduct
separations, since most small molecules, polymers, and par- or a charged form, HBþ, after proton addition to an
ticulates of biological origin are unstable in the vapor phase. uncharged weak base, B:
Thermodynamics of bioseparations thus focuses on molecu- H2 O þ HBþ À H3 Oþ þ B ð2-109Þ
lar ionization states, interactions, and forces at physiologic
conditions rather than the state of a continuous fluid phase.
Biological activity is influenced by (1) solution conditions Acid-ionization constant
(e.g., pH buffering, ionization, solubility); (2) biocolloid In practice, buffers and biological species are commonly
interactions (e.g., van der Waals interactions, electrostatic employed in complex solutions at dilutions sufficient to eval-
forces, solvation forces, and hydrophobic effects); and (3) uate activity coefficients at unity and to neglect deviation in
biomolecule reactions (e.g., actions of proteases, nucleases, water concentration away from 55.5 mol/L, M, in calculating
lipases; effects of divalent cations, metals, chelating agents; pH. Apparent acid-ionization constants (i.e., apparent equili-
rate/equilibrium of enzyme/substrate interactions and de- brium constants) are rarely distinguished from true equili-
activation). Understanding these interrelated influences brium constants by using the Debye–H€uckel limiting law or
allows an engineer to (1) choose effectively between alterna- its extensions to calculate activity coefficients. Use of dilute
tive bioseparation process options and (2) optimize opera- buffers allows rearranging the expression for the equilibrium
tional parameters of a selected bioseparation operation to constant, Kc, for proton dissociation in order to write the acid
maintain activity of target biological species. ionization constant, Ka, for an uncharged weak acid as
Solution conditions, biocolloid interactions, and bio-
molecule reactions affect separation of bioproducts by ½Hþ ½A
extraction (§8.6), membranes (§14.8), electrophoresis K a ¼ K c ½H2 O ¼ ð2-110Þ
½HA
(§15.8), adsorption (§15.3), and crystallization (§17.11). In
this section are important fundamental concepts upon which Similarly, the Ka for an uncharged base is
discussion in these later sections will be based. Biological
suspensions contain a large number of complex biochemical ½Hþ ½B
species and are often incompletely specified. Therefore, the K a ¼ K c ½H2 O ¼ ð2-111Þ
½HBþ
application of fundamental principles is balanced in practice
with relevant experience from similar systems and careful
Adding a small volume of simple, dilute, weak acid (acetic
attention to detail.
acid, 1 M) or weak base (Tris, 1 M) to a well-stirred pro-
tein solution, for example, allows its pH to be adjusted
§2.9.1 Solution Conditions between 5 and 8 in the presence of buffering salts with mini-
Effects of temperature, ionic strength, solvent, and static mal risk of inactivation. Acetic acid, CH3COOH, is an impor-
charge on pH buffering impact biological stability as well as tant weak biochemical acid responsible for vinegar’s pungent
chromatographic adsorption and elution, membrane selectiv- odor. It is excreted from bacteria such as Acetobacter and
ity and fouling, and precipitation of biological molecules and Clostridium which oxidize vinegar from ethanol and sugar
entities. substrates during food spoilage. Acetic acid has a measured
K c ¼ 3:19 107 . By comparison, the ion product for the
dissociation of water, Kw, at 25 C is
pH buffers
K w ¼ ½Hþ ½OH ¼ 1:0 1014 ð2-112Þ
Controlling pH by adding a well-suited buffer to absorb (or
release) protons produced (or consumed) in biochemical re-
actions is important to maintain activity of biological prod- Determining pKa, pH, and ionization
ucts (e.g., to preserve catalytic activity). For example,
reducing pH to <5.0 is sufficient to dissociate the rigid, 80- Small values of Kc are typical, and so Ka is conveniently
nm icosahedral protein coat of adenovirus, a nonenveloped, expressed in logarithmic form as
165 MDalton double-stranded DNA (dsDNA) virus used as a
viral vector for gene therapy [68]. Suitability is determined pK a ¼ logðK a Þ ð2-113Þ
by several buffer attributes: (1) acid-ionization constant,
C02 09/29/2010 Page 65
§2.9 Thermodynamic Activity of Biological Species 65
Substituting (2-110) or (2-111) into (2-113) and using the charge is zero), for an amino acid can be determined. This is
definition of pH, illustrated in Example 2.9 and Exercises 2.25 and 2.26.
pH ¼ logðHþ Þ ð2-114Þ
EXAMPLE 2.9 Net Charge on an Amino Group.
yields, upon rearrangement, the Henderson–Hasselbalch The amino acid glycine has hydrogen as its side-chain (R) group.
equation Values of pK ca ¼ 2:36 and pK aa ¼ 9:56 have been previously
reported for glycine. Superscripts c, a, and s refer to a-carboxylic
½basic form acid, a-amino base, and side chain, respectively. Using these values,
pH ¼ pK a þ log ð2-115Þ
½acid form determine the net charge on the a-amino group of glycine at a phys-
iologic pH of 7.2 and a pH of 3 [70].
which gives the pH of a solution containing both forms of a
buffer. The pK of an acid or base is the pH at which it is half- Solution
dissociated, which corresponds to the inflection point in a The ionization reactions for glycine are:
titration curve.
low pH pH 7 high pH
Equation (2-115) allows the ratio of ionized basic form þ K ca þ K aa
H3 N CH2 CO2 H !þ H3 N CH2 CO !þ H2 N CH2 CO
(A) to un-ionized acid form (HA) of a weak acid buffer to glycinium
þ
H =þH
2
glycine
þ
H =þH
2
glycinate
cation zwitterion cation
be determined using a measured pH and a known value of
pKa (and, similarly, for a weak base ionized acid —HBþ— The fraction of a-carboxylic groups present as glycine zwitterions
and un-ionized basic—B—forms). with net neutral charge is obtained by rearranging (2-115) to obtain
the deprotonation ratio:
Determining pI and net charge ½A

