15 Chemical Reactions

As we have learned over the last few lessons, intermolecular interactions affect phase transitions and other properties of
condensed phases, but do not change the participating molecules. Now we are ready to explore processes in which molecules change
their identities. It turns out that even stable molecules may engage in even stronger types of interactions in which electrons are
transferred, bonds are broken and remade, and energy is exchanged with the surroundings. In such processes, called chemical
reactions, reactants (the initial participants) are transformed into products (new chemical species). The only constant in such reactions
are atoms, whose number and type remain unchanged even as their bonding arrangements are reconfigured.

15-1 Reaction types

Reactions are divided into categories depending on their outcome. The categories we introduce include combination,
decomposition, combustion, single displacement and double displacement. Chemical reactions are described by chemical equations,
listing reactants on the left and products to the right of the reaction arrow. The stoichiometric coefficients are the numbers in front of
reactants and products that express the molar ratios in which they participate in the reaction. In order to obey the law of conservation
of mass, the stoichiometric coefficients must be such that the number of each type of atom is the same on both sides of the equation.
Equations with coefficients that satisfy this condition are called balanced equations, and they constitute the basis of all stoichiometric
calculations.

15-2 Driving force

For a reaction to proceed as indicated by its equation, there must be some driving force. This driving force might be a lowering of
the system’s enthalpy (this happens when products are more stable than reactants), or an increase of entropy (when products are
statistically more likely than reactants). The driving force of double exchange reactions is most commonly manifested in the formation
of a precipitate, the formation of a weak electrolyte or nonelectrolyte, or the formation of a gas.

15-3 Redox reactions

Redox reactions are chemical processes in which electrons are transferred between reactants, resulting in reduction of one and
oxidation of the other. The reactant that loses electrons is oxidized, and the reactant that gains electrons is reduced. The transferred
electrons are accounted for by assigning oxidation states (or oxidation numbers) to each element in reactants and products. In single
exchange redox reactions the driving force is the transfer of electrons from metals of higher activity to metals of lower activity, as
ordered in the metal activity series.

15-4 Stoichiometry

Stoichiometry deals with relative quantities of reactants and products in chemical reactions. It is based on the stoichiometric
coefficients of balanced chemical equations and the proportionality between molecules and moles. It is used to determine the amounts
of reactants and products of a given reaction in mass, moles, or volumes. The stoichiometric calculations are used to identify the
limiting reactant, which is the reactant that determines the maximum theoretical yield of products. The amount of product actually
formed is commonly expressed as percent yield, which is calculated by dividing the actual yield by the theoretical yield.

15-5 Example calculations

Stoichiometric calculations are applicable to all types of reactions, including combustion, elemental analysis, redox reactions,
solution reactions, titrations, and reactions of gases utilizing the ideal gas law.

15-6 Drug binding to proteins

The pharmaceutical industry is a multibillion dollar industry that develops medications that treat a wide range of diseases, from
bacterial and viral infections to cancer and asthma. Understanding how these medications work is critical for a range of professions,
such as doctors, pharmacists, and nurses. In this section we’re going to examine how drug molecules work at the molecular level.
Drugs, which are usually small molecules, typically work by binding to either a protein or RNA in a way that changes the activity of the
protein/RNA. Exactly how this works varies from one drug to the next and depends on the biological role of the target protein/RNA.
15-7 Arrow pushing mechanisms

In this section we introduce a formalism for describing the movements of electrons that take place during chemical reactions. As
we have seen already, a chemical reaction is a rearrangement of valence electrons that typically leads to the cleavage and/or
formation of bonds. The specific electron movements associated with each reaction are described by the reaction mechanism.
Reaction mechanisms show where electrons originate in the reactant and where they ultimately reside in the product. This is
represented graphically using a formalized system called arrow pushing in which the movement of electrons is diagrammed using a
series of curved arrows. Arrow pushing mechanisms are commonly used to describe organic and biochemical reactions. Many such
reactions occur in multiple discrete steps, with a separate arrow pushing mechanism used to describe the electron movements
associated with each reaction step.
15-1 Reaction types

Combination, decomposition, combustion, and single and double displacement

are the common types of chemical reactions

A chemical reaction is a process that transforms one set of molecules, called reactants, into a different set of molecules, called
products. Chemical reactions encompass changes in the apportionment of bonding and lone-pair electrons between atoms, and the
resulting energy changes. The nuclei remain unchanged, preserving the atoms' identities. Elements can only undergo transmutation
into a new element in nuclear reactions, which will not be explored until the second semester of general chemistry.

There are a wide variety of chemical reactions, from the relatively simple, such as the production of carbon dioxide bubbles when
an Alka-Seltzer tablet dissolves in water , to the complex reactions that take place in our eyes and brain as we read this sentence.
Some go almost unnoticed, like the constant oxidation reactions in our bodies, providing energy that allows us to function. Others may
be spectacular, like the 4th of July fireworks, which release energy in the form of light, heat, and acoustic waves for our entertainment.
All reactions can be represented by chemical equations, which are a form of symbolic notation that captures the essence of the
changes taking place. We will only explore a very small subset of reactions to illustrate some basic concepts of chemical reactivity.
Even with a limited scope, it helps to categorize reactions into several groups that describe the net change. These categories are listed
below with illustrative examples.

Combination: elements react to form compounds, or small compounds combine to make larger ones

2 Mg(s) + O (g) ⟶ 2 MgO(s)

2
C15-1-1

CaO(aq) + CO (g) ⟶ CaCO (s)

2 3
C15-1-2

Decomposition: a compound breaks apart into two or more smaller compounds

PbCO (s) −
→ PbO(s) + CO (g)
C15-1-3
3 2

Combustion: a compound (usually organic) reacts (usually violently) with oxygen, O2(g); complete combustion means that the
highest-oxidation state oxides are produced (CO2 for carbon, H2O for hydrogen).

2 CH OH(g) + 3 O (g) ⟶ 2 CO (g) + 4 H O(g)

3 2 2 2
C15-1-4

Single displacement: one element replaces another in a compound

CuSO (aq) + Zn(s) ⟶ ZnSO (aq) + Cu(s)

4 4
C15-1-5

Double displacement (metathesis): exchange of ions or atoms between two compounds

CaCl (aq) + 2 AgNO (aq) ⟶ 2 AgCl(s)↓ + Ca(NO ) (aq)

2 3 3 2
C15-1-6

HNO (aq) + KOH(aq) ⟶ KNO (aq) + H O(l)

3 3 2
C15-1-7

Na S(aq) + 2 HCl(aq) ⟶ H S(g)↑ + 2 NaCl(aq)

2 2
C15-1-8

Chemical equations follow certain conventions to standardize their meaning. The reactants are always listed on the left. The
arrow translates to "react" and points to the products. You may recall from our previous encounter with such symbols, that an arrow
pointing to the right signifies a reaction that essentially goes in one direction; products are formed from the reactants, and there is no
significant reaction in the opposite direction. The chemical formulas of the reactants and products are often supplemented by
designation of their physical state in parentheses (g meaning gas, ℓ meaning liquid, s meaning solid, and aq indicating an aqueous
solution). For ionic, metallic, or extended solids the elemental symbols or empirical formulas are used, sometimes specifying the
allotropic form in parentheses (for example, K, NaCl, C(graphite), etc). Occasionally, some additional symbols may be included such
as "Δ" above the reaction arrow to indicate heat has been added, an upward pointing arrow after the formula (↑) to indicate gas
formation, or a downward pointing arrow (↓) after the formula to indicate precipitation of a solid.
 Balanced chemical equations document that no atoms are created or destroyed in chemical reactions

Although listing the reactants and products on opposite sides of the arrow identifies the reaction unambiguously, the complete equation
must still be balanced. We can balance many simple reactions by inspection of the coefficients. A balanced equation allows us to carry
out the stoichiometric calculations that describe the relative amounts of reactants and products, and to determine the percent yield
of the products. A balanced equation is a reflection of the law of conservation of mass; the number of atoms of each element must be
equal on both sides of the equation—no atoms can be created or destroyed in regular chemical reactions (nuclear reactions
notwithstanding). Balancing an equation can be achieved only by changing the stoichiometric coefficients (the numbers in front of each
chemical formula). Altering subscripted numbers within a formula changes the identity of the molecule, and therefore changes the
entire reaction rather than balancing it.

