Physical chemistry

Thermodynamics Kinetics
•  Will something happen, •  How fast will it happen?
and to what extent?

These are fundamentally different issues

A simple example: It is thermodynamically favorable for
diamonds to change in graphite. However, this of course takes
an incredibly long time to happen.

transition
Free energy

You will see later that kinetics

state
is related to this
reactants Thermo only tells you about this
(diamond)
products
(graphite)
 Relevance of Thermodynamics to Pharmacy
Solubility;
Acid-base equilibrium

Binding to macromolecules:
Chemical Equilibrium;
Scatchard Plots; Permeability
Macromolecular forces (Phase Partitioning)

Osmotic pump delivery system

But first it’s critical to understand the basics ... enthalpy, entropy, and free energy.
Introduction to thermodynamics:

The first law, enthalpy, and

calorimetry
 The Power of Thermodynamics
is the power to predict
1) whether something will occur ...
“Something” could be:
•  a drug binding to a protein
•  a drug passing through a
membrane
•  a drug dissolving in aqueous
solution
•  just about anything, really

2) ... or to what extent it will occur

(equilibrium constant K). (if you don’t know these
formulas already, don’t
worry, you’ll see them
again, and again ...)

Note that the central quantity is G, the “free energy”. To understand and
calculate this quantity, we need to understand its components: the
enthalpy H (Chapter 4 in Chang) and the entropy S (Chapter 5).
 Some key parameters in thermodynamics
Pressure
SI units are Pascals, 1 Pa = 1 N/m2
1 bar = 100 kPa
1 atm = 101.325 kPa = 760 Torr

Temperature
Temperature is not trivial to define, and we will come back to it soon, in
the discussion of entropy and the 2nd and 3rd laws of thermodynamics.
But your everyday knowledge of temperature is fine for now.

SI units are Kelvin (first problem solving hint: always use Kelvin, not Celsius!)

Number of Molecules
1 mole = 6.022·1023 molecules (Avogadro’s number)

Volume
Various SI units: m3, 1 L = (1 dm)3 = 10-3 m3, 1 mL = (1 cm)3 = 10-6 m3

ENERGY!
 Energy comes in many different flavors
including gravitational, kinetic, heat, chemical, nuclear, “free energy”, etc.

All of these share the same units:

SI units are Joules, 1 J = 1 N·m

1 calorie (cal) = 4.184 J

In this course, we’re concerned only with a few relevant flavors of energy

U (internal energy)
q (heat)
H (enthalpy)
w (work)
G (free energy)

I’ve divided these into 2 groups like this for a reason. As you’ll see in a
moment, the ones on the left are called “state functions”; they describe the
amount of energy in a molecule, a bucket of water, any “system” you care to
define. The ones on the right describe exchange of energy between the
system and the rest of the universe.
 Intensive vs. Extensive Quantities
These terms sound mysterious, but the concept is pretty simple.

Extensive quantities depend on the amount of the substance being described.

Intensive quantities do not.

Extensive quantities include mass, volume, and energy.

Intensive quantities include temperature, pressure, and density.

Note that extensive quantities can be turned into intensive quantities, by

dividing by the number of moles of the substance.

Extensive Intensive
mass (g) molar weight (g/mol)
volume V (L) molar volume (L/mol)
internal energy U (kJ) molar internal energy (kJ/mol)
enthalpy H (kJ) molar enthalpy (kJ/mol)
free energy G (kJ) molar free energy (kJ/mol)

IMPORTANT: Chang is inconsistent about using the “bar” to indicate molar quantities.
Usually this does not cause too much confusion, but occasionally it does. Also, the
terms “molar energy” and “energy” are typically used interchangeably.
Thermodynamics often focuses on changes in these quantities
and not the absolute amounts, especially with energy

T1 H1 T2 H2

P1 P2
V1 G1 V2 G2
U1 U2

State 1 State 2

For example:
drug not bound to protein drug bound to protein
drug outside cell membrane drug inside cell membrane
drug not dissolved in water drug dissolved in water

Not all of these will change in every process:

ΔT = 0 (isothermal), ΔV = 0 (constant volume), ΔP = 0 (constant pressure)

Also, as you’ll see later, you frequently don’t need to define all of these
variables to define the state of a system; often just 2 are sufficient!
 States vs. paths
(the destination vs. the journey)

path 2

T1 H1 (q2, w2) T2 H2
path 1
P1 P2
V1 G1 (q1, w1) V2 G2
U1 U2

State 1 State 2
 Analogy: Traveling from San Francisco to NYC

State 1 State 2
Elevation Elevation
Latitude Latitude
Longitude Longitude

Path-dependent quantities include miles traveled, amount of gas guzzled,

cups of coffee consumed, cost, etc.
 1st and 2nd Laws
•  1st law often described as “conservation of energy”. Put
philosophically, the first law states that there is some
quantity (energy!) that does not change when something
happens.
•  Specifically, ΔU = q + w
•  That means that the sum of two path-dependent
quantities is path-independent!
•  You will see soon that the internal energy is related to the
€
temperature of a substance.
•  In this same language, the 2nd law will state that there is
a quantity, entropy, that always increases whenever
something happens!
 We can skip many traditional topics in
thermodynamics
The origins of modern The applications to
thermodynamics pharmacy