¼ 10ðpHpK a Þ
c
ð2-116Þ
½HA
Amino acids each contain a primary –COOH that ionizes at
pH 2 to 3 and a primary –NH2 group that ionizes at pH 8 The corresponding fraction of the protonated a-carboxylic group
present as glycinium cation is then:
to 10. In some cases another ionizable group appears on a
side chain. Amino acids exist mostly as zwitterions, which ½HA 1
¼ ð2-117Þ
contain both acidic and basic groups (i.e., amphoteric) across ½HA þ ½A 1 þ 10ðpHpK ca Þ
a wide range of pH values that brackets a physiologic value This fraction is equivalent to the magnitude of the fractional charge
of 7.4. Zwitterions buffer solutions at high pH by releasing of the amino group. To obtain the net charge, multiply the fraction
Hþ, as well as at low pH by accepting Hþ. Table 2.11 lists pK by the unit charge of þ1. At a physiologic pH of 7.2, this gives þ1.4
values for a-carboxylic acid, a-amino base, and the ionizable 105. In other words, there are 14 glycinium cations with pro-
side chain (if present) on representative amino acids. tonated a-amino groups and a net molecular charge of þ1 for every
Using the base-to-acid ratio in (2-115) for a-carboxylic 106 glycine zwitterions in solution. At a pH of 3, the net charge in-
acid, a-amino base, and side-chain groups, the net charge at creases to 1.9 101—nearly 2 glycinium cations with protonated
a given pH and isolectric point, pI (i.e., pH at which net a-amino groups and net positive charge per 10 amphoteric glycines.
An analogous development for net charge on a-carboxylic acid
shows that the isoelectric point, pI, of an amino acid with a nonio-
nizing side group is (see Exercise 2.25):
Table 2.11 pK Values of Some Amino Acids,
pK ca þ pK aa
R-CðNH2 ÞðHÞ-COOH pHzero- net- charge ¼ pI ¼ ð2-118Þ
2
pK Values (25 C)
Protein pI values are similar to those of the predominant constituent
Amino Acid a-COOH group a-NH3+ group Side chain amino acid residue and are almost always <7.0 (anionic at physio-
logic pH). Exact calculation of protein pI using (2-118) is precluded
Alanine 2.3 9.9 by complex factors that influence ionizability. Ionization of one
Glycine 2.4 9.8 amino acid group in a polypeptide chain, for example, affects ion-
Phenylalanine 1.8 9.1 ization of functional groups farther along the same chain. Tertiary
Serine 2.1 9.2 structure, desolvation, and post-translational modifications also
Valine 2.3 9.6 influence ionizability.
Aspartic acid 2.0 10.0 3.9
Glutamic acid 2.2 9.7 4.3
Histidine 1.8 9.2 6.0 pKa criterion for buffer selection
Cysteine 1.8 10.8 8.3
Tyrosine 2.2 9.1 10.9
Equation (2-115) and corresponding acid/base titration
Lysine 2.2 9.2 10.8
curves show that the pH of solution changes less per proton
Arginine 1.8 9.0 12.5
absorbed (or released) as [basic form] approaches [acid
form]. For this reason, it is preferable to (1) use a buffer
Source: Stryer [69]. whose pKa is 0.5 unit of desired pH—on the () side if
C02 09/29/2010 Page 66
acidification is anticipated, or on the (+) side for expected for small values of standard-state entropy of dissociation,
basification; and (2) prepare the buffer with equal portions of DSo. This decreases pKa as T increases, viz.
acid and basic forms. A constant value of targeted pH is
d log K a DH o
maintained by selecting from among buffers such as MES, ¼ ð2-122Þ
dT 2:3RT 2
2-(N-morpholino) ethanesulfonic acid (pKa ¼ 6.8); inorganic
orthophosphate (pKa ¼ 7.2); HEPES, N-hydroxyethylpipera- The value of DSo depends mainly on the number of H2O
zine-N’-2-ethanesulfonic acid (pKa ¼ 6.8); or Tris, tris molecules that hydrate dissolved species, a process that pro-
(hydroxymethyl) amino-methane (pKa ¼ 8.3). duces order in a solution. Dissociation of amine buffers (e.g.,
Tris; n ¼ þ1), for example, yields no net formation of
Ionic strength effects charged ions, so entropy increases slightly—DSo ¼ 5.7 J/
mol-K—and the free-energy change is absorbed by DHo.
Values of pKa change more with buffer concentrations in solu- Equation (2-122) thus shows that pKa decreases substantially
tions of multivalent buffers like phosphate or citrate than in upon heating. On the other hand, physiologic buffers, acetic
simple monovalent buffers like acetate or Tris. The amount of acid (n ¼ 1) and sodium phosphate (n ¼ 3), dissociate to
change is indicated by the simplified Debye–H€uckel equation form two new charged ions. This orders surrounding water
0:5nI 1=2 molecules and significantly decreases entropy:
pK a ¼ pK 0a þ ðat 25 CÞ ð2-119Þ DSo ¼ 90.5 J/mol-K for acetic acid and DSo ¼ 122 J/
1 þ 1:6I 1=2 mol-K for phosphoric acid at pK2. Therefore, DHo changes
where I represents ionic strength, given by less for acetic and phosphoric acid buffers, which exhibit rel-
atively constant pKa values upon heating. This preserves cell
1X and organism viability.
I¼ ci ð zi Þ 2 ð2-120Þ
2 i
Freezing
where ci ¼ concentration of ionic species i, which has charge zi;
pK 0a represents a value of pKa in (2-119) extrapolated to I ¼ 0; Lowering the temperature of biological samples in order to
and n ¼ 2z 1 for a given charge (valence) z on the acid buffer slow microbial growth and preserve enzymatic activity can
form. Examples of ionic strength effects on buffers with repre- significantly change local pH and solute concentrations dur-
sentative values of pK 0a , n, and z are illustrated in Table 2.12. ing phase changes [71]. Free water freezes first, growing ice
Note that the value of n in (2-119) is always odd and crystals that destroy membrane layers and organelles and
increases pKa as ionic strength is increased only when the locally concentrating electrolytes and biocolloids, which pre-
acid form of the buffer has valence þ1 or higher. cipitates insoluble salts, changes pH, increases osmolarity,
and depresses local freezing point. Proteins are left largely
intact, so freeze-thaw cycles are used to lyse mammalian
Temperature effects cells to release intracellular proteins and propagated virus.
Increasing temperature, T, decreases the pKa value of a Any dissolved salt crystallizes as temperature approaches its
buffer. Tris buffer provides an extreme example: its pKa in eutectic point. Freezer temperatures between 15 and
solution at 37 C physiologic conditions is 1 pH unit lower 25 C allow protease and nuclease degradation at reduced
than at 4 C (on ice). Heating increases a buffer’s standard- rates. Consequently, flash freezing to 80 C and rapid thaw-
state free energy, DGo, in proportion to the value of pKa: ing without local overheating preserves cell viability and
enzymatic activity more effectively than freezing to about
DGo ¼ DH o TDSo ¼ RT ln K a ¼ 2:3RT ðpK a Þ ð2-121Þ
20 C in a conventional freezer.
Equation (2-121) shows that the standard-state enthalpy of
dissociation, DHo, likewise increases with pKa, particularly
EXAMPLE 2.10 Preparation of Phosphate-Buffered
Saline (PBS).
Table 2.12 Effect of Ionic Strength on pKa of Some
Phosphate-buffered saline (PBS) finds wide usage in biological proc-
Characteristic Buffers
essing, formulation, and research. Its pKa and ionic strength mimic
pKa pKa physiologic conditions and maintain pH across temperature changes
Common acid form z n pKa0 I = 0.01 I = 0.1 expected in biological systems (4–37 C). PBS contains sodium chlo-
ride, sodium phosphate, and (in some formulations) potassium chlo-
Tris HCl, 1 1 8.06 8.10 8.16 ride and potassium phosphate at osmolarity (the concentration of
ClH+NH2C(CH2OH)3 osmotically active particles in solution) and ion concentrations that
acetic acid, CH3COOH 0 1 4.76 4.72 4.66 match those in the human body (isotonic). One common formulation
monobasic sodium 1 3 7.2 7.08 6.89 is to prepare 10-liter stock of 10 PBS by dissolving 800 g NaCl,
phosphate, NaH2PO4 20 g KCl, 144 g Na2HPO42H2O, and 24 g KH2PO4 in 8 L of distilled
disodium citrate 2-hydrate, 2 5 6.4 6.29 5.88 water, and topping up to 10 L. Estimate the pH of this solution in its
HOC(COOH) concentrated form when stored at 4 C, after being diluted to 1 PBS
(CH2COONa)22H2O at 4 C, and after being warmed to 37 C.
C02 09/29/2010 Page 67
Solution to the extent that KHA > MHþ. Relative to a solubility value
reported for pure water, STpH¼7 , the pH effect on total solubil-
The ionic strength of the 10 PBS solution is
2 3 ity is given by
800g 2
2 ð 1Þ
1X 16
6 58:44g/mol 10L 7
7 1 þ 10ðpK HA pHÞ
I¼ ci ðzi Þ2 ¼ 6 7 ¼ 1:396 ST ðpHÞ ¼ STpH¼7 ð2-126Þ
2 i 24 20g 25 1 þ 10ðpK HA 7Þ
þ2 ð 1Þ
74:55g/mol 10L
Similarly, the total solubility of a partially soluble weak base
The effect of ionic strength on pKa from Table 2.12 using the simpli- that ionizes according to
fied Debye–H€uckel equation (2-119) is
0:5ð3Þð1:396Þ1=2
BOH À Bþ þ OH ð2-127Þ
pK a ¼ 7:2 þ ¼ 6:59
1 þ 1:6ð1:396Þ1=:2 with an ionization constant given by
o
Using DH ¼ 4.2 kJ/mol for monobasic phosphate, decreasing tem- ½Bþ ½OH
K BOH ¼ ð2-128Þ
perature increases pKa according to ½BOH
4200 Jmol1 relative to solubility in water is
pK 277K
a ¼ pK 298K
a
ð2:3Þ8:314 Jmol1 K1 ð287:5 KÞ2
ð277 298Þ 1 þ 10ðpK BOH þpHpK W Þ
ST ðpHÞ ¼ STpH¼7 ð2-129Þ
¼ 6:59 þ 0:06 ¼ 6:65 1 þ 10ðpK BOH þ7pK W Þ
Using MW for the mono- and dibasic phosphate salts of 178.0 g/mol It can be shown that the total solubility of a zwitterionic
and 136.1 g/mol, respectively, the pH of a solution with the given amino acid relative to water solubility is given by
masses is, using (2-115), h i

1 þ 10ðpK a pHÞ þ 10ðpHpK a Þ
a c
144
178 10 ST ðpHÞ ¼ STpH¼7 h i
1 þ 10ðpK a 7Þ þ 10ð7pK a Þ
a c
pH ¼ pK a þ log ¼ 7:31
24
136:1 10 ð2-130Þ
After 10 dilution, I ¼ 0.1396, a¼ 6:85,
pK 298 K
¼ 6:91,
pK 277
a
K
and pH ¼ 7.57.
After increasing T to a physiologic value of 310 K, pK 310
a
K
¼ EXAMPLE 2.11 Effect of pH on Solubility
6:82, and pH ¼ 7.48. in Biological Systems.
Upon dilution, the resultant 1 PBS at physiologic conditions
has a final concentration of 137 mM NaCl, 10 mM phosphate, and As an example of solubility of weak organic acids, bases, and zwit-
2.7 mM KCl, at a pH near that of arterial blood plasma, pH ¼ 7.4. terions in biological systems, prepare total solubility curves for the
following species across a broad pH range ( pH ¼ 1 to pH ¼ 11).
1. Caprylic acid (C8H16O2) is an oily, naturally occurring liquid

pH affects solubility in coconuts that has anti-fungal and anti-bacterial properties.
Its water solubility is 0.068 g/100 g at 20 C with a value of
Water solubility of ionized species is high. An uncharged or pKa ¼ 4.89.
undissociated weak acid, HA, exhibits partial solubility,
2. Thymidine (T, C5H6N2O2, 5-methyluracil) is a pyrimidine base
So. In a solution saturated with undissolved HA, the partial that forms two hydrogen bonds with adenine (A) to stabilize
solubility is dsDNA. Its water solubility is 4.0 g/kg at 25 C and its pKBOH
So ¼ M HA ð2-123Þ is 9.9 (neglect further dissociation that occurs at higher pH).
3. The hydrophobic amino acid valine (C5H11NO2), which substi-
where Mi represents molality (moles of solute per kg solvent) tutes for hydrophilic glutamic acid in hemoglobin, causes mis-
of component i. Total solubility, ST, the concentration of both folding, which results in sickle-cell anemia. Its water solubility
undissociated and ionized acid is given by is 8.85 g/100 mL at 25 C. Its ionization constants are pK ca ¼
2:3 and pK ca ¼ 9:6.
ST ¼ M HA þ M A ¼ So þ M A ð2-124Þ
Calculate the solubility of each component in the following
Substituting the relations for MA and MHA given by (2-123) bodily fluids: cell cytosol, pH ¼ 7.2; saliva, pH ¼ 6.4; urine,
and (2-124), respectively, into the corresponding terms in the pH ¼ 5.8.
Henderson–Hasselbalch equation (2-115) and solving for ST
provides total solubility in terms of pH: Solution