To balance a chemical equation we follow a systematic approach, balancing one element at a time and adjusting as necessary.
For example, the combustion of ethane (C15-1-9) produces carbon dioxide and water. It is unbalanced when written with coefficients of
1 in front of each formula. For instance, there are 2 carbon atoms in the reactants but only 1 carbon atom in the products.

CH CH (g) + O (g) ⟶ CO (g) + H O(g)

3 3 2 2 2
C15-1-9

Indeed, we can start the balancing with carbon: we have 2 carbon atoms among the reactants on the left, so we must also have
2 carbon atoms in the products. We need to place a "2" in front of CO2, the only carbon-containing product. We can then move on to
the hydrogen atoms; we have 6 of them on the left, and all must be included in water, which is the only hydrogen-containing product.
We need to put a “3” in front of H2O on the right to account for those 6 hydrogen atoms. The last element to balance is oxygen; we
have total of 7 oxygen atoms on right side of the equation (2 x 2 in carbon dioxide and 3 in water). We need the same number on the
left, but the oxygen atoms come in sets of two since dioxygen is the reactant; we must have a coefficient of 7/2 in front of O2 (C15-1-
10).

7
CH CH (g) +
3 3
O (g) ⟶ 2 CO (g) + 3 H O(g)
2 2 2
C15-1-10
2

Although C15-1-10 is balanced, chemists often prefer to use the smallest possible whole number coefficients instead of fractions.
Whole number coefficients can be obtained by multiplying all coefficients on both sides of the equation by two (C15-1-11). The ability to
multiply a balanced equation in this way illustrates the meaning of stoichiometry: it gives the relative ratio of atoms or molecules
involved in a reaction, with a focus on proportions and not on specific absolute amounts. We will return to this concept later in the
lesson.

2 CH CH (g) + 7 O (g) ⟶ 4 CO (g) + 6 H O(g)

3 3 2 2 2
C15-1-11

Figure F15-1-1. Stoichiometry of the combustion reaction of ethane. The balanced equation uses the smallest whole number
stoichiometric coefficients to reflect the whole numbers of molecules participating in the reaction.
15-2 Driving force

Reactions of electrolytes are presented as net ionic equations with spectator ions omitted

Consider a double-exchange reaction between lead nitrate and potassium iodide carried out in water. The two compounds are about to
exchange their cations, creating lead iodide and potassium nitrate. The molecular equation, a balanced equation showing the complete
chemical formulas without indicating the ionic nature of the reactants and products, is shown below.

Pb(NO )
3 2
+ 2 KI ⟶ PbI
2
+ 2 KNO
3
C15-2-1

However, both reactants are ionic solids and strong electrolytes and are completely dissociated into hydrated ions, as should be
indicated thusly (C15-2-2):

Pb
2 +
(aq) + 2 NO
−

3
(aq) + 2 K
+
(aq) + 2 I
−
(aq) ⟶ C15-2-2

At the starting point, we formally have four different kinds of ions floating in solution. Dissolving NaCl in water yields two kinds of
ions (Na+ and Cl−), which will reconstitute as NaCl(s) if the water is evaporated. Following this logic, if there is no reaction, after the
evaporation of water, we would get a mixture of all four ionic solids: two reactants, and two products; that would be quite a messy
exchange. However, when we actually pour a solution of potassium iodide into the solution of lead nitrate, a yellow precipitate of lead
iodide, PbI2, forms (F15-2-1).

Figure F15-2-1. Precipitation of lead iodide (PbI2) that is created in a

double exchange reaction upon the addition of drops of potassium
iodide to a solution of lead nitrate

It turns out that lead iodide is essentially insoluble in water. Taking the precipitation of one of the products into account, we can
now complete equation C15-2-2 as follows:

2 + − + −
Pb (aq) + 2 NO (aq) + 2 K (aq) + 2 I (aq) ⟶
3
C15-2-3
+ −
PbI (s)↓ + 2 K (aq) + 2 NO (aq)
2 3

The equation above is a complete ionic equation showing all reactant and product ions and the insoluble solid of PbI2 that
separated from the solution. A closer examination of the equation indicates that we have some of the same ions on both sides of the
equation (K+ and NO3−). These ions actually do not participate directly in the reaction; they are spectator ions. We can remove them
from both sides (like in an algebraic equation), giving us the net ionic equation:

Pb
2 +
(aq) + 2 I
−
(aq) ⟶ PbI (s)↓ C15-2-4
2

Notice that the net ionic equation is still balanced. Charges on ions are balanced as well; the sum of the ionic charges must be
the same on both sides of the equations.

The net ionic equation is especially important: it shows only those species that actually take part in the reaction and the chemical
change that takes place. For example, from the net ionic equation above, we can tell that to make solid PbI2, we need a source of Pb2+
(aq) and I−(aq) ions. We will obtain the same result by using HI(aq) and lead acetate, for example.
 The driving forces for exchange reactions include formation of a precipitate, gas,
weak or nonelectrolyte, and redox activity

This example demonstrates that for double exchange to work, it needs some kind of driving force that will assure that products (as
written in the chemical equation) actually form. Normally, the most obvious driving force is an exothermicity of the process (ΔH < 0),
i.e., the product stability exceeding that of the reactants. For example, the products of combustion reactions of hydrocarbons, carbon
dioxide and water, are much more stable than the reactants, hydrocarbons and oxygen. Another driving force in reactions can be a
favorable entropy change, analogous to the dissolution process. We will explore these thermodynamic aspects of reactions in the
next Chapter and in the second semester of general chemistry.

The driving forces at work in exchange reactions that we consider here are:

formation of a precipitate
formation of a gas
formation of a weak electrolyte or nonelectrolyte
redox (activity series)

You may observe that in the first three categories a product is removed from the reaction phase. Insoluble solids separate from
the aqueous phase, gases escape the solution, and the formation of nonelectrolytes (often water) involves converting ionic species
into covalent compounds. In all of these cases at least one of the products is removed from the reaction mixture, driving the reaction to
completion. In the reduction-oxidation (redox) processes, electrons are transferred from a higher energy state in a more active metal to
a lower energy state in less active metals.

To be able to predict the outcome of a double exchange reaction, we need to recognize which type of the driving force is present.
For example, for precipitation reactions, we need to know whether any of the ions involved in the reaction form an insoluble salt. It
turns out that the solubility of many salts follows similar patterns, which may be generalized into a set of widely applicable guidelines
(Table T15-2-1).