Much of classic thermo Everything we care about here

concerned with gasses, and the happens in solution, at constant
ability to generate useful “work”. pressure. This leads to many
simplifications, starting on next slide.
 Energy and enthalpy
Enthalpy is defined as

H = U + PV
ΔH = ΔU + Δ ( PV )
for constant pressure (i.e., 1 atmosphere)
ΔH = ΔU + PΔV

But essentially everything you guys care about as pharmacists happens

in water. What happens when you push on water, even really hard?

€ A: Not much. i.e.,

ΔV ≈ 0
ΔH ≈ ΔU

This basically means that we can skip several chapters from Chang (ideal gasses)

€
 But what is enthalpy?
•  At constant pressure
ΔH ≈ ΔU
=q+ w
w = 0 (for processes we care about, in solution)
ΔH = q

In words, at constant pressure, the change in enthalpy is the same as the

€ of heat given off or consumed during the process.
amount
 Sign conventions and vocabulary
reactants  products

ΔH > 0 endothermic heat is consumed temp goes down

ΔH < 0 exothermic heat is released temp goes up

The enthalpy change of various reactions can vary widely.

An example of an exothermic reaction: thermite

Fe2O3 + 2Al  2Fe + Al2O3 ΔH=-849 kJ/mol (!)

http://www.youtube.com/watch?v=WrCWLpRc1yM&feature=player_embedded

Drugs binding to protein targets is usually also exothermic. More subtle than
thermite, but can determine ΔH by measuring amount of heat given off when
binding happens.
 Which brings us to the first useful
application: calorimetry
•  The preceding discussion means that we can measure
ΔH for a process pretty simply, if we can measure the
heat given off or used up.
•  How can we measure heat?
•  Everyday experience suggests that heat is related to
temperature: add heat, temperature goes up, and vice
versa.
•  But how much?
•  Depends on a property of the substance called the “heat
capacity”. For constant P, we call this Cp.
qP = C p ΔT
= nC p ΔT
subscript just means “constant P”
How do we know the heat capacity for
a substance?

•  A: Look it up.
•  The only one we really care about is water, for which
C p = 75.3 J/(K ⋅ mol)
•  Sometimes useful to have this in other units, such as
4.18 J/(Kg)=1 cal/(Kg)
•  In this case, q = ΔT * Cp(H2O) * m(H2O)
€
•  i.e., a calorie is defined as the amount of heat it takes to
raise temperature of 1 gram of water by 1 degree
•  What is your heat capacity? How much heat would it
take to raise your temp by 1 degree?
 What is your heat capacity?
•  Meaning, how much heat would it take to
increase your temperature by 1 C?
•  Let’s take me:
⎛ 1kg ⎞⎛1000g ⎞⎛ 1cal ⎞ cal kcal
150 pounds⎜ ⎟⎜ ⎟⎜ ⎟ = 68182 = 68.2
⎝ 2.2 pounds ⎠⎝ 1 kg ⎠⎝ K⋅ g ⎠ K K

•  So this is yet another type of “heat

€
capacity”, same concept, but different
units.
 Calorimetry example
You put 500 g of water into a “coffee cup” calorimeter
(aka, “constant pressure, adiabatic calorimeter”), and
then dissolve in it 5 grams of a drug with molecular
weight 500. The temperature increases by 0.5 C. What
is ΔHsoln for the drug in units of kcal/mol?

(Assume that thermometer and other parts of the

calorimeter other than water contribute negligibly to heat
capacity. There is a way around this assumption by
calibrating the calorimeter; see problem set.)

The reaction is drug(s)  drug(aq), as when it dissolves

in the stomach. Why, physically, might this be
exothermic? (That’s not always the case.)

[You can ignore materials from previous years on “constant

volume”, or “bomb” calorimeters.]
 Calorimetry example solution
What is ΔH (kcal/mol) for drug(s)  drug(aq)?

Data: 5 grams of a drug with molecular weight 500

500 g of water
Temperature increases by 0.5 C

First, before we plug anything in, we do know one thing: the sign on ΔH.
This is an exothermic reaction, so ΔH is negative. We just need to find the
exact value.