K HA The solubilities are calculated from (2-126) for the acid, (2-129) for
ST ðpHÞ ¼ So 1 þ 10½pK HA pH ¼ So 1 þ ð2-125Þ
M Hþ the base, and (2-130) for the zwitterion. In (2-130), the pK for water
is computed to be 14 from (2-129). Table 2.13 shows solubility val-
Equation (2-125) shows that solubility of a weak acid in- ues in each bodily fluid. Figure 2.17 shows extended, calculated
creases above the partial solubility of its undissociated form solubility curves for each component. Caprylic acid solubility
C02 09/29/2010 Page 68
eluent buffered at pH 5.5 may be denatured upon purification

Table 2.13 Solubility of Organic Acid, Base, and Amino
Acid in Bodily Fluids
by cation exchange adsorption on media whose local pH is
4.5. On the other hand, since most enzymes are anionic (pI <
Solubilities (g/kg) 7.0) and remain stable at mildly alkaline conditions (pH ¼ 8–
10), fewer problems occur in anion exchange purification.
Fluid: pH Caprylic acid Thymidine Valine
Protein elution from ion-exchange media can produce sud-
Cell cytosol: 7.2 1.07 4.00 88.6
den, large, local pH changes, particularly at low ionic
Saliva: 6.4 0.175 4.01 88.3
strength, which decreases resolution of closely related spe-
Urine: 5.8 0.0478 4.07 88.3
cies. On the other hand, some ion-exchange adsorbents like
DEAE and some proteins may provide significant local buff-
10000 ering capacity. Donnan effects thus affect selection of opera-
Caprylic acid
tional pH ranges of ion-exchange adsorption separations.
1000 Thymidine
Valine
100 Applications to Bioseparations

Solubility, g/kg
In solvent selection (§8.6.1, ‘‘Organic-Aqueous Extraction of

10
Bioproducts’’), it is shown how pH, I, T, and ST affect the
state of a bioproduct (e.g., pI) to influence its solvent parti-
1
tion coefficient, KD (e.g., see Eq. 8-82) and guide selection
0.1
of a suitable solvent for liquid–liquid extraction. The charge
on bioproducts affects rejection and passage through ultra-
0.01
filtration membranes (see §14.8.3) and determines adsorptive
partitioning in ion-exchange chromatography (see §15.3.3).
0.001 Interactions between pH and bioproduct isoelectric points
2 4 6 8 2 are the basis for bioproduct separation using different modes
pH for electrophoresis, distinguished in §15.8.2.
Figure 2.17 Solubility curves for caprylic (biological acid),
thymidine (base), and valine (zwitterion) acids.
§2.9.2 Biocolloid Interactions
Biological polymers, macromolecular species, and cells
increases at pH pKa. Thymidine solubility increases at pOH ¼ exhibit many features of colloids—0.001 to 1.0 mm parti-
log[OH] ¼ 14 pH pKBOH. Valine exhibits solubility increases cles that interact via long-range hydrophobic, electrostatic,
at pH pKaa and pOH pKac. Reduced water solubility at the pI of and van der Waals forces, which arise from colloid size and
a biomolecule may be used for selective precipitation or for extrac- accessible surface features [72, 73]. Such forces contrast with
tion into a less-polar phase. Effect of pH on bioproduct solubility is short-range hydrogen bonding and dipole-dipole interactions,
further illustrated in Examples 8.13 and 8.14 of §8.6.1. Pharmaceu- which originate from electron orbitals of chemical functional
tical formulation for drug delivery requires good understanding of groups on biocolloid surfaces and occur at separations
solubility. approximately the length of a chemical bond. Separation dis-
tances and bond energies of interactions between biocolloids
are summarized in Table 2.14. Colloid forces impact
Solvent effects
Adding miscible organic solvents increases pKa values of ace-
Table 2.14 Bond Energies and Separation Distances of
tate, phosphate, and other buffers with negative n values by
Biomolecular Interactions
reducing activity of water, which causes resistance to proton
dissociation. For example, the pKa of phosphate increases 1 pH Equilibrium Bond Energy
unit upon increasing the volumetric content of ethanol from 0 Interaction Separation (nm) (kJ/mol)
to 50%. On the other hand, values of pKa for buffers like Tris,
Ionic bond 0.23 580–1050
which have positive n values, are only slightly affected.
Covalent bond 60–960
Metallic bond 105–355
Static charges (Donnan effects) Ion–dipole interaction 0.24 84
Static negative (positive) charges attract (repel) protons, pro- Dipole–dipole 0.28 5–30
ducing an adjacent micro-environment with lower (higher) (hydrogen bond) (0.18–0.30)
interaction
pH—the Donnan effect. For example, porous cation
Dipole-induced dipole <21
exchange media used for adsorptive biochromatography (see
interaction
§15.3.3) has a pH in the matrix about 1 unit lower than that in
Hydrophobic 0.30 4.0
the eluting buffer—a difference that increases with decreas-
Dispersion forces 0.33 <42 ( 0.25)
ing buffer ionic strength. An enzyme that remains stable in
C02 09/29/2010 Page 69
dissolution, aggregation, and other interactions between bio-