Table T15-2-1 Solubility guidelines for ionic solids in water

Guidelines Exceptions

ammonium (NH 4+)

alkali metals (Li +, Na+, K+, Rb+, Cs+)
nitrates (NO 3−)
soluble acetates (CH 3COO−)
perchlorates (ClO 4−)
halides (Cl −, Br−, I−) Ag +, Hg22+. Pb2+
sulfates (SO 4 2−) Ca 2+, Sr2+, Ba2+, Ag+, Hg22+, Pb2+
NH 4+, Li+, Na+, K+, Rb+, Cs+
sulfides (S 2−) and hydroxides (HO−)
insoluble Ca 2+, Sr2+, Ba2+
carbonates (CO 3 2−) and phosphates (PO4 3−) NH 4+, Li+, Na+, K+, Rb+, Cs+

A second driving force for exchange reactions is the formation of a weak electrolyte or a nonelectrolyte. This driving force is most
often encountered in acid-base neutralization reactions, wherein an acid reacts with a base to produce a salt and water. For example,
the molecular equation for a reaction between hydrochloric acid and sodium hydroxide is shown in C15-2-5:

HCl(aq) + NaOH(aq) ⟶ H O(ℓ) + NaCl(aq)

2
C15-2-5

When the molecular equation is rewritten as a complete ionic equation, we can see that chloride ion and sodium ion are
spectator ions:

+ − + − + −
H (aq) + Cl (aq) + Na (aq) + OH (aq) ⟶ H O(ℓ) + Na
2
(aq) + Cl (aq) C15-2-6

The net ionic equation makes the key transformation more obvious; the net change is the formation of water by a reaction
between H+ and HO−:
 H
+
(aq) + OH
−
(aq) ⟶ H O(ℓ)
2
C15-2-7

Equation C15-2-7 represents the main feature of a neutralization reaction between any strong acid and any strong base. The
formation of a covalent nonelectrolyte molecule (water) from ions (H+ and HO−) provides the driving force for this type of reaction by
removing a pair of ions from the solution.

Formation of a gas is another driving force. In these types of reactions a gas is produced that escapes the solution due to its
limited solubility in water. For example, hydrogen sulfide gas forms when hydrochloric acid reacts with sodium sulfide, as shown in the
molecular equation C15-2-8.

2 HCl(aq) + Na S(aq) ⟶ H S(g)↑ + 2 NaCl(aq)

2 2
C15-2-8

The net ionic reaction (C15-2-9) resembles the neutralization reaction of equation C15-2-7, although sulfide ion is a weak base.
The product is a weak electrolyte, like water. It also happens to be a gas; it escapes the solution, driving the reaction to completion.

2H
+ 2 −
(aq) + S (aq) ⟶ H S(g)↑
2
C15-2-9

Other gases often produced in exchange reactions include CO2, NO2, or SO2. Sometimes a weak acid is produced first, with
decomposition into gas in a subsequent step. For example, the reaction of hydrochloric acid with sodium hydrogen carbonate (baking
soda) produces carbonic acid (C15-2-10). This weak acid is a weak electrolyte, which decomposes to produce carbon dioxide gas and
water (C15-2-11).

HCl(aq) + NaHCO (aq) ⟶ H CO (aq) + NaCl(aq)

3 2 3
C15-2-10

H CO (aq) ⟶ CO (g) + H O(ℓ)

2 3 2 2
C15-2-11

The net ionic equation is obtained by combining these two steps, and removing the spectator ions and carbonic acid (which is
only an unstable intermediate):

+ −
H (aq) + HCO
3
(aq) ⟶ CO (g)↑ + H O(ℓ)
2 2
C15-2-12

The exchange reactions presented above are all very similar; they can be thought of as acid-base neutralization reactions. Their
products are all weak electrolytes or nonelectrolytes, and are all covalent molecules that exist as gases or liquids.
15-3 Redox reactions

In a redox reaction one reactant gets oxidized, losing electrons,

while another reactant gets reduced, gaining electrons

A redox reaction is a type of reaction where oxidation and reduction of the reactants take place. When an atom, an ion, or a molecule
has lost one or more electrons, we say it has been oxidized.

Figure F15-3-1. Transfer of electrons in a redox reaction

The name oxidation is used because the first reactions of this type studied
involved oxygen, yielding oxygen-containing products. Oxygen is an excellent
oxidizing agent, as we can see by the formation of rust on iron bridges parts, or
the formation of green copper oxide on copper roof tiles after long exposure to
oxygen in the air. However, the oxidation is only part of the process; when one
chemical entity loses electrons, another must gain electrons. Such electron
transfer from one species to another occurs in every redox reaction. The species
that gains electrons is said to be reduced.

Since reduction cannot occur without oxidation and vice versa, we can say that each species is acting as an agent of the change
that the other species undergoes. An oxidizing agent (or oxidant) oxidizes something else, but in the process is itself reduced (it gains
electrons from the other reactant). A reducing agent reduces something else, but in the process is itself oxidized (it loses electrons to
the other reactant).

The oxidation of magnesium is a fantastic example of a redox process. Shiny, silver-colored magnesium metal can be ignited in
air, creating a bright flame, as it is converted into a dull, gray magnesium oxide powder (C15-3-1).

2 Mg(s) + O (g) ⟶ 2 MgO(s)

2
C15-3-1

In this reaction each magnesium atom loses two electrons, and each oxygen atom gains two electrons. Thus, oxygen is reduced
and magnesium is oxidized; oxygen is the oxidizing agent, and magnesium is the reducing agent.

Oxidation numbers are used to account for electrons gained and lost
by atoms participating in redox reactions

To keep track of the gained and lost electrons we assign oxidation numbers (or oxidation states) to each atom in the reaction.
Oxidation numbers are assigned based on the difference between the number of valence electrons the neutral atom would have, and
the number of electrons assigned to it in a Lewis structure. The number of electrons assigned to the atom includes all lone-pair
electrons, plus half of the electrons shared with atoms of equal electronegativity, plus all electrons shared with atoms of lesser
electronegativity. In this model, for the purpose of determining the oxidation numbers, the bonds between different atoms are treated
as ionic; the atom with greater electronegativity is awarded all electrons in a bond.

Based on this rule, species in elemental form always have oxidation numbers equal to zero. Any monatomic ion has an oxidation
number equal to its charge. In compounds, nonmetals (as being more electronegative) usually have negative oxidation numbers, but
exceptions are known. Oxygen is usually −2 (with the exception of peroxides, where it is −1). Hydrogen is usually +1 when bonded to
nonmetals, and −1 when bonded to metals (when it is called a hydride). The oxidation number of fluorine (the most electronegative
element) is always −1 unless it is in elemental form. Other halogens are commonly −1 as well, but in compounds with more
electronegative elements they have positive oxidation numbers. The sum of the oxidation numbers of all atoms must always add up to
the overall charge of the species.
 Using the guidelines above, we can rewrite our redox reaction from equation C15-3-1 while explicitly showing oxidation numbers:

C15-3-2

The metallic magnesium and molecular oxygen both have an oxidation number of 0. In the MgO product the magnesium ion
(Mg2+) has a +2 oxidation number, while the oxide ion (O2−) has a −2 oxidation number. The overall reaction can be divided into two
half-reactions that separately describe the oxidation and reduction processes:

Mg(s) ⟶ Mg
2 + −
+ 2e C15-3-3

O (g) + 4 e
2
−
⟶ 2O
2 −
C15-3-4

The overall redox reaction (C15-3-2) is the sum of the two half reactions. However, in order for the overall redox reaction to be
balanced, the overall number of electrons lost and gained in the half-reactions must be the same. We cannot lose only 2 electrons
from magnesium and gain 4 electrons on oxygen. We must multiply all coefficients in the oxidation half-reaction (C15-3-3) by 2 before
we add the half reactions to get the overall redox reaction.

