1.1.
Introduction to Physical Organic Chemistry
Physical Organic Chemistry, a term coined by Louis Hammett in 1940, refers to a
discipline of organic chemistry that focuses on the relationship between chemical
structures and reactivity, in particular, applying experimental tools of physical chemistry
to the study of organic molecules. It is mainly centered on two main components: Kinetics
and thermodynamics. These should normally have been covered in your Basic Physical
Chemistry course, but here we will apply these quantitative tools to help us understand
what is happening in an organic reaction.
In this context, thermodynamics deals with energy and entropy changes that take place
during a chemical reaction. It also deals with equilibrium constants for reversible
reactions. In contrast, kinetics deals with rates of reactions and energy barriers/activation
energies, it is less useful for reversible reactions, but can be very useful for understanding
irreversible reactions.
Field Questions Usual parameters
Will a reaction occur? If
Thermodynamics so, how far will the reaction ΔG, ΔH, ΔS, Keq
go?
How quickly wiil the [X] (concn. of X), k (rate
Kinetics
reaction go? constant), Ea, ΔG‡.
In some cases, the course of a reaction may be determined by the stability of the favored
product. This is referred to as thermodynamic control, and it implies that the reaction
can happen easily as most reactant molecules have enough energy to cross the energy
barrier (free energy of activation, ΔG‡). In other cases, we have kinetic control, where
the course of a reaction may be determined by which product has the lowest energy
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barrier, which implies that the molecules barely have enough energy to cross even the
lowest barrier. Both of these scenarios can be seen in the diagram below:
1.2. Thermodynamics of reactions
Fundamentals
Consider a simple equilibrium
The equilibrium constant will be given by
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If Keq >1, the reaction favors the products. If Keq = 1, the reaction will be equally
balanced. Recall that the standard free energy change ΔGo = -RTlnKeq where
ΔGo = Go(reactants) – Go(products) ΔGo represents the driving force for the
reaction:
ΔGo = 0, Keq = 1, the reaction is equally balanced.
ΔGo is negative, Keq > 1, the reaction favors the products
ΔGo is positive, Keq < 1, the reaction favors the reactants
Free energy relates to the heat change (ΔH) through the equation
This tells us that a more negative ΔH (exothermic reaction) will help favor the
products. Also, a positive entropy change (increase in disorder) will also help form the
products, especially at higher temperatures.
Bond Dissociation Energy
The homolytic bond dissociation energy is the amount of energy needed to break apart
one mole of covalently bonded gases into a pair of radicals. The SI units used to describe
bond energy are kiloJoules per mole of bonds (kJ/Mol). It indicates how strongly the
atoms are bonded to each other.
Introduction
Breaking a covalent bond between two partners, A-B, can occur either heterolytically,
where the shared pair of electron goes with one partner or another
A−B→A+ + B:− or A−B→A:− + B+
or homolytically, where one electron stays with each partner.
A−B→A•+B•
The products of homolytic cleavage are radicals and the energy that is required to break
the bond homolytically is called the Bond Dissociation Energy (BDE) and is a measure of
the strength of the bond.
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Calculation of the BDE
The BDE for a molecule A-B is calculated as the difference in the enthalpies of
formation of the products and reactants for homolysis.
Officially, the IUPAC definition of bond dissociation energy refers to the energy change
that occurs at 0 K, and the symbol is Do. However, it is commonly referred to as BDE, the
bond dissociation energy, and it is generally used, albeit imprecisely, interchangeably
with the bond dissociation enthalpy, which generally refers to the enthalpy change at
room temperature (298K). Although there are technically differences between BDEs at 0
K and 298 K, those difference are not large and generally do not affect interpretations of
chemical processes.
Bond breakage/formation
Bond dissociation energy (or enthalpy) is a state function and consequently does not
depend on the path by which it occurs. Therefore, the specific mechanism in how a bond
breaks or is formed does not affect the BDE. Bond dissociation energies are useful in
assessing the energetics of chemical processes. For chemical reactions, combining bond
dissociation energies for bonds formed and bonds broken in a chemical reaction
using Hess’s Law can be used to estimate reaction enthalpies.
EXAMPLE: CHLORINATION OF METHANE
Consider the chlorination of methane
CH4 + Cl2 → CH3Cl + HCl
The overall reaction thermochemistry can be calculated exactly by combining the BDEs for the
bonds broken and bonds formed, i.e., ΔH = BDE(bonds broken) – BDE(bonds made)
The “bonds made” part of the equation is negative because it represents the opposite of
bonds broken, the BDE.