logical species such as cells, micelles, vesicles, and virus par-
ticles [74]. For example, Allison and Valentine [75, 76]
reported binding of fowl plague and vaccinia virus to sus-
pended HeLa cells at one-third the rate predicted by Fick’s
first and second laws of diffusion, due to electrostatic repul-
sion. The impact of colloid forces on biomolecular interac-
tion affects properties in many bioseparations, including
salting out effects in precipitation (see §17.11), particle
aggregation in flocculation, solute mobility in electrophoresis
(see §15.8.3), and charge dependence in phase partitioning
(e.g., liquid–liquid extraction in §8.6 and liquid–solid
adsorption in §15.3), and filtration in Chapter 19.
Consider the forces that contribute to the double-helix
structure of DNA. Covalent bonds link adjacent nucleotides
in each individual DNA strand. Hydrogen bonds between
nucleotide bases (Watson–Crick base pairing) and van der
Waals’ interactions between stacked purine and pyrimidine
bases hold the two complementary DNA strands in a helix
together. Relatively hydrophobic nucleotide bases are buried Figure 2.18 Potential energy between two like-charged particles.
in the helical interior, while charged phosphate groups and
polar ribose sugars solvate dsDNA in aqueous solutions.
Electrostatic interactions between adjacent negatively
charged backbone phosphates are minimized by the extended
backbone. arise from intrinsically high-area colloid surfaces that
Cyclic manipulation of noncovalent force interactions by encourage (1) adsorption of ions; (2) molecular ionization on
precise, consecutive, temperature adjustments—a technique the surface, which leaves behind a surface charge; and/or
called polymerase chain reaction (PCR)—allows a specific (3) dissolution of ions from the solid into the suspending liq-
gene fragment (template) to be amplified for purposes such uid [78].
as gene sequencing or analysis of genetic mutations. In PCR, The Gouy–Chapman theory postulates that an electro-
complementary DNA strands are thermally denatured (sepa- static potential, cE(r), forms at a surface with uniformly dis-
rated) at 94 C and then annealed to 21 base-pair complemen- tributed charge and decays exponentially away with distance,
tary primer strands at 55 C. Primers are subsequently r, due to thermal motion of oppositely charged ions in the
elongated by polymerase at 72 C using dissolved nucleo- adjacent solution
tide base pairs. Repeating this cycle n times allows 2n ampli- CE frg ¼ CE;o expðkrÞ ð2-131Þ
fication of the original DNA template. The forces that bind
DNA and influence other biomolecular interactions originate where cE,o(r) is the potential at the surface and k is the
in colloidal interactions between suspended particles, small Debye–H€uckel constant. An attractive potential cL(r) arises
solutes, and solvent molecules. due to long-range induction, orientation, and dispersion
forces (simple systems consider only attractive vdW forces).
Evaluated together, as in Figure 2.18, these potentials yield
DLVO theory
an overall interaction energy curve—c(r)—that exhibits
The theory of Derajaguin and Landau (of Russia) and Vervey two minima: a shallow secondary minimum at r 4/k in
and Overbeek (DLVO) describes attractive forces such as van which colloids remain stably suspended (>5 nm apart at low
der Waals (vdW) interactions and repulsive double-layer I values); and a deep primary minimum associated with rapid
(electrostatic) forces between suspended colloids at approach coagulation. Coagulation results from increasing I such that
distances >2 nm in the limit of low surface potentials free energy due to electrostatic interactions between particles
[77], which occur when an elementary charge on the colloid decreases to kBT, corresponding to particle separations
surface has a potential energy kBT (the thermal energy k1, the Debye length.
scale), where kB is the Boltzmann constant. Potential energy,
c(r), between two like-charged colloids separated by dis-
Electrostatic double-layer interactions
tance r is the sum of attractive vdW and repulsive electro-
static forces. Coulomb’s law holds that the force of electrical Colloid surface charges form an electrical double layer that sur-
interaction between two charged particles varies directly with rounds ionic charged particles and exerts electrostatic forces on
the product of their charges and inversely to the square of the adjacent colloids when their double layers overlap [80]. To
distance between them, r2. Adjacent colloids are repelled— maintain electrical neutrality, a charged surface dissolved in a
thereby stabilizing colloid suspensions—by net respective medium attracts hydrated ions of opposite charge (counter-
surface charges (same sign) of 30–40 mV. These charges ions), which become strongly bound, forming an inner Stern
C02 09/29/2010 Page 70
(or Helmholtz) layer of thickness, d. A less-homogeneous, dif- to 1–3 nm at physiologic conditions normally found in bio-
fuse outer shell of moderately bound Gouy (or Gouy–Chapman) logical fluids (0.01 < ci < 0.2 M).
second-layer ions is comprised of hydrated ions of alternat-
ing charge. An external electric current will move the hy-
EXAMPLE 2.12 Colloidal Forces of Dissolved
drated ions in the Gouy layer toward the electrode, forming
Biomolecules.
a line of shear between fixed counterions and migrating
ions. The measurable difference in electro-kinetic potential Colloidal forces on dissolved biomolecules affect their separability.
between the fixed boundary layer of charges on a surface and Selection of appropriate molecular-weight cut-off values for an
the shear line of mobile charges in the bulk of the solution ultrafiltration bioseparation requires accurate estimation of bioprod-
is the zeta potential (or Stern potential), z. It indicates the uct size (see §14.8.3). Determine the concentration of a 1:1 salt
fixed-charge density unsatisfied by counterions in the Stern in moles/dm3 below which the apparent radius of bovine serum
layer and the corresponding distance into the solution albumin (BSA) is more than 10% larger than its actual radius of
a ¼ 3.6 nm.
required to satisfy it. That distance, the Debye length, k1,
or double-layer thickness, may be estimated with the Debye–
Solution
H€uckel approximation for modest surface potentials (Co <
25 mV) as For a 1:1 salt, ionic strength, I, in (2-133) reduces to c in mol/dm3.
1=2 The apparent radius (a þ k1) of a molecule is significantly differ-
1 2000e2 N A I ent from its actual radius a if k1/a > 0.1. Substituting this expres-
¼ ð2-132Þ
k ekB T sion into (2-137) and solving for c in mol/dm3 yields
2
in an electrolyte or colloid dispersion, where NA is Avoga- 3:05 109
c< ð2-138Þ
dro’s number. The ionic strength, I, is given by (2-120) for ci a
(Mi) in mol/dm3 (M) for a in meters. Therefore, the apparent radius of BSA is greater
than its actual radius, a ¼ 3.6 109 m, if salt concentration is less
1X 2
I¼ z Mi ð2-133Þ than 0.72 M.
2 i i
The static permittivity for zero wavelength, e, of the medium

Van der Waals forces
is given by
Instantaneous quantum fluctuations in charge distribution of
12 C2
e ¼ er eo ¼ 78:54 8:85 10 ð2-134Þ one molecule distort the electron cloud in a neighboring
Jm atom or molecule to induce momentary polarization, and
for water, using the relative static permittivity, er, of H2O at vice versa, resulting in short-range attraction between the
25 C (commonly called the dielectric constant) and the elec- transient dipole moments [82]. The cumulative effect is van
tric constant, eo (i.e., vacuum permittivity, eo ¼ m1 2
o co ,
der Waals (vdW), or London dispersion forces. Between
where mo is a magnetic constant and co is speed of light in a atoms, these forces act over distances that are of the order of
vacuum). The Boltzmann constant, kB, is atomic dimensions, while between colloids, they are of the
order of colloid dimensions. vdW forces are responsible for
kB ¼ 1:381 1023J=K molecule ð2-135Þ phase transitions (e.g., condensation of gas to liquid) and
interfacial tension between adjacent phases, reaching up to
The charge on an electron, e, is
10 mN/m at 1 nm separations. The potential energy of
e ¼ 1:60 1019 coulomb ð2-136Þ interaction, WD, via dispersion forces between two identical
atoms separated by distance r is
The dielectric constant measures how much a material re-
duces the magnitude of an electric field. At 25 C for I in l
WD ¼ ð2-139Þ
mol/dm3, this gives [81] r6
where l is a constant parameter of interaction given by
k1 ¼ 3:05 1010 I 1=2 ð2-137Þ
3
in meters. l ¼ a2 hvo ð2-140Þ
4
In practice, it is easier to measure the streaming current
for atom polarizability a and ionization potential hvo. The
potential by anchoring charged particles and moving the
characteristic energy for the quantized energy at frequency
hydrated ions past them than it is to measure z. The Debye
vo constitutes the ionization potential. A single atom that
length decreases as ionic strength increases from 100 A
3
2
1 closely approaches a macroscopic body of volume V pro-
(10 M); 30 A (10 M) to 10 A (10 M) for a 1-1 (mono-
duces an overall dispersion force felt by each atom that is
valent) electrolyte solution. These values are small relative to
estimated by integrating the energy of dispersion, WD,
particle diameter and decrease as zeta potential is lowered.
Z
Repulsive forces are <1 mN/m for spheres with moderate dW D
surface potentials (Co < 100 mV). Electrostatic repulsion F 12 ¼ dV ð2-141Þ
dr
can be felt at up to 60 nm in deionized water, but weakens V
C02 09/29/2010 Page 71
Table 2.15 Interaction Energies for Several Geometries adsorbed into the Stern layer) electrolytes is [84]
Geometry Interaction Energy 9:85 104 e3 k5B T 5 g4
cfi loc ¼ ð2-144Þ
pql N A e6 A2 z6i
Atom—flat body w¼
6r3
A where g is a constant that approaches 1.0 at high potentials
Two flat bodies w¼ (>240 mV) and zecEd/4kBT at low potentials (cEd 75
12pr2
Aa mV), and cfi loc is the lower molar concentration of the electro-
Sphere—flat body w¼ lyte that induces particle coagulation. In water at 25 C, this
6r
Aa1 a2 relation becomes
Two spheres w¼
6rða1 þ a2 Þ
f loc 3:38 1036 J2 -mol-m3 g4
ci ¼ ð2-145Þ
Source: A.A. Garcia et al. [73]. A2 z i 6
with cfi loc in mol/m3 and the Hamaker constant A in J. Equa-
tion (2-145) predicts that the relative values for critical floc-
Potential energies of interaction, w, for more complex geom-
culating concentration of electrolytes such as Kþ, Ca2+, and
etries may be obtained by extending this approach. Table
Al3+ containing counterions with charge numbers z ¼ 1, 2,
2.15 shows values of w for spheres of radius ai, as well as
and 3 will be 1:26:36 or 1000:15.6:1.37 at wall potentials
other superatomic scale geometries. Negative interaction
> 240 mV, where g 1. This is the Schulze–Hardy rule. It is
energies are associated with spontaneous processes.
illustrated by the common practice of settling colloids during
Comparing (2-139) with the interaction energies in Table
water treatment by adding alum, a double salt of aluminum
2.15 shows that dispersion forces decay more slowly as sepa-
and ammonium sulfates, to increase ionic strength.
ration increases for colloidal bodies than for atoms. At sepa-
rations exceeding 10 nm, vdW interaction potential decays
faster than r6 due to retardation by phase difference between
instantaneous dipoles on opposing bodies. The Hamaker con- EXAMPLE 2.13 Temperature, Charge, and Colloid
stant, A, for vdW interactions between body (1) and body (2) Effects on Flocculation by an Electrolyte.
defined by The first step in recovering bioproducts expressed in bacterial fer-
mentation is often removal of aqueous culture broth to reduce
A12 ¼ p lr1 r2
2
ð2-142Þ process volume. Flocculation of bacteria by adding electrolyte
indicates the interaction parameter, l, and respective number enhances settling and broth removal. The ease of flocculation is a
of atoms per unit volume, ri, (i.e., atomic densities) in each function of the electrolyte concentration. Determine the critical
flocculation concentration, cfi loc (in mol/dm3), of an indifferent
body, which determine the attractive force between them. The
1-1 electrolyte at 25 C and low potential. Calculate the effect on cfi loc
moderating influence of a fluid (1) intervening between two
of (a) lowering temperature to 4 C; (b) changing to an indifferent
same bodies (2) may be determined using a pseudo-chemical 2-2 electrolyte at 4 C (maintaining low potential); (c) using electrolyte
model to modify the Hamaker constant in part (b) to flocculate a viral colloid at 1/10 the concentration; and
2 (d) flocculating at high potential.
1=2 1=2
A212 ¼ A11 A22 ð2-143Þ
Solution
Values of the Hamaker constant vary only slightly from one med-
ium to another: 4.3 1020 J for water, 7.8 to 9.8 1020 J At 75 mV,

for polystyrene, and 8.6 1020 J for natural rubber [83]. zeCEd ð1Þ 1:6 1019 C ð0:075VÞ
g ¼ ¼ ¼ 0:7295
4kB T 4 1:38 1023 J=K ð298KÞ