The activity series organizes metals in order of their reactivity with water
or their ability to lose electrons

In redox processes, the driving force for the reaction is based on the products being of lower energy than the reactants. In single
exchange reactions, this means that electrons are transferred from a higher energy state in a more active metal to a lower energy
state in less active metals. For example, in the reaction between zinc metal and copper sulfate, zinc ions replace copper ions in
solution:

Zn(s) + CuSO (aq) ⟶ ZnSO (aq) + Cu(s)

4 4
C15-3-5

In this reaction the zinc atom transfers two electrons to the copper ion, and zinc is oxidized. Its oxidation number changes from 0
to +2, while copper accepts two electrons and is reduced; its oxidation number changes from +2 to 0. The redox nature of this reaction
is clearly apparent from the net ionic reaction:

Zn(s) + Cu
2 +
(aq) ⟶ Zn
2 +
(aq) + Cu(s) C15-3-6

Zinc is a more active metal than copper; the valence electrons have higher energy in zinc metal than in copper metal. This
difference in stability provides the driving force for this reaction. Similarly, the difference in the activity of different metals provides the
driving force for other reactions of metals. Indeed, metals can be arranged according to their decreasing activity, forming the activity
series. The most active metals lose electrons most easily, and are listed at the top. The inert metals that give up their electrons with
great difficulty are listed at the bottom. The activity series is presented in Table T15-3-1.
 Table T15-3-1. Activity series for metals
Element Oxidation half reactions
Lithium Li → Li + + e−
Potassium K → K + + e−
Barium Ba → Ba 2+ + 2e−
Active Calcium Ca → Ca 2+ + 2e−
Sodium Na → Na + + e−
Magnesium Mg → Mg 2+ + 2e−
Aluminum Al → Al 3+ + 3e−
Manganese Mn → Mn 2+ + 2e−
Zinc Zn → Zn 2+ + 2e−
Chromium Cr → Cr 3+ + 3e−
Iron Fe → Fe 2+ + 2e−
Cadmium Cd → Cd 2+ + 2e−
Cobalt Co → Co 2+ + 2e−
Nickel Ni → Ni 2+ + 2e−
Tin Sn → Sn 2+ + 2e−
Lead Pb → Pb 2+ + 2e−
Hydrogen H 2 → 2 H+ + 2e−
Copper Cu → Cu 2+ + 2e−
Silver Ag → Ag + + e−
Inert Mercury Hg → Hg 2+ + 2e−
Platinum Pt → Pt 2+ + 2e−
Gold Au → Au 3+ + 3e−

You may notice that the alkali and alkaline earth metals (group 1 and 2) appear at the top of the table (they are easily oxidized),
which is consistent with their low ionization energy. Yet the activity series matches ionization energy trends only very crudely. For
example, lithium is more active than potassium, even though it has a higher first ionization energy. Ionization energies measure the
ease of removal of an electron from an isolated atom in the gas phase. However, the activity series represents the ease with which an
electron may be removed from a solid-state metal and transferred to an ion in aqueous solution.

From the point of view of the driving force of a single-exchange redox reaction, we can conclude that a metal higher in the
activity series will reduce any metallic element below it and displace it from its compounds. Zn(s) will reduce Cu2+ (C15-3-5), and Cu(s)
will reduce Ag+ , but no reaction will take place between Zn2+ and Cu(s), or between Cu2+ and Ag(s).

The activity series includes hydrogen. All metals above hydrogen in the activity series react with water or aqueous acids to
reduce H+(aq) to H2(g). The most active metals (K, Na, and Li , for example) react violently with water, reducing H+ within the water
molecules. Less active metals like magnesium and zinc react sluggishly with water; Zn, for example, reacts imperceptibly slowly at
room temperature. Increasing the temperature or adding acid can accelerate these reactions. In general, higher temperatures
accelerate chemical reactions by increasing the energy of the reactants. The addition of an acid increases the concentration of H+
(which is actually in the form of H3O+) and facilitates the reaction. Examples of these reactions are provided below:

0 +1 +1 0

2 K(s) + 2 H O(ℓ) ⟶ 2 K OH(aq) + H2 (g)

C15-3-7
2

0 +1 +1 0

2 Na (s) + 2 H O(ℓ) ⟶ 2 Na OH(aq) + H2 (g)

C15-3-8
2

0 +1 +2 0

Mg (s) + 2 H O(ℓ) ⟶ Mg (OH) (aq) + H2 (g)

C15-3-9
2 2

0 +1 +2 0

Zn(s) + 2 H Br(aq) ⟶ ZnBr (aq) + H2 (g)

C15-3-10
2
 However, not all metals react with water. Metals that are below hydrogen in the activity series do not produce H2 in water , even
at higher temperature or in the presence of acids. Such metals are commonly called noble metals because of their resistance to
oxidation; they are often used in the production of jewelry because they do not tarnish in air. It is possible to oxidize noble metals if the
acid used is a strong oxidant. For example, the noble metal copper reacts with nitric acid: copper is oxidized and the nitrogen of the
nitrate ion is reduced, forming nitrogen dioxide. The oxidation states of Cu and N are included below the reaction in C15-3-11.

0 +5 +2 +4

Cu(s) + 4 H N O (aq) ⟶ Cu(NO ) (aq) + 2 H O(ℓ) + 2 N O (g)

C15-3-11
3 3 2 2 2

Gold is also a noble metal, and the least active of all metals. However, it can be oxidized by a 1:3 mixture of concentrated nitric
and hydrochloric acid called aqua regia as shown in C15-3-12. The oxidation states of Au, N and H are included below the reaction.
Notice that even though H+ is a reactant, its oxidation number does not change (it is not part of the redox process). In this case the
nitrogen of the nitrate gets reduced, yielding nitrogen oxide.

0 +5 +1 +3 +1 +2

Au (s) + N O
−
(aq) + 4 H
+
+ 4 Cl
−
⟶ Au Cl
−
(aq) + 2 H O(ℓ) + N O(g)
C15-3-12
3 4 2
15-4 Stoichiometry

Molar ratios of reactants and products expressed in balanced equations

are the basis of all stoichiometric calculations

Stoichiometry is the application of proportions to chemical reactions. It allows us to calculate and measure out the amounts of
reactants needed to carry out a reaction, and to predict the amounts of products formed. It all starts with a balanced equation that
describes the transformation taking place. For example, the coefficients in the equation for the combustion of hydrogen to yield water
tell us that 2 molecules of hydrogen combine with one molecule of oxygen to form two molecules of water (C15-4-1).

2 H (g) + O (g) ⟶ 2 H O(l)

2 2 2
C15-4-1

Table T15-4-1 Stoichiometry of combustion of H2

Equation 2 H 2(g) + O 2(g) → 2 H 2O(ℓ)

structures + →

molecules 2 molecules of H 2 + 1 molecule of O 2 → 2 molecules of H 2O

mass (amu) 4.0 amu of H 2 + 32.0 amu of O 2 → 36.0 amu of H 2O
amount (mol) 2 mol of H 2 + 1 mol of O 2 → 2 mol of H 2O
mass (g) 4.0 g of H 2 + 32.0 g of O 2 → 36.0 g of H 2O

We can express this information as the masses of elements participating in the reaction. Using atomic masses we calculate that
two molecules of hydrogen have a mass of 4.0 amu, while a molecule of oxygen has a mass of 32.0 amu. When the reaction is over,
we should have 36.0 amu of water.

Of course, it is impractical to measure or manipulate such small quantities. Even if we wanted to carry out the reaction on a
molecular scale, dealing with just a couple of molecules is extremely hard, if not impossible. We need to convert the proportions
expressed in the chemical equation to practicable scale. The mole is the perfect "conversion" tool. On a macroscopic scale, the
proportions are the same as on the microscopic scale; we have two moles of hydrogen (H2) reacting with one mole of oxygen (O2) to
produce 2 moles of water (H2O). Instead of dealing with individual molecules, we deal with Avogadro's numbers of them.