CH4 → CH3• + H• BDE(CH3-H)
Cl2 → 2Cl• BDE(Cl-Cl)
H• + Cl• → HCl -BDE(H-Cl)
CH3• + Cl• → CH3Cl -BDE(CH3-Cl)
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CH4 + Cl2 → CH3Cl + HCl
ΔH = BDE(CH3−H) + BDE(Cl-Cl) − BDE(H-Cl) − BDE(CH3−Cl)
Because reaction enthalpy is a state function, it does not matter what reactions are combined to
make up the overall process using Hess’s Law. However, BDEs are convenient to use because
they are readily available.
Alternatively, BDEs can be used to assess individual steps of a mechanism. For example,
an important step in free radical chlorination of alkanes is the abstraction of hydrogen
from the alkane to form a free radical.
RH + Cl• → R• + HCl
The energy change for this step is equal to the difference in the BDEs in RH and HCl
ΔH=BDE(R−H)–BDE(HCl) ΔH=BDE(R−H)–BDE(HCl)
This relationship shows that the hydrogen abstraction step is more favorable when
BDE(R-H) is smaller. The difference in energies accounts for the selectivity in the
halogenation of hydrocarbons with different types of C-H bonds.
Representative C-H BDEs in Organic Molecules
R-H Do, kJ/mol D298, kJ/mol R-H Do, kJ/mol D298, kJ/mol
CH3-H 432.7±0.1 439.3±0.4 H2C=CH-H 456.7±2.7 463.2±2.9
CH3CH2-H 423.0±1.7 C6H5-H 465.8±1.9 472.4±2.5
(CH3)2CH-H 412.5±1.7 HCCH 551.2±0.1 557.8±0.3
(CH3)3C-H 403.8±1.7
H2C=CHCH2-H 371.5±1.7
HC(O)-H 368.6±0.8 C6H5CH2-H 375.3±2.5
CH3C(O)-H 374.0±1.2
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1.3. Reaction coordinate diagrams
You may recall from general chemistry that it is often convenient to describe chemical
reactions with energy diagrams. In an energy diagram, the vertical axis represents the
overall energy of the reactants, while the horizontal axis is the ‘reaction coordinate’,
tracing from left to right the progress of the reaction from starting compounds to final
products. The energy diagram for a typical SN2 reaction might look like this:
Despite its apparent simplicity, this energy diagram conveys some very important ideas
about the thermodynamics and kinetics of the reaction. Recall that when we talk about
the thermodynamics of a reaction, we are concerned with the difference in energy
between reactants and products, and whether a reaction is ‘downhill’ (exergonic, energy
releasing) or ‘uphill (endergonic, energy absorbing). When we talk about kinetics, on the
other hand, we are concerned with the rate of the reaction, regardless of whether it is
uphill or downhill thermodynamically. First, let’s review what this energy diagram tells us
about the thermodynamics of the reaction illustrated by the energy diagram above. The
energy level of the products is lower than that of the reactants. This tells us that the
change in standard Gibbs Free Energy for the reaction (ΔG˚rxn) is negative. In other words,
the reaction is exergonic, or ‘downhill’. Recall that the ΔG˚rxn term encapsulates both
ΔH˚rxn, the change in enthalpy (heat) and ΔS˚rxn, the change in entropy (disorder): ΔG˚ =
ΔH˚- TΔS˚ where T is the absolute temperature in Kelvin. For chemical processes where
the entropy change is small (~0), the enthalpy change is essentially the same as the
change in Gibbs Free Energy. Energy diagrams for these processes will often plot the
enthalpy (H) instead of Free Energy for simplicity. The standard Gibbs Free Energy
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change for a reaction can be related to the reaction’s equilibrium constant (K eq) by a
simple equation:ΔG˚ = -RT ln Keq
where:
Keq = [product] / [reactant] at equilibrium
R = 8.314 J×K-1×mol-1 or 1.987 cal× K-1×mol-1
T = temperature in Kelvin (K)
If you do the math, you see that a negative value for ΔG˚ rxn (an exergonic reaction)
corresponds – as it should by intuition – to Keq being greater than 1, an equilibrium
constant which favors product formation.
In a hypothetical endergonic (energy-absorbing) reaction the products would have a
higher energy than reactants and thus ΔG˚rxn would be positive and Keq would be less than
1, favoring reactants.
Here is one more interesting and useful expression. Consider a simple reaction where
the reactants are A and B, and the product is AB. If we know the rate constant k for the
forward reaction and the rate constant kreverse for the reverse reaction (where AB splits
apart into A and B), we can simply take the quotient to find our equilibrium constant K eq:
This too should make some intuitive sense; if the forward rate constant is higher than the
reverse rate constant, equilibrium should lie towards products.