Colloid flocculation by electrolytes 3:38 1036 J2 mol m3 ð0:7295Þ4 m3
cfi loc ¼ ¼ 0:15 M
8 1020 J ð1Þ6 1000 dm3
Like-charged electrostatic double layers and lubrication
forces inhibit close approach of repellant surfaces and associ-
ation due to London dispersion or vdW forces. On the other 277
(a) cfi loc ð277 CÞ ¼ cfi loc ð298 CÞ ¼ 0:14 M
hand, surfaces with oppositely charged z values are adherent. 298
Addition of ions (electrolyte salts or hydronium ions) to a 277 1
(b) cfi loc ð277 C; 2 2Þ ¼ cfi loc ð298 C; 1 1Þ ¼ 0:035 M
colloid suspension structures the waters, attenuates the zeta 298 ð2Þ2
potential, reduces the Debye length, and allows closer
approach of like-charged surfaces, while reducing adherence (c) DLVO theory and (2-145) indicate that while critical electrolyte
of oppositely charged double layers. Coulombic repulsive flocculation concentration is sensitive to temperature and elec-
trolyte valence, it is independent of colloid particle size or
forces dominate until the distance separating two surfaces is
concentration.
reduced sufficiently (i.e., to r 4/k) for attractive forces to
be asserted. DLVO theory predicts that the critical flocculat- (d) Equation (2-145) indicates that at high potential, cfi loc is propor-
tional to T6 and z6 rather than to T and z2, respectively, at low
ing electrolyte concentration, ci, for symmetric (e.g., 1:1,
potential.
2:2, 3:3, but not 1:2, etc.), indifferent (not chemically
C02 09/29/2010 Page 72
Protein aggregation, crystallization, and adsorption have structures reduce interfacial area and surface free energy of
been shown to be controlled by long-range DLVO forces. hydrocarbon–water systems as they assemble, minimizing
However, nonclassical DLVO forces due to solvation, and hy- entropy (maximizing degrees of freedom) and maximizing
drodynamic and steric interactions also influence protein enthalpy (from hydrogen bonding). This process drives
interactions—generally at short range and with magnitudes attraction of nonpolar groups in aqueous solution via forces
up to the order of several kBT—by altering biomolecular up to 100 mN/m at separations <3 nm, culminating in phase
association rates or enhancing stability of protein complexes. separation. Hydrophobic interactions allow formation of
reverse micelles (§8.6.1) into which bioproducts partition for
subsequent extraction. Other biological examples of hydro-
Solvation or hydration forces
phobic interactions include aggregation of mycobacteria to
At separation distances closer than 3 to 4 nm, continuum form cords and clustering of hydrophobic protein patches
DLVO forces based on bulk properties of intervening solvent due to side chains of phenylalanine (Phe), tyrosine (Tyr),
(e.g., density, dielectric constant, refractive index) give way tryptophan (Trp), leucine (Leu), isoleucine (Ile), methionine
to non-DLVO forces that account for structures formed by (Met), and valine (Val). Hydrophobic forces between macro-
individual solvent molecules at solid interfaces based on their scopic surfaces are one to two orders of magnitude greater
discrete size, shape, and chemistry. Normal to a surface and than vdW attraction, decaying exponentially with a character-
within several molecular diameters, solvent molecules form istic length of 1–2 nm in the range 0–10 nm and remaining
ordered layers. Attractive interactions between the surface significant at distances up to 80 nm. Hydrophobicity scales
and liquid molecules and the constraining effect of an developed for amino acids are useful to explain protein parti-
approaching surface, which squeezes one layer after another tioning in liquid–liquid extraction (see ‘‘Reverse Micelles’’
out of the closing gap, cause desolvation (‘‘lubrication’’) in §8.6.1 and ‘‘Salt Effect’’ in §8.6.2), retention order, and
forces between the surfaces, FSOL (known as hydration, hy- retention time in reversed-phase and hydrophobic-interaction
drodynamic, or drainage forces when the solvent is water). chromatography.
These are decaying oscillatory functions of separation dis-
tance, D, for spherical molecules between two hard, smooth
Structuring water, kosmotropes and chaotropes
surfaces
Hydrophobic forces are influenced by biomolecule structures
D
F SOL fDg ¼ Kexp ð2-146Þ and the nature of dissolved ionic and nonionic species.
l
Hydrophobic interactions are increased by dispersion forces
where K > 0 and K < 0 relate to hydrophilic repulsion and between planar surfaces (i.e., stacking) of aromatic groups in
hydrophobic attraction forces, respectively, and l is the corre- aromatic amino acids, purines or pyrimidines, chlorophyll,
lation length of orientational ordering of water molecules. and haem, for example. Small or multiple-charged ionic kos-
Equation (2-146) explains short-range forces measured motropes (‘‘order-maker,’’ e.g., citrate, sulfate, phosphate,
between neutral lipid bilayer membranes, DNA polyelec- hydroxide, magnesium, and calcium) interact more strongly
trolytes, and charged polysaccharides that are relatively with water than water itself. This enhances formation of
insensitive to ionic strength. Polar solvent molecules like water structure, stabilizes biomolecule structures in solution,
water that intervene between adjacent colloids form head-to- and promotes hydrophobic interactions like aggregation.
tail (positive-to-negative) conduit chains of partial charge Large, singly charged ions with low charge density, called
interactions that can either attenuate forces between charged chaotropes (e.g., guanidinium, tetramethylammonium, and
colloids or increase the effective distance of typically short- thiocyanate), interact weakly with water and disrupt water
range ion–ion or acid–base interactions. structure formation, which solvates hydrophobic structures
Molecular dipoles align in an orientation that opposes and unfolds amphipathic proteins, which have interior
(and thereby diminishes) the originating electric field. Water regions rich in nonpolar characteristics as well as polar func-
dipoles also surround charged ions (e.g., electrolytic salt mol- tional groups on the exterior. Chaotropic ions like octylme-
ecules) and displace ionic bonds, solvating the individual thylammonium chloride enhance aqueous/organic extraction
ions. Long-range (>10 nm) hydrophobic effects are also pro- (§8.6.1) of polar zwitterions like amino acids.
duced by water molecules. Nonionic kosmotropes including zwitterions (e.g., proline,
ectoine, glycine, betaine) and polyhydroxy compounds (e.g.,
trehalose) hydrogen-bond strongly to water (e.g., sugar
Hydrophobic interactions
hydration). This reduces availability of water freely diffusing
The free energy of attraction of water for itself due to hydro- around proteins, exchange rates of backbone amide protons,
gen bonding is significant. Hydrophobic (‘‘water-fearing’’) and hydration of larger surfaces exposed by denaturation.
groups restrict the maximum number of energetically favor- Dehydration reduces biomolecule flexibility, which promotes
able hydrogen bonds (i.e., degrees of freedom) available to stability in solution and prevents thermal denaturation, but
adjacent water molecules. Water thus forms ordered and reduces enzymatic activity. Kosmotropic ions and nonionic
interconnected tetrahedral hydrogen-bonded structures that polymers are used to form partially miscible aqueous phases
exclude hydrophobic entities like hydrocarbons or surfaces that allow stable, two-phase aqueous extraction of biomole-
to minimize the number of affected water molecules. These cules (§8.6.2). Nonionic chaotropes (e.g., urea) weaken
C02 09/29/2010 Page 73
hydrogen bonding, decrease the order of water, and increase or exclude proteins from chaotropically disordered (e.g. low-
its surface tension, which weakens macromolecular structure. density) water.
The Hofmeister series Steric forces