We can measure out the 4.0 g of H2 and 32.0 g of O2 needed to produce 36.0 g of H2O. We are also not limited to whole number
molar quantities; we can double or quarter the scale of our reaction, or we can multiply the amounts by any whole or fractional
multiplier. The mass ratio of the two reactants will always remain 1:8. The power of proportion will always deliver just the right relative
amounts of reactants, and allows us to predict the amount of products that will be formed from any given amount of reactants.

Basic stoichiometric calculations always rely on the proportion of moles of reactants and products, as derived from the
stoichiometric coefficients of a balanced chemical equation (F15-4-1). The number of moles is commonly obtained from direct
measurements of the masses of the substances involved. For gases, the number of moles can be obtained from the ideal gas law,
given the pressure, volume and the temperature. For a given volume of solution, the number of moles may be obtained directly, if the
molar concentration is known, or indirectly if the weight percent and mass of the solution or its density are known. Whatever
information is available, finding the solution is a matter of converting the given values into moles using unit conversions and
stoichiometry.
Figure F15-4-1. Basic stoichiometric calculations always rely on the proportions of reactants and products. These are derived from the
stoichiometric coefficients of the balanced reaction equation. We convert experimentally measured quantities (mass, concentration,
P,V,T of a gas) to moles using appropriate connections.

A well-designed problem-solving strategy utilizing ICF tables facilitates all

stoichiometric calculations

Next we need to know how to use the information provided to solve stoichiometry problems. The real challenge in doing this is
mapping out a problem-solving strategy without being distracted by side-tasks. The "moles of reactants" to "moles of products" ratio
will always be at the center of our strategy (F15-4-1), while other calculations and conversions will play a "supporting" role. To be
successful we must organize the given information and find connections between this information and the quantities we need to
determine. The balanced chemical reaction, which provides the stoichiometric coefficients, is the most important part of this strategy.
Starting with the balanced reaction, we can develop a basic template that will allow us to organize the given information and chart the
steps we must execute to reach the solution.

Basic Template:

1. Write the balanced chemical equation for the reaction.

2. Make an ICF table (Initial, Change, Final) below the equation and enter the given information. Make note of what you want to determine as well.

Start by including a row to record experimental information given or to be determined and a row for additional information needed to make the
connections to numbers of moles.

In this second row, note connections between measured quantities and moles.

I. When given mass, use formula weight (FW) to get numbers of moles.
II. For solutions, use molarity (M) and volume (V) to get numbers of moles.
III. For gases, use P, V, and T within the ideal gas equation to get numbers of moles.

Below this initial information, add more rows for the initial number of moles, (I), calculated from the experimental quantities, the change in number of
moles (C) as the reaction proceeds to completion, the change in experimental quantity, and the final number of moles (F) after the reaction is done. You may
supplement the table with additional rows converting the number of moles into the masses of reactants and products. We will call this table the ICF table to
indicate that it tracks the number of moles from their initial quantities to the final values.

3. Solve the problem. Fill in the table until you are able to solve the problem.

I. Use the connections to convert given measured quantities into moles, and the final number of moles back to experimentally determinable quantities.
II. Use the stoichiometry of the balanced reaction (the mole ratios) to relate the number of moles of reactants to the number of moles of products.
III. Use conservation of mass (total mass of reactants = total mass of products) when it is appropriate.

4. Make sure your answer is reasonable.

As you peruse the examples provided to illustrate this problem-solving strategy, note that not all steps or connections are used
for every problem, just as in some problems not all of the information provided will be needed to answer the questions asked. The
ability to determine which information is relevant to the posed question is an important skill that is best developed through abundant
practice.

Consider this example of a combustion reaction:

 Example 1. If a clean-burning engine burns exactly 1 gallon of gasoline, how many grams of CO2 will it produce?
Assume that the gasoline consists of only octane and that its density is d = 0.6929 g/mL.

The essence of the reaction that the example addresses is the conversion of octane (and oxygen) to carbon dioxide (and water)
as expressed in the balanced equation (C15-4-2):

2C H
8 18
(l) + 25 O (g) ⟶ 16 CO (g) + 18 H O(g)
2 2 2
C15-4-2

Our strategy for solving the problem will center around finding out how many moles of octane (C8H18) will burn, as it—being the
sole carbon-containing reactant—will determine the number of moles of CO2 produced, taking into account the 2:16 molar ratio of the
reactant (octane) to the product (CO2). The supporting calculations will include calculating the number of moles of octane available,
and the conversion of moles of CO2 produced into grams of CO2. The complete calculations using our strategy outlined above are
presented on a separate page, but the example brings into focus two additional concepts that we need to consider. In our example, we
assumed that we had an excess of oxygen, and that the entire amount of octane was converted completely into the product. This may
not always be the case.

The theoretical and actual yields of products are determined by

the amount of the limiting reactant

The reactant that is used up first in a reaction is called the limiting reactant (or limiting reagent); its amount limits the amount of the
product that can form in the reaction. Excess reagents are those present in quantities greater than necessary to completely react with
the limiting reagent. In our example, octane was the limiting reactant, and oxygen was the excess reactant.

The limiting reactant sets the upper limit on the amount of product that the reaction can produce. This amount is called the
theoretical yield. The theoretical yield is the amount that will be produced if the reaction works perfectly, as predicted by the reaction’s
stoichiometry. A calculation based on the balanced equation and the amount of limiting reactant available predicts a theoretical yield of
products. In our example, we assumed that the octane was completely converted to CO2 as the only carbon-containing product; we
calculated the theoretical yield of carbon dioxide. In practice, the actual yield, the amount actually obtained from the reaction, is less
than the theoretical yield. This outcome may be due to an incomplete reaction, side reactions (formation of other products), or
mechanical losses during the separation of the product from the reaction mixture. During hydrocarbon combustion, other carbon
containing products may form, such as carbon monoxide or soot (carbon particles); these are formed in side reactions that decrease
the actual yield of the expected product. We neglected such complications in our example by assuming there would be clean,
complete combustion.

In general, chemists calculate percent yield using equation E15-4-1. The percent yield is usually less than 100%, and cannot
ever be more than 100%. Efficient reactions have high yields (>90%).

actual yield
% yield = × 100% E15-4-1
theoretical yield

Many commercially important products, such as pharmaceuticals, are produced in multistep reactions. If the synthesis
(preparation from simpler components) involves just 7 steps and each has 90% yield, the desired product is obtained in only 48% yield
(0.97), meaning that over 50% of the materials are lost in the entire process. This simple calculation illustrates the importance of
finding reaction conditions that maximize the percent yield. For example, we might change the temperature or add a catalyst.

To understand how to use the limiting reagent, let's consider another example:

Example 2. Lithium oxide is used on the space station to remove water from the air via the following reaction. If we
need to remove 100.0 kg of water and 82.00 kg of Li2O is available, which is the limiting reactant? How much
product is formed?

Li O(s) + H O(g) ⟶ 2 LiOH(s)

2 2
C15-4-3

In this example, the mole ratio of the two reactants is 1:1. In cases like this we can determine the limiting reagent by comparing
the number of moles of each reactant. The limiting reagent will be the one with the smaller number of moles. The complete
calculations for this example are presented on a separate page. When the mole ratio of reactants is not 1:1, or if more than two
reactants are involved, it is a bit harder to determine which is the limiting reagent.
 There are two approaches to determining the limiting reactant. The first approach is to choose one of the reactants (usually the
first one in the balanced reaction) and determine the number of moles of the second reactant needed to react completely with the first
by using the stoichiometric mole ratio. If the number of moles of the second reactant is equal to or greater than the number of moles
needed to react completely, then the first reactant is the limiting reagent (it will be used up completely). However, if there is not enough
of the second reactant to react completely, then the second reactant is the limiting reagent. The second approach is to assume in turn
that each reactant is the limiting reagent and calculate the number of moles (or mass) of one of the products. The limiting reagent is
the one that produces the smaller amount of product.