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1.4. Kinetics
Now, let’s move to kinetics. Look again at the energy diagram for exergonic reaction:
although it is ‘downhill’ overall, it isn’t a straight downhill run.
First, an ‘energy barrier’ must be overcome to get to the product side. The height of this
energy barrier, you may recall, is called the ‘activation energy’ (ΔG‡). The activation
energy is what determines the kinetics of a reaction: the higher the energy hill, the slower
the reaction. At the very top of the energy barrier, the reaction is at its transition
state (TS), which is the point at which the bonds are in the process of breaking and
forming. The transition state is an ‘activated complex’: a transient and dynamic state
that, unlike more stable species, does not have any definable lifetime. It may help to
imagine a transition state as being analogous to the exact moment that a baseball is
struck by a bat. Transition states are drawn with dotted lines representing bonds that are
in the process of breaking or forming, and the drawing is often enclosed by brackets. Here
is a picture of a likely transition state for our simple SN2 reaction between hydroxide and
chloromethane:
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The SN2 reaction involves a collision between two molecules: for this reason, we say that
it has second order kinetics (this is the source of the number ‘2’ in SN2). The rate
expression for this type of reaction is:
rate = k[reactant 1][reactant 2]
. . . which tells us that the rate of the reaction depends on the rate constant k as well as
on the concentration of both reactants. The rate constant can be determined
experimentally by measuring the rate of the reaction with different starting reactant
concentrations. The rate constant depends on the activation energy, of course, but also
on temperature: a higher temperature means a higher k and a faster reaction, all else
being equal. This should make intuitive sense: when there is more heat energy in the
system, more of the reactant molecules are able to get over the energy barrier.
This study of reaction rates and the reaction coordinate diagram turns out to be invaluable
for determining the mechanism for a reaction. The mechanism tells us how the bonds
are broken and made, and shows what intermediates (if any) are formed along the way.
KEY TAKEAWAYS
The rate determining step is the slowest one – the one with the highest energy
barrier
The rate of the rate determining step is equal to the rate for the overall reaction
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Catalysis
We come now to the subject of catalysis. Our hypothetical bowl of sugar (from end of
the previous section) is still stubbornly refusing to turn into carbon dioxide and water,
even though by doing so it would reach a much more stable energy state. There are, in
fact, two ways that we could speed up the process so as to avoid waiting several
millennia for the reaction to reach completion. We could supply enough energy, in the
form of heat from a flame, to push some of the sugar molecules over the high energy
hill. Heat would be released from the resulting exothermic reaction, and this energy
would push more molecules over their energy hills, and so on – the sugar would literally
burn up. A second way to make the reaction go faster is to employ a catalyst. You
probably already know that a catalyst is an agent that causes a chemical reaction to go
faster by lowering its activation energy.
Enzymes – nature’s catalysts
How might you catalyze the conversion of sugar to carbon dioxide and water? It’s not too
hard – just eat the sugar, and let your digestive enzymes go to work catalyzing the many
biochemical reactions involved in breaking it down. Enzymes are proteins, and are very
effective catalysts. ‘Very effective’ in this context means very specific, and very fast. Most
enzymes are very selective with respect to reactant molecules: they have evolved over
millions of years to catalyze their specific reactions. An enzyme that attaches a phosphate
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group to glucose, for example, will not do anything at all to fructose.
Glucose kinase is able to find and recognize glucose out of all of the other molecules
floating around in the ‘chemical soup’ of a cell. A different enzyme, fructokinase,
specifically catalyzes the phosphorylation of fructose. We have already learned that
enzymes are very specific in terms of the stereochemistry of the reactions that they
catalyze. Enzymes are also highly regiospecific, acting at only one specific part of a
molecule. Notice that in the glucose kinase reaction above only one of the alcohol groups
is phosphorylated. Finally, enzymes are capable of truly amazing rate accele-
ration. Typical enzymes will speed up a reaction by anywhere from a million to a billion
times, and the most efficient enzyme currently known to scientists is believed to
accelerate its reaction by a factor of about 1017. We will now begin an exploration of some
of the basic ideas about how enzymes accomplish these amazing feats of catalysis, and
these ideas will be revisited often throughout the rest of the text as we consider various
examples of enzyme-catalyzed organic reactions. But in order to begin to understand
how enzymes work, you will first need to learn (or review, as the case may be) a little bit
about protein structure.
Organic Chemistry 1: An open textbook
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