The Hofmeister series classifies ions in order of their ability Either repulsive stabilizing or attractive coagulating forces
to change water structure. It was initially developed to rank may be produced by dissolved biopolymers in solution. The
cations and anions in terms of their ability to increase solvent close approach of two surfaces at which polymers are anch-
surface tension and lower solubility of (‘‘salt out’’) proteins ored confines the thermal mobility of dangling chain mole-
[85]: cules, resulting in a repulsive entropic force. Adding
polysaccharides or proteins can sterically stabilize coagula-
Anions: F SO42 > HPO42 > acetate > Cl > tive colloids with a force that depends on surface coverage,
NO
3 > Br > ClO3 > I > ClO4 > SCN

reversibility of anchoring, and solvent. One example is gela-
þ þ þ
Cations: NHþ4 > K > Na > Li > Mg
2+
> Ca2+ > tin, an irreversibly hydrolyzed form of collagen, which con-
guanidinium stitutes 50% of proteins in mammals and is commonly used
as a gelling agent in foods, pharmaceuticals, and cosmetics.
Early ions in the series strengthen hydrophobic interac-
On the other hand, colloid flocculation may be induced by
tions (e.g., ammonium sulfate is commonly used to precipi-
polymeric nonionic or ionic surfactants. Nonionic [nondis-
tate proteins). Later ions in the series increase solubility of
sociating, e.g., polyethylene oxide (PEO), polyethylene gly-
nonpolar molecules, ‘‘salting in’’ proteins at low concentra-
col (PEG)] or ionic [e.g., polyacrylamide and sodium
tions: iodide and thiocyanate, which weaken hydrophobic
dodecylsulfate (SDS)] polymer surfactants may adsorb to
interactions and unfold proteins, are strong denaturants.
and envelope adjacent repellant surfaces via hydrophobic
Effects of pH, temperature, T, and ionic strength, I, of an interactions. This results in steric (or entropic) stabilization,
ionic salt on solubility, S, of a given solute may also be corre-
which can match the potential energy barrier that prevents
lated using
the approach of repellent colloids and induce flocculation.
log S ¼ a K s I ð2-147Þ At the same time, attractive interactions like biomolecular
interactions or affinity adsorption may be buffered or pre-
where Ks is a constant specific to a salt–solute pair and a is a
vented by polymer surfactants. A surfactant may disrupt mu-
function of pH and T for the solute. The relative positions of
tual hydrophobic interactions by masking a hydrophobic
ions in the Hofmeister series change depending on variations
ligand, while the hydrophilic moiety of the surfactant inter-
in protein, pH, temperature, and counterion. Anions typically
acts with water.
have a larger influence. The series explains ionic effects on
38 observed phenomena, including biomolecule denatura-
tion, pH variations, promotion of hydrophobic association,
Surface force measurements of protein interactions
and ability to precipitate protein mixtures. The latter two
phenomena occur in roughly reverse order. Hofmeister rank- Particle detachment and peeling experiments, force-measur-
ing of an ionic salt influences its effect on solvent extraction ing spring or balance, and surface tension and contact angle
of biomolecules, including formation of and partitioning into measurements are used to gauge surface interaction; but
reverse micelles, and lowers partition coefficients, KD, of these conventional methods do not provide forces as a func-
anionic proteins between upper PEG-rich and lower dextran- tion of distance. Scanning force probes [atomic force micros-
rich partially miscible aqueous phases (§8.6.2, ‘‘Aqueous copy (AFM), scanning probe microscopy (SPM)] use
Two-Phase Extraction’’). Table 2.16 orders ions in terms of improved piezoelectric crystals, transducers and stages,
their ability to stabilize protein structure and to accumulate nanofabricated tips and microcantilevers, and photodiode-
Table 2.16 Ability of Cations and Anions to Stabilize Protein Structure
Effect of Ion on Proteins Cations Anions Effect of Ion on Proteins
Protein stabilizing N(CH3)4+ Citrate C3H4(OH)(COO)33 Protein stabilizing

Weakly hydrated NH4+ Sulfate SO42 Strongly hydrated
+
Accumulate in low-density water Cs Phosphate HPO42 Excluded from low-density water
Rb+ Acetate CH3COO

K+ F
Na+ Cl
H+ Br
Protein destabilizing Ca2+ I Protein destabilizing
Strongly hydrated Mg2+ NO3 Weakly hydrated
Excluded from low-density water Al3+ ClO4 Accumulate in low-density water
C02 09/29/2010 Page 74
detectable laser light to measure the accuracy of calculated solvent (water) molecules are displaced from hydrated polar
DLVO and non-DLVO potentials for biological systems. groups on hydrophilic exteriors of water-soluble biomole-
cules. Release of bound water decreases its fugacity and
increases the solvent entropic effect associated with surface
Applications to bioseparations reduction, which contributes to binding energy. Solvent dis-
In §8.6, it is shown how biocolloid interactions that influence placement can make sterically hindered ligands more acces-
solvation, hydrophobicity, water structure, and steric forces sible for interaction through short-range, dipole–dipole, or
can enhance extraction of bioproducts via organic/aqueous charge-transfer forces. Next, conformational adjustments in
and aqueous two-phase extraction. In §14.9.2, it is observed ligand and receptor produce a steric fit (i.e., ‘‘lock-and-key’’
how biocolloid interactions affect membrane selectivity, siev- interaction). Steric effects and redistribution of valence elec-
ing, and prediction of permeate flux. In §15.3.3, effects of trons in the ligand perturbed by solvent displacement pro-
biocolloid interactions on ion-exchange interactions are duce conformational rearrangements that yield a stable
described. Bioproduct crystallization, §17.11, is also affected complex. Rehydration completes the binding process. Meth-
by biocolloid interactions. ods to compute forces that control protein interactions
account for (1) absorbed solvent molecules and ions; (2)
non-uniform charge distributions; (3) irregular molecular sur-
§2.9.3 Biomolecule Reactions faces that amplify potential profiles at dielectric interfaces;
Unique structural features of ligands or their functional (4) shifts in ionization pK’s due to desolvation and interac-
groups allow specific, noncovalent interactions (e.g., ionic tions with other charged groups; and (5) spatially varying
and hydrogen bonding, hydrophobic effects, vdW forces, and dielectric permittivity across the hydration shell between the
steric forces) with complementary structures of target biomo- protein surface and bulk solvent. Interaction with a PEG-
lecules like receptor proteins that result in biochemical coupled ligand may be used to increase selective partitioning
reactions, which sustain viability of cells. These interactions of a target biomolecule into an upper PEG-rich phase during
typically operate over short (<2 nm) intermolecular dis- aqueous two-phase extraction (§8.6.2).
tances with binding energies associated with noncovalent
bond formation, typically >4kBT. Examples include: (1) Ionic interactions
immunologic recognition of a specific region (epitope) on a
Ionic interactions between a net charge on a ligand and coun-
foreign substance (antigen) by protein immunoglobulins
terions in the receptor have high dissociation energies, up to
(antibodies); (2) regulation of gene expression by protein
103 kJ/mol. As an example, amino groups RNH3þ , protonated
transcription factors that bind to control regions of DNA with at physiologic pH on lysine [R ¼ (CH2)4; pK ¼ 10.5], or argi-
high-affinity domains (motifs), such as zinc finger, leucine nine [R ¼ (CH2)3NHCNH; pK ¼ 12.5] can interact with car-
zipper, helix-turn-helix, or TATA box; (3) cell surface recep- boxyl groups, R’COO, on ionized aspartate (R’ ¼ CH2; pK ¼
tor (e.g., ion-channel, enzyme-linked, and g-protein linked 3.9) or glutamate [R’ ¼ (CH2)2; pK ¼ 4.2] forms of aspartic
receptor classes) binding to chemical substances (ligands) acid and glutamic acid, respectively. Hard (soft) acids form
secreted by another cell in order to transduce cell-behavior- faster and stronger ionic bonds with hard (soft) bases. Hard
modifying signals; and (4) specific binding of a mono- acids (e.g., Hþ, Naþ, Kþ, Ti4þ, Cr3þ) and bases (e.g., OH,
saccharide isomer by a carbohydrate-specific lectin—a pro- Cl, NH3, CH3COO, CO2 3 ) are small, highly charged ions
tein with 2+ carbohydrate-binding sites. that lack sharable pairs of valence electrons (i.e., the nucleus
Binding energies of noncovalent interactions require inter- strongly attracts valence electrons precluding their distortion or
molecular proximities on the order of 0.1 nm and contact removal), resulting in high electronegativity and low polariz-
areas up to 10 nm2 (usually 1% of total solvent-accessible ability. Soft acids (e.g., Pt4þ, Pd2þ, Agþ, Auþ) and bases (e.g.,
surface area) for these reactions to occur. Hydrogen bonds
RS, I, SCN, C6H6) are large, weakly charged ions that have
involving polar charged groups, for example, add 2.1 to 7.5
sharable p or d valence electrons, producing low electronegativ-
kJ/mol, or 12.6 to 25.1 kJ/mol when uncharged groups are
ity and high polarizability. Examples of ionic stabilization of
involved. Hydrophobic bonds may generate 10 to 21 kJ/mol/
ligand–biomolecule or intrabiomolecule interactions are bond-
cm2 contact area.
ing between oppositely charged groups (i.e., salt bridges) and
bonding between charged groups and transition-series metal
cations. Example 8.15 in §8.6.1 demonstrates how desolvation
Ligand–receptor binding cascade
via ion-pairing or acid–base pairing of organic extractants can
Recognition and binding of the receptor by a ligand is initi- enhance organic/aqueous extraction of bioproducts.
ated by electrostatic interactions. Solvent displacement and
steric selection follow, after which charge and conforma-
EXAMPLE 2.14 Selection of a Metal for Immobilized
tional rearrangement occur. Rehydration of the stabilized
Metal Affinity Chromatography (IMAC).
complex completes the process. From 20 to 1 nm, the
approach and complementary pre-orientation of ligand and Using the stability constant of metal-ion base complexes in Table
receptor maximize dominant coulombic attractive forces. 2.17, identify an appropriate metal to entrap in the solid phase via
Binding progresses from 10 to 1 nm as hydrogen-bonded
C02 09/29/2010 Page 75
Affinity thermodynamics and equilibrium