We will illustrate both of these methods in Example 3:

Example 3. Silicon carbide (SiC) is widely used in the production of car brakes (because of its abrasiveness and
high thermal endurance) and in the production of high-temperature semiconductor electronics. It is made from sand
(SiO2) and carbon at high temperatures. CO is also formed as shown in C15-4-4. If 100.0 kg of sand reacts with
100.0 kg of C, and 55.0 kg of SiC are formed, what is the percent yield?

SiO (s) + 3 C(s) ⟶ SiC(s) + 2 CO(g)

2
C15-4-4

Since we base the percent yield calculation on the amount of the limiting reagent available, we need to start by determining
which reagent is present in a limiting amount. Reaction stoichometry indicates that in this case, we need three times as many moles of
carbon as SiO2; our calculations (see this separate page), therefore, must account for this ratio.
15-5 Example calculations

Stoichiometric calculations are central to quantitative analysis of chemical reactions

Stoichiometry calculations form the basis of quantitative examination of chemical reactions with regard to mass balance, but their use
is not limited to calculating the masses of products and their yields. We can apply these concepts to any chemical reaction, including
combustion, elemental analysis, redox reactions, solution reactions, acid-base reactions, titrations, or reactions of gases (utilizing the
ideal gas law). To be able to apply our problem-solving template to such situations we have to understand the nature of the
experiment so we can extract and interpret the numerical data correctly.

Elemental analysis applies stoichiometry to determine compositions of compounds

For example, you may recall that when we discussed molecular composition we used elemental analysis based on the combustion of
a known amount of the sample. Now that we understand reactions better, let’s consider another example of calculations directed
toward finding the empirical formula from the experimental data.

Example 4. An alcohol is composed only of C, H, and O. A 4.00 g sample of the alcohol is completely combusted
with an excess of oxygen, producing 7.65 g of CO2 and 4.70 g of H2O. What is the empirical formula of the alcohol?

To get the empirical formula we need to determine the molar ratio of the elements present, x:y:z in CxHyOz. In this case we
cannot start with the balanced equation for combustion as we do not know the formula of the alcohol, which is precisely what we need
to find out. We know that the complete combustion will convert all carbon atoms present in the alcohol into carbon dioxide and all
hydrogen atoms into water. We will not be able to directly learn about the oxygen content because oxygen atoms are present in both
reactants (the alcohol and O2) and both products (CO2 and H2O). However, we have information on the identity (CO2 and H2O) and
the mass of the products formed in the combustion. Thus, we can calculate both the molar ratio of carbon to hydrogen and the mass of
carbon and hydrogen in the products. Applying the mass conservation law, we can then calculate the mass of oxygen in the sample
as we know the mass of the sample that was analyzed. The calculations in this case proceed in the "reverse" order; we start with
masses of products to learn about the composition of the reactants, but the use of stoichiometric proportions (F15-4-1) and the overall
scheme of "connecting" masses with moles remain the same.

Titrations illustrate concentration-based stoichiometry calculations for reactions in solution

The example above illustrates how molar ratios are the true underpinning of stoichiometric calculations. If molar information can be
obtained by other means, such calculations do not need to involve masses of reactants or products. For example, consider a titration
experiment where a known volume of solution with an unknown concentration is allowed to react with a solution of known
concentration called the titrant. The volume of the titrant needed to react completely with the unknown can be measured, and the
concentration of the unknown solution can then be determined using the stoichiometry of the balanced reaction.

Figure F15-5-1. Titration of an acid with a base. A sample of H2SO4 (aq) of unknown
concentration (the analyte) is analyzed. A base solution of known concentration (NaOH, the
titrant) is added dropwise from a burette (a long, calibrated tube with a stopcock at the
bottom end). Phenolphthalein is added to the H2SO4 solution and acts as an indicator
by turning the solution pink when a small excess of base is added beyond the equivalence
point. In the example shown, the volume of titrant used is 12.3 mL.
 In an acid-base neutralization reaction experiment (F15-5-1), a strong base of known concentration is added drop-wise to a
solution of a strong acid of unknown concentration (or vice versa) and the volume needed to reach the equivalence point (or endpoint)
is measured. The titration equivalence point is the point when the amount of H+ and HO− ions in the solution is equal, usually indicated
by a change in the color of an indicator added to the solution.

Example 5. If 12.3 mL of 0.200 M NaOH solution is needed to neutralize 10.0 mL of H2SO4 solution, what is the
concentration of H2SO4?

Since we want to find the concentration of sulfuric acid, we want to use the balanced molecular equation rather than the net ionic
equation. Taking into account that sulfuric acid is a diprotic acid (it can give up two H+ ions), we need two moles of NaOH for each
mole of the acid to neutralize it completely. The numbers of moles present in solution are easily obtained if the molar concentrations
are known (n = V × M). In this case, the stoichiometric calculations follow the basic template. The full solution is presented on a
separate page.

Stoichiometric calculations involving gases utilize the ideal gas law

to quantify moles of gaseous reactants and products

Gas reactions are also amenable to stoichiometric calculations, and may involve volume or pressure rather than mass quantities. In
general, the ideal gas law provides sufficient accuracy for reactions near room temperature and under relatively low pressures. In
many cases, even further simplifications are possible. To illustrate, let’s consider another example:

Example 6. A reaction between ozone (O3) and water was carried out at 40 °C and 780 mmHg as shown in C15-5-1
below. How many liters of ozone are needed to produce 3 L of O2?

O (g) + H O(l) ⟶ H (g) + 2 O (g)

3 2 2 2
C15-5-1

Given the balanced equation and a specified temperature and pressure, one might be tempted to use the ideal gas law to
calculate the number of moles. However, that is unnecessary, as all measurements are of gases at constant P and T. Under these
conditions, the number of moles is directly proportional to the gas volume as stated in Avogadro's law (n = V(P/RT)const). From the
reaction stoichiometry we can set up a simple proportion: one mole of ozone produces 2 moles of oxygen, and thus 1 L of ozone
produces 2 L of O2. Therefore, we need 1.5 L (1 × 3/2 L) of ozone to produce 3 L of O2.

In other reactions involving gases the use of the ideal gas law may be needed. Such is the case in heterogeneous reactions
combining masses of solid species or concentrations of solutions with gas calculations. We always convert the given information to
moles, and use the stoichiometry of a balanced reaction. Let’s consider the following example:

Example 7. Sodium azide, NaN3, is used in automobile airbags to produce a large volume of N2 gas within
milliseconds of a collision as shown in C15-5-2 below. How many liters of N2 gas at 735 mmHg and 26 °C are
produced from 126 g of NaN3?