Heat absorbed by water: q = ΔT * Cp(H2O) * m(H2O)

⎛ 1 cal ⎞⎛ 1 kcal ⎞
q = 0.5 K ⎜ ⎟⎜ ⎟500g = 0.25 kcal
⎝ K⋅ g ⎠ 1000 cal ⎠
⎝
Heat given off by reaction has opposite sign. q=-0.25 kcal ⎛1 mol ⎞
To get the intrinsic value, we need to divide by number of moles: 5g⎜ ⎟ = 0.01 mol
⎝ 500g ⎠
€
So, ΔH = -0.25 kcal/0.01 mol = -25 kcal/mol
€
 Standard enthalpies of formation
•  The enthalpies of a great many reactions have
standard state:
been measured. How to tabulate them all?
298 K, 1 atm
•  There is no such thing as the “absolute enthalpy”
of a given substance. However, we can arbitrarily
molar quantity
assign a value of 0 to all elements at standard
temp/pressure, and then measure the formation of
any substance from the elements. o
•  For example
C(graphite) + O2(g) CO2(g)
ΔH f
ΔH (298 K, 1 bar) = -393.5 kJ/mol
formation
Therefore, ΔH fo (CO 2 ) = −393.5 kJ/mol
•  These values are called standard enthalpies of
change relative
formation. Nice tables in the back of Chang and to elements
other textbooks.
€ can then be used to compute ΔH for any
•  These
reaction involving these substances.
€
 Standard enthalpies example
ΔH o = ∑ f−
ΔH o
∑ f
ΔH o

products reactants

•  Alcoholic fermentation is a source of energy in yeast. A

key step can be written as
€
Pyruvate(aq) + H+(aq)  acetaldehyde(aq) + CO2(aq)

•  What is ΔH for this reaction?

•  Why is standard enthalpy of formation 0 for H+?
•  How do you deal with stoichiometry, e.g., 3O2(g)2O3
(g)
stoichiometric coefficients
ΔH o = ∑ f−
νΔH o
∑ f
νΔH o

products reactants
 Concept of a thermodynamic cycle

Suppose you want to know

ΔX4 = XD – XA
Of course, you can just
(1,10) ΔX4 = ? (5,10)
calculate it, but let’s pretend
A D that you can’t. Instead you
ΔX1 = 1 can add up
ΔX3 = 1
Y ΔX4 = ΔX1 + ΔX2 + ΔX3 = 4
B C
ΔX2 = 2 In the language of
(2,5) (4,5) thermodynamics, points A/B/
C/D are “states” and X is a
path-independent “state
function”. (So is Y.)

X The total distance travelled of

course is path-dependent.
 Temperature dependence of ΔH
Suppose we know ΔH at one temperature. How can we estimate it at a different T?
ΔH2
T2 Reactants Products

ΔH3=Cp(reactants)(T1-T2) ΔH4=Cp(products)(T2-T1)

ΔH1
T1 Reactants Products
ΔH2 = ΔH1 + ΔH3 + ΔH4 =
= ΔH1 + Cp(reactants)(T1-T2) + Cp(products)(T2-T1)
=  ΔH1 - Cp(reactants)(T2-T1) + Cp(products)(T2-T1)
=  ΔH1 + [Cp(products)-Cp(reactants)](T2-T1) [Note that this assumes Cp is
constant as a function of T. In
ΔH2 = ΔH1 + ΔCp(T2-T1) general, true only for small ΔT.]
ΔCp = Cp(products) - Cp(reactants)
This is called Kirchhoff’s law, and is an example of a thermodynamic cycle.
It takes advantage of ΔH being an intrinsic (path-independent) property.
 Kirchhoff’s law example
•  A relevant example would be taking measurements done
at room temp (i.e., standard state) and predicting value at
body temp, 37 C.
•  But let’s do a simpler example for now:
3O2(g)2O3(g)
ΔH298 = 285.4 kJ/mol
What is ΔH at 380 K?

Cp(O2) = 29.4 J/(K mol) Cp(O3) = 38.2 J/(K mol)

ΔCp = 2*38.2 – 3*29.4 = -11.8 J/(K mol) = -0.0118 kJ/(K mol)

ΔH380 = ΔH298 + ΔCp(380-298) =
= 285.4 kJ/mol – 0.0118 kJ/(K mol) * (380 K – 298 K)
= 284.4 kJ/mol
[Watch your units, i.e., J vs. kJ]
The explicit thermodynamic cycle for the ozone example

3O2(g)2O3(g)

ΔH2
380 K 3O2(g) 2O3(g)

ΔH3=3Cp(O2)(298-380) ΔH4=2Cp(O3)(380-298)

ΔH1
298 K 3O2(g) 2O3(g)

Adding up ΔH3 + ΔH1 + ΔH4 of course gives the same

answer as just plugging into Kirchhoff’s law.
 Next up ...
•  Entropy and the second law
•  Free energy and equilibrium