Table 2.17 Stability Constants of Metal-Ion Base Complexes
From a thermodynamics perspective, the overall Gibbs free-
Thiourea Histidine
energy change in forming the receptor-ligand complex, DG,
(Log K) (Log K)
consists of free-energy contributions due to water displace-
Soft metal ions Ag+ 7.11 0.07 – ment from receptor and ligand (DGR,L_hydration), receptor-
Cd2+ 1.3 0.1 5.74 ligand interactions (DGRL_interactions), and rehydration of the
Borderline metal ions Cu2+ 0.8# 10.16 0.06 stabilized complex (DGRL_hydration), viz.,
Zn2+ 0.5 6.51 0.06
DG ¼ DGR;L- hydration þ DGRL- interaction þ DGRL- hydration

in aqueous solution: I ¼ 0.1, 25 C ð2-148Þ
#
in aqueous solution: I ¼ 1.0, 25 C
Source: A.A. Garcia et al. [73] The free-energy change contributed by receptor-ligand inter-
actions results from an increase in receptor potential energy
chelation to perform immobilized metal affinity chromatography from a low-energy, unbound state to a high-energy, complex
(IMAC) of thiourea and histidine. state, DUconf, a change in potential energy due to receptor-
ligand interactions in the complex, DURL; and an entropy
Solution change due to receptor-ligand interactions, viz.,
The R-group nitrogen in the amino acid histidine donates an elec- DG2 ¼ DU conf þ DU RL TDS ð2-149Þ
tron pair to borderline soft-metal ions such as Cu2+, Zn2+, Ni2+, or
Co2+ to form a coordination covalent bond that can be displaced This thermodynamic model is supplemented by computa-
upon elution with imidazole. Data in the table suggest Cu2+ > Zn2+ tional chemistry calculations that quantify alterations in
for histidine and Agþ > Cd2+ at the conditions shown. rDNA tech- arrangements of chemical bonds using quantum mechanics
niques can be used to genetically modify target proteins to include and statistical physics. From an equilibrium perspective, bio-
multiples of this amino acid as a tag (His6-tag) on a fusion protein affinity interaction between a ligand, L, and a complemen-
to facilitate purification. tary receptor, R, may be expressed as
kA
R þ L !
RL ð2-150Þ
kD
Amino acid–metal bonds
Nearly all amino acids exhibit affinity for divalent metal ions. where kA and kD are forward (association) and reverse (disso-
Log K-values for interacting amino acids range from 1.3 to ciation) rate coefficients, respectively. Diffusion-controlled
2.4 for Mg2+ and Ca2+, and from 2.0 to 10.2 for Mn2+, Fe2+, binding rates are typically less than 108/s, compared with
Co2+, Ni2+, Cu2+, and Zn2+. Interactions between amino acids diffusion-controlled collision rates of 1010/s, because
and copper generally exhibit the highest log K-values. Histi- spatial localization reduces the probability of binding. Rate
dine and cysteine exhibit the strongest metal affinities. Dou- constants define the equilibrium dissociation constant, KD,

ble-stranded nucleic acids contain accessible nitrogen (i.e., kD ½R½L zR ½RL=½Ro ½L
N7 atom in guanidine and adenine) and oxygen (i.e., O4 KD ¼ ¼ ¼ ð2-151Þ
kA ½RL ½RL=½Ro
atom in thymine and uracil) sites that donate electrons to
metal ions in biospecific interactions. Soft- and borderline- where bracketed terms denote concentrations (unity activity
metal ions generally have stronger affinity for N7 and O4, coefficients have been applied), subscript o represents an ini-
while hard-metal ions have greater affinity for oxygen atoms tial value, and zR is the receptor valency, the number of lig-
in the phosphate groups of nucleic acids. and binding sites per receptor molecule. Reaction
thermodynamics is related to equilibrium by
Hydrogen bonds DG ¼ RT ln K 1
D ð2-152Þ
3
Hydrogen bonds between biomolecules result from electro- Table 2.18 shows values of KD decrease from 10 M for
static dipole–dipole interactions between a hydrogen atom enzyme-substrate interactions to 1015 M for avidin-biotin
covalently bonded to a small, highly electronegative donor complexation.
atom (e.g., amide nitrogen, N) and an electronegative accep-
Scatchard plots
tor (e.g., backbone O or N), which contributes a lone pair of
unshared electrons. Regular spacing of hydrogen-bonded Equilibrium concentration values of L obtained from dialyzing
amino acid groups between positions i and i þ 4 forms an a- a known initial mass of ligand against a number of solutions of
helix protein 2 structure. Hydrogen bonding between alter- known initial receptor concentration may be used to determine
nate residues on each of two participating amino acid strands the dissociation constant and receptor valency by plotting
forms a b-pleated sheet. Tertiary protein structures form in ([RL]/[R]o)/[L] versus [RL]/[R]o in a Scatchard plot, viz.,
part through hydrogen bonding between R-groups. Hydrogen
bonding between G–C and A–T base pairs forms the anti- ½RL=½Ro ½RL=½Ro zR
¼ þ ð2-153Þ
parallel double-helical DNA structure. ½L KD KD
C02 09/29/2010 Page 76
Table 2.18 Dissociation Constants of Some Bioaffinity interaction rate measurements

Bioaffinity Interactions
Quantifying interactions of macromolecules such as DNA, a
Ligand–Receptor Pair KD (M) protein or a virus is important to developing bioseparations,
biocompatible materials, biosensors, medical devices, and
Enzyme-substrate 103 – 105
pharmaceuticals. Intrinsic sorption (i.e., forward and reverse
Lectin-monosaccharide 103 – 105
interaction) rates provide information about specificity, affin-
Lectin-oligosaccharide 105 – 107
ity, and kinetics [86, 87]. Intrinsic sorption rates of macromo-
Antibody-antigen 107 – 1011
lecules including whole virus [88] can be measured by
DNA-protein 108 – 109
surface plasmon resonance (SPR) in label-free methods that
Cell receptor—ligand 109 – 1012
are simpler, faster, and potentially more sensitive than total
Avidin/Streptavidin—biotin 1015
internal reflectance fluorescence (TIRF) or nuclear magnetic
resonance (NMR) spectroscopy. Alternatives for quantitative
sorption rate measurement include quartz crystal micro-
balance/dissipation (QCMD), calorimetry, ellipsometry, and
Inhomogeneous receptor populations with varying affinity val-
voltammetry. SPR has the advantage of providing direct,
ues (i.e., KD) will produce nonlinearity in the plot.
unambiguous measurements to evaluate effects of binding
site and concentration down to subnanomolar analyte levels
EXAMPLE 2.15 Scatchard Analysis of Ligand- without secondary reagents to enhance the signal. SPR
Receptor Binding. measurements are 15 times faster and consume 100-fold
less sample than curve-fitting chromatographic breakthrough
From the Scatchard plot for two antibodies (Ab1 and Ab2) interact- profiles to determine protein sorption rates.
ing with an antigen in Figure 2.19, determine: (a) the respective dis-
sociation constants; (b) the valency for each antibody; and (c) the
homogeneity of population for each antibody.
Applications to bioseparations
8.00
In ‘‘Extractant/diluent Systems’’ (§8.6.1), it is shown how
desolvation via ion pairing or acid–base pairing can enhance
7.00
Ab1 organic/aqueous extraction of bioproducts. Ion pairing and
Ab2 acid–base pairing are also used to enhance selectivity of
6.00
high-performance tangential flow filtration (see §14.9.2) and
biochromatographic adsorption (§15.3.3).
[RL]/[R]o[L]×108
5.00
4.00
SUMMARY
3.00
1. Separation processes are energy-intensive. Energy
requirements are determined by applying the first law of
2.00
thermodynamics. Estimates of irreversibility and mini-
mum energy needs use the second law of thermo-
1.00
dynamics with an entropy or availability balance.
0.00 2. Phase equilibrium is expressed in terms of vapor–liquid
and liquid–liquid K-values, which are formulated in
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
terms of fugacity and activity coefficients.