2 NaN (s) ⟶ 2 Na(s) + 3 N (g)

3 2
C15-5-2

This calculation follows the established pattern. Since we are already given the balanced reaction, we follow our standard
template and first calculate the number of moles of sodium azide available and then, using reaction stoichiometry, calculate the
number of moles of N2 produced. Only in the final stages of our calculations we use the ideal gas law to calculate the volume of gas
formed under the specified conditions. As the result of our calculations illustrate, a relatively small sample of solid NaN3 can very
rapidly provide a large quantity of gas that fills the airbag, cushioning the car occupants and minimizing the effects of a collision.
15-6 Drug binding to proteins

Most drug molecules bind to and alter the activity of a target protein or RNA

The pharmaceutical industry is a multibillion dollar industry that develops medications that treat a wide range of diseases, from
bacterial and viral infections to cancer and asthma. Understanding how these medications work is critical for a range of professions,
such as doctors, pharmacists, and nurses. In this section we’re going to examine how drug molecules work at the molecular level.
Drugs, which are usually small molecules, typically work by binding to either a protein or RNA in a way that changes the activity of the
protein/RNA. Exactly how this works varies from one drug to the next and depends on the biological role of the target protein/RNA. The
most common scenario, presented in Figure F15-6-1, is for the target protein (blue) to be an enzyme that is turned “off” and rendered
nonfunctional when a drug molecule (yellow) binds to it. Figure F15-6-2 shows an example of this in which a drug called gefitinib
(colored magenta) binds to an enzyme called EGFR (epidermal growth factor receptor, colored cyan). The EGFR enzyme catalyzes a
reaction that transfers a phosphoryl (-PO32−) group onto the side chains of certain amino acids. This reaction acts as a regulatory
signal that promotes cell growth. Certain lung and breast cancers proliferate because unregulated EGFR activity continually signals
the cells to grow and divide. Gefitinib is a drug used to treat patients with such cancers, and it works by binding to EGFR and
preventing it from catalyzing its phosphoryl transfer reaction, thus removing the signal that tells the cancer cell to grow.

Figure F15-6-1. Many drugs work by binding to an enzyme an inhibiting its activity. Shown is a schematic in which a small drug
molecule (yellow) binds to an enzyme (blue). The free enzyme is active and able to catalyze its particular chemical reaction. The drug-
bound enzyme, however, is inactive (or inhibited), meaning that it is no longer capable of converting substrates (reactant molecules)
into product molecules.

Figure F15-6-2. Gefitinib is a specific example of a drug that binds to an enzyme in order to inhibit its function. Shown are three-
dimensional models of a drug called gefitinib (magenta) binding to an enzyme called EGFR (cyan). The structure on the right shows
the drug-enzyme complex.

Enzymes bind to their substrates in order to catalyze chemical reactions

To understand how drugs inhibit an enzyme, it’s helpful to first understand the cycle of events that take place during enzyme-catalyzed
reactions (F15-6-3). Recall that an enzyme is a biological catalyst (usually a protein) that catalyzes a chemical reaction. The reactants
in an enzyme-catalyzed reaction are called the substrates. In order to react, the substrate binds to the enzyme in a location called the
active site. The active site is a binding pocket (or cavity) on the enzyme whose size and shape complement the substrate, allowing it to
fit inside. The active site possesses chemical features that, in one way or another, accelerate the rate of the chemical reaction. The
active site accelerates reactions through several means, including 1) holding reactants close together and in the right orientation to
react, 2) by positioning key amino acids in just the right locations so that they can participate in the reaction, and 3) by stabilizing the
high energy transition state that transiently exists as bonds are formed and broken during the reaction. During the reaction the
substrate is converted to product and released from the enzyme. The free enzyme, which has returned to its original state, can
participate in this cycle again and again, converting more substrate molecules into product. Via this cycle a single enzyme molecule
can convert a multitude of substrate molecules into product.

Figure F15-6-3. Enzymatic catalysis requires the enzyme to bind to its substrate in order to convert it to product. Enzymatic
catalysis can be viewed as a cycle in which the free enzyme (blue) binds to the substrate (red), catalyzes the reaction to form the
product (green), and then releases the product to complete the cycle. This process can repeat indefinitely, allowing a single enzyme
molecule to convert thousands of substrate molecules into product. Thus, enzymes are an excellent target for drug molecules because
targeting a single enzyme molecule can allow a drug to have a significant effect on the chemistry that takes place inside of a cell.

Effective drugs bind to specific targets

There are many, many enzymes in the human body, and many of them are evolutionarily similar to one another. The EGFR enzyme
that we saw before, for example, belongs to a group of enzymes called kinases. Kinases are common regulatory enzymes that control
many vital cellular processes. In fact, the human genome encodes 518 different kinase enzymes, most of which have similar structures
and active sites. This presents a problem of specificity for scientists who design drugs: the drug molecule must be specific and bind
only to the target of interest, and not to the other “look-alike” enzymes (F15-6-4). In the case of gefitinib, that means that it must bind
specifically to EGFR while avoiding the other 517 kinase enzymes since inhibiting those other kinases could do incredible harm to the
patient who’s taking the drug. To accomplish this, scientists must design drug molecules that have three-dimensional shapes that
perfectly complement the size and shape of the binding pocket they wish to bind. Just like your hand fits into a glove, the drug
molecule is engineered to fit perfectly into the binding site on the enzyme. No drug is perfect though, and at high enough
concentrations, drugs will often begin to bind to enzymes other than the intended target, often causing detrimental effects; these “off-
target” effects are a major source of drug side effects.

Figure F15-6-4. Effective drugs bind specifically to the correct target enzyme. Here the drug (yellow) binds only to a target
enzyme (blue) and not to other off-target enzymes with similar shapes and sizes.

Enzymes can be inhibited by competitive, noncompetitive, or covalent inhibitors

Drugs that inhibit enzymes generally fall into three categories. These three types of inhibitors are: 1) competitive inhibitors, 2)
noncompetitive inhibitors, and 3) covalent inhibitors. Competitive inhibitors are perhaps the simplest class; they work by binding non-
covalently to the active site of the enzyme. By binding to the active site, the competitive inhibitor blocks access to the active site,
preventing substrates from binding, and preventing the reaction from being catalyzed. In other words, competitive inhibitors “compete”
with the substrate to bind to the enzyme’s active site. Gefitinib, from figure F15-6-2, is an example of a competitive inhibitor. Other
drugs work by noncompetitive inhibition, meaning that they bind to locations other than the active site. Upon binding, noncompetitive
inhibitors often subtly change the folded shape of the protein in ways that prevent the enzyme from functioning correctly. Covalent
inhibitors react chemically with the active site of the enzyme, altering its structure in often irreversible ways. The pain reliever aspirin
(acetylsalicylic acid) is a familiar example of a covalent inhibitor. C15-6-1 shows how aspirin reacts with the active site of the
cyclooxygenase (COX) enzyme, permanently transforming a key serine side chain into an ester. The single, one-way arrow in C15-6-
1 indicates that this process is irreversible, as opposed to the bidirectional arrows in F15-6-2, which indicate a reversible process. We
will see later that common antibiotics like penicillin and amoxicillin are also covalent inhibitors.

C15-6-1

Changes in entropy and enthalpy take place during drug binding

The binding of a drug to a protein can be viewed like a chemical reaction. It involves changes in enthalpy (H) and entropy (S) as
intermolecular forces are broken and formed and as molecules gain and lose entropy. How well the drug binds to the protein depends
on these changes in enthalpy and entropy. A drug will bind most favorably when entropy increases (ΔS > 0) and enthalpy decreases
(ΔH < 0) during binding. We will now consider each of these terms.