[RL]/[R]o
3. For separation systems involving an ideal-gas and an
Figure 2.19 Scatchard plot for ligand–receptor interaction. ideal-liquid solution, thermodynamic properties can be
estimated from the ideal-gas law, a vapor heat-capacity
Solution equation, a vapor-pressure equation, and an equation for
Equation (2-153) shows that the slope and intercept of each line cor-
the liquid density.
respond to KD1 and zR=KD, respectively. The dissociation constants 4. Graphical representations of thermodynamic properties
are therefore [(8-0)=(2-0)]1 108 ¼ 0.25 108 M and [(3- are widely available and useful for making manual cal-
0.33)=(1.8-0.2)]1 108 ¼ 0.60 108 M for antibody 1 and 2, culations, and for visualizing effects of temperature and
respectively. These values lie within the range given in Table 2.18 pressure.
for antibody–antigen interactions. From (2-153), the valency values
are 2 for each antibody, meaning each antibody can bind 2 antigens.
5. For nonideal mixtures containing nonpolar components,
Homogeneity of the antibody and receptor preparations is indicated P–y–T equation-of-state models such as S–R–K, P–R,
by the linear data in the Scatchard plot. and L–K–P can be used to estimate density, enthalpy,
entropy, fugacity, and K-values.
C02 09/29/2010 Page 77
References 77
6. For nonideal liquid solutions of nonpolar and/or polar as a function of temperature, ionic strength, solvent, and
components, free-energy models such as Margules, electrostatic interactions.
van Laar, Wilson, NRTL, UNIQUAC, and UNIFAC 9. Evaluating effects of electrolyte and solvent composition
are used to estimate activity coefficients, volume and on electrostatic double layers and forces due to vdW, hyd-
enthalpy of mixing, excess entropy of mixing, and K- rophobic, solvation, and steric interactions allows engi-
values. neering of separation systems that control solubility and
7. Special models are available for polymer solutions, elec- maintain structural stability of biocolloid suspensions.
trolyte solutions, mixtures of polar and supercritical 10. Characterizing noncovalent interaction forces and free-
components, and biochemical systems. energy changes by interpreting measurements using
8. Effects of solution conditions on solubility and recovery applicable theory allows quantitative evaluation of
of active biological products can be quantified by evalu- biospecific interactions in order to enhance biorecovery
ating the ionization of water and organic acids and bases operations.
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STUDY QUESTIONS
2.1. In an energy balance, what are the two most common refer- 2.4. How is the K-value for vapor–liquid equilibria defined?
ences (datums) used for enthalpy and entropy? Does one have an 2.5. How is the distribution coefficient for a liquid–liquid mixture
advantage over the other? defined?
2.2. How does availability differ from Gibbs free energy? 2.6. What are the definitions of relative volatility and relative
2.3. Why is fugacity used in place of chemical potential to deter- selectivity?
mine phase equilibria? Who invented fugacity?
C02 09/29/2010 Page 79
Exercises 79
2.7. What are the two types of models used to estimate thermo- 2.13. What is the critical solution temperature?
dynamic properties? 2.14. Why must electrolyte-solution activity-coefficient models
2.8. What is the limitation of the Redlich–Kwong equation of consider both chemical and physical equilibrium?
state? How did Wilson and Soave modify it to overcome the 2.15. Describe three effects of pH on ionization of a weak acid or
limitation? base that impact biological stability of a protein.
2.9. What is unique about regular-solution theory compared to 2.16. Compare Tris and PBS as buffers in terms of temperature,
other activity-coefficient models for nonideal solutions? (This dif- ionic strength, and solvent effects.
ference makes it much easier to use regular-solution theory when it 2.17. What colloidal features do proteins and DNA exhibit?
is applicable.)
2.18. What is the relation between the Debye length and the zeta
2.10. What are the six most widely used methods for estimating potential?
liquid-phase activity coefficients?
2.19. Describe the role that the following colloidal forces play in
2.11. What very important concept did Wilson introduce in 1964? biomolecular reactions: electrostatic, steric, solvent, hydrogen-
2.12. What is a minimum-boiling azeotrope? What is a maxi- bonding, ionic.
mum-boiling azeotrope? Which type is by far the most 2.20. What is responsible for the large range in values of dissocia-
common? tion constants listed in Table 2.18?
EXERCISES
Section 2.1
2.1. Minimum work of separation. Split Fraction (SF)
A refinery stream is separated at 1,500 kPa into two products
under the conditions shown below. Using the data given, compute Feed, Product Product Product
the minimum work of separation, Wmin, in kJ/h for T0 ¼ 298.15 K. Component lbmol/h 1 2 3
Ethylbenzene 150 0.96 0.04 0.000

p-xylene 190 0.005 0.99 0.005
kmol/h
m-xylene 430 0.004 0.99 0.006
Component Feed Product 1 o-xylene 230 0.00 0.015 0.985
Ethane 30 30
Propane 200 192
n-butane 370 4
n-pentane 350 0 Product Product Product Product
n-hexane 50 0 Feed 1 2 3
Phase condition Liquid Liquid Liquid Liquid

Temperature, F 305 299 304 314
Feed Product 1 Product 2 Enthalpy, 29,290 29,750 29,550 28,320
Btu/lbmol
Phase condition Liquid Vapor Liquid Entropy, 15.32 12.47 13.60 14.68
Temperature, K 364 313 394 Btu/lbmol- R
Enthalpy, kJ/kmol 19,480 25,040 25,640
Entropy, kJ/kmol-K 36.64 33.13 54.84
2.3. Second-law analysis of a distillation.
Column C3 in Figure 1.8 separates stream 5 into streams 6
and 7, according to the material balance in Table 1.5. The sepa-
2.2. Minimum work of separation.
ration is carried out at 700 kPa in a distillation column with 70
In refineries, a mixture of paraffins and cycloparaffins is
plates and a condenser duty of 27,300,000 kJ/h. Using the fol-
reformed in a catalytic reactor to produce blending stocks for gaso-
lowing data and an infinite surroundings temperature T0, of
line and aromatic precursors for petrochemicals. A typical product
298.15 K, compute: (a) the duty of the reboiler in kJ/h; (b) the
from catalytic reforming is ethylbenzene with three xylene isomers.
irreversible production of entropy in kJ/h-K, assuming condenser
If this mixture is separated, these four chemicals can be processed to
cooling water at 25 C and reboiler steam at 100 C; (c) the lost
make styrene, phthalic anhydride, isophthalic acid, and terephthalic
work in kJ/h; (d) the minimum work of separation in kJ/h; and
acid. Compute the minimum work of separation in Btu/h for T0 ¼
(e) the second-law efficiency.
560 R if the mixture below is separated at 20 psia into three
Assume the shaft work of the reflux pump is negligible.
products.

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Chapter 2

Thermodynamics of Separation Operations

§2.0 INSTRUCTIONAL OBJECTIVES

36 Chapter 2 Thermodynamics of Separation Operations

⋅⋅⋅ ⋅⋅⋅ Energy balance:

§2.1 Energy, Entropy, and Availability Balances 37

First law: T = Ts work of separation. The second-law efficiency, therefore, is

Qin Qout EXAMPLE 2.1 Use of Thermodynamic Laws.

Feed (F) Liquid 13,338 4.1683

38 Chapter 2 Thermodynamics of Separation Operations

LW ¼ nF bF þ QR ð1 T 0 =T R Þ where superscript (p) refers to each of N phases. Conserva-

§2.2 Phase Equilibria 39

Table 2.2 Thermodynamic Quantities for Phase Equilibria

Limiting Value for Ideal Gas and

40 Chapter 2 Thermodynamics of Separation Operations

If (2-23) and (2-25) are used, a so-called activity co-

Equation Recommended Application

§2.3 Ideal-Gas, Ideal-Liquid-Solution Model 41

ð1Þ ð2Þ oð2Þ ð2Þ

42 Chapter 2 Thermodynamics of Separation Operations

Vapor–liquid equilibria: The enthalpy of an ideal-liquid mixture is obtained by

§2.3 Ideal-Gas, Ideal-Liquid-Solution Model 43

yL ¼ ð0:4848Þð0:1300Þ þ ð0:5152Þð0:1221Þ ¼ 0:1259 m3 /kmol

44 Chapter 2 Thermodynamics of Separation Operations

§2.4 GRAPHICAL CORRELATIONS OF

§2.5 Nonideal Thermodynamic Property Models 45

Figure 2.3 Vapor pressure as a function of temperature.

46 Chapter 2 Thermodynamics of Separation Operations

Figure 2.4 Vapor–liquid equilibria, 40 to 800 F.

§2.5 Nonideal Thermodynamic Property Models 47

Figure 2.5 Vapor–liquid equilibria, 260 to 100 F.

48 Chapter 2 Thermodynamics of Separation Operations

C1 Equation (2-46), a cubic in Z, can be solved analytically

1.0 The intermediate value of Z is discarded.

Table 2.5 Useful Equations of State

Name Equation Equation Constants and Functions

§2.5 Nonideal Thermodynamic Property Models 49

Solution Following the work of Wilson [21], Soave [6] added a

50 Chapter 2 Thermodynamics of Separation Operations

§2.5.2 Derived Thermodynamic Properties "

Mixture enthalpy: ð2-57Þ

Pure-component fugacity coefficient:

Partial fugacity coefficient: hL

§2.5 Nonideal Thermodynamic Property Models 51

52 Chapter 2 Thermodynamics of Separation Operations

Note that the material balances are always precisely satisfied.

§2.6 Liquid Activity-Coefficient Models 53

where g ¼ h Ts and excess molar free energy is the sum of X

and d is the solubility parameter, which is defined in terms of

54 Chapter 2 Thermodynamics of Separation Operations

§2.6.3 Nonideal Liquid Solutions

1.5 with Flory–Huggins correction

Class Description Example

§2.6 Liquid Activity-Coefficient Models 55

Table 2.8 Molecule Interactions Causing Deviations from Raoult’s Law

Type of Deviation Classes Effect on Hydrogen Bonding

Always negative III þ IV H-bonds formed only

56 Chapter 2 Thermodynamics of Separation Operations

§2.6 Liquid Activity-Coefficient Models 57

Name Equation for Species 1 Equation for Species 2

(1) Margules logg1 ¼ Ax22 logg2 ¼ Ax21

(2) Margules (two-constant) 12 þ 2x1 ðA

Mixtures of self-associated polar molecules (class II in §2.6.6 Local-Composition Concept

Figure 2.12 Activity coefficients for ethanol/n-hexane.

Determining pI and net charge ½A