Changes in enthalpy occur when bonds and IMFs form or break. Breaking bonds and IMFs absorbs energy (increasing
enthalpy). Forming bonds and IMFs releases energy (decreasing enthalpy). Figure F15-6-5 describes the IMFs that form and break
when a drug and protein bind to one another. Prior to binding, both the drug and protein are surrounded by water molecules. In order
to bind to one another, the drug and protein must give up some of the interactions that they were forming with water. Thus, upon
binding, drug-water and protein-water interactions must break. Breaking interactions is unfavorable and makes ΔH more positive. This
is balanced out, however, by the drug-protein interactions that are formed. Additionally, the water molecules that are released from the
drug and binding pocket are returned to the bulk solvent where they can form interactions with other water molecules. Thus, the drug-
protein and water-water interactions that form contribute favorably to ΔH, making it more negative. Since enthalpy is a state function,
the overall enthalpy change that takes place during the binding is the sum of these component steps.
 Figure F15-6-5. Changes in enthalpy take place during drug binding as IMFs form and break. Panel A shows the net reaction in
which a solvated drug binds to a solvated binding pocket. Panel B shows the same process broken down by each component step that
contributes to the overall change in enthalpy. Notice that the final state is lower in enthalpy than the initial state, implying an overall
negative enthalpy change, which is typical for most instances of drug-protein binding.
 Changes in entropy also take place when a drug bindings to a protein. You should recall that the thermodynamic quantity called
entropy can be simplistically described as the amount of randomness in a system. Increasing entropy favors spontaneity (increasing
randomness), while decreasing enthalpy favors spontaneity (decreasing energy and increasing stabilization). In this case, the enzyme
and drug move and rotate independently one of another prior to the binding of the drug to a protein, but after binding they move and
rotate as a single complex. This reduces the modes of motion that exist, reduces their entropy, and makes ΔS more negative and
unfavorable (F15-6-6, top panel). The binding of the drug to the enzyme also tends to rigidify the drug molecule. This is because when
the drug is free it is capable of adopting a wide range of conformations, but in order to fit into the binding pocket of the enzyme the
drug must adopt a specific conformation. This lowers the entropy of the drug molecule because it loses conformational freedom,
making ΔS more negative (F15-6-6, middle panel). These unfavorable changes in entropy are balanced out by a favorable increase in
entropy coming from the hydrophobic effect (F15-6-6, bottom panel). Drug molecules and binding pockets often contain hydrophobic
surfaces that when solvated by water cause water to form low-entropy, ice-like structures [See hydrophobic effect]. Upon drug
binding, these hydrophobic surfaces are concealed from water, releasing the ordered water molecules and increasing their entropy,
making the ΔS of drug binding more positive. Entropy is a state function; therefore, the overall entropy change that takes place during
the binding is the sum of these component steps.

Figure F15-6-6. Changes in entropy occur when a drug binds to a protein. Top panel (ΔS1): the enzyme and drug move
independently prior to binding but move together as a complex after binding. This leads to a loss of entropy upon binding since modes
of motion are lost. Middle panel (ΔS2): prior to binding the drug is able to adopt a wide range of conformations. After binding the drug is
locked into a specific conformation that fits into the binding pocket. This loss of conformational freedom results in a decrease in
entropy. Bottom panel (ΔS3): the drug and binding pocket contain hydrophobic surfaces. When the drug binds, the hydrophobic
surfaces are concealed from water, releasing ordered water molecules and increasing their entropy.
15-7 Arrow pushing mechanisms

The arrow pushing formalism is used to describe the mechanisms of organic and biochemical reactions

In this section we will introduce a formalism for describing the movements of electrons that take place during chemical reactions. As
we have seen already, a chemical reaction is a rearrangement of valence electrons that typically leads to the cleavage and/or
formation of bonds. The specific electron movements associated with each reaction are described by the reaction mechanism.
Reaction mechanisms show where electrons originate in the reactant and where they ultimately reside in the product. This is
represented graphically using a formalized system called arrow pushing in which the movement of electrons is diagrammed using a
series of curved arrows. Arrow pushing mechanisms are commonly used to describe organic and biochemical reactions. Many such
reactions occur in multiple discrete steps, with a separate arrow pushing mechanism used to describe the electron movements
associated with each reaction step.

Arrow pushing diagrams adhere to the following rules:

1. Each arrow represents the movement of one pair of valence electrons.

2. Each arrow begins where the pair of electrons originates (either a lone pair of electrons or a bond) and ends where the
electrons are going (either an atom or a bond).
3. An arrow that starts at an atom represents the movement of a lone pair of electrons.
4. An arrow that starts at the center of a bond represents the breaking of that bond.
5. An arrow that ends at an atom represents the formation of a new covalent bond or a new lone pair.
6. An arrow that ends at a bond represents adding of a bond to form a double (or triple) bond.

Shown in Figure F15-7-1 are four generic examples of arrow pushing mechanisms that involve just one arrow. The top panel
shows an example in which an arrow points from a bond to one of the atoms in the bond. This arrow represents the movement of the
electron pair from the bond onto the indicated atom as a lone pair. Notice that the bond broke, which makes sense since the electron
pair that made up the bond was transformed into a lone pair. Also notice that this shift in electrons changed the formal charges of the
atoms that were involved; the atom that received the electrons became one unit of charge more negative while the atom that lost the
electrons became one unit of charge more positive. The second panel shows a mechanism that is essentially the opposite of the
previous one. This arrow points from a lone pair to a separate atom. This arrow signifies that the lone pair is being used to form a bond
between the two atoms. Notice, again, that the formal charges of the atoms have changed in the product, with the atom that gave up
its lone pair becoming one unit of charge more positive, with the other atom becoming one unit of charge more negative. The third
panel shows an arrow pointing from a double bond to one of the atoms in the bond. This signifies that one of the electron pairs in the
double bond will become a lone pair on the atom to which the arrow is pointing. This transfer of electrons out of the double bond will
decrease the bond order by one, transforming the bond into a single bond. The formal charge of the atom that receives the electron
pair becomes one unit of charge more negative, whereas the other atom becomes positive. The last panel shows an arrow that points
from a lone pair to a bond with an adjacent atom. This arrow means that the lone pair will be used to form an additional bond between
the two already-connected atoms. Thus, the bond order will increase by one. The atom that gives up its lone pair becomes positively
charged and the other atom became negatively charged.
 Figure F15-7-1. Examples of arrow pushing mechanisms involving only one arrow. Shown are four examples of reaction
mechanisms that involve a single arrow. The left-hand column shows generic examples using hypothetical atoms “X” and “Y”. The
middle column shows an example of an actual chemical reaction with the indicated mechanism. The right-hand column indicates the
interpretation for each arrow. In each example, the transferred pair of electrons is highlighted in blue on both the reactant and product
sides of the reaction equation.

By convention, we always use double-hooked arrows to demonstrate the movement of electron pairs. To specify the movement
of an individual electron, we use a single-hooked arrow. Reactions that involve the transfer of individual electrons are relatively rare, so
most arrow pushing mechanisms that you see will feature only double-hooked arrows. F15-7-2 shows the difference between these
two arrow types. It is also important to note that we always use curved arrows to show reaction mechanisms rather than straight
arrows. Straight arrows are used to separate products from reactants rather than to show electron movement.

Figure F15-7-2. Double-hooked arrows show the transfer of two electrons, whereas single-hooked arrows show the transfer of
one individual electron.

Bond-forming reactions involve a nucleophile and an electrophile

As we have seen, many molecules contain atoms that carry full or partial charges. Reactions between molecules (small molecules or
functional groups on macromolecules) often occur when the electrons from an atom carrying a negative charge (full or partial) form a
bond with an atom in another molecule that carries a positive charge (full or partial). For reactions in which a bond is formed between
atoms that were not previously bonded, the electron-rich atom from which the bond-forming electrons originate is known as the
nucleophile and the electron-deficient atom that receives these electrons to form the new bond is known as the electrophile. As the
name implies, nucleophiles are “nucleus-loving” (philos being Greek for love). This means that the nucleophile is attracted to the
positive charge of the nucleus; therefore, the nucleophile itself is typically negatively or partially negatively charged. In contrast,
electrophiles are “electron-loving” and are attracted to negative charges; therefore, the electrophile itself is typically positively or
partially positively charged.
 Shown in Figure F15-7-3 are examples of nucleophiles and electrophiles in simple bond-forming reactions. The top panel shows
a generic reaction in which a nucleophile is forming a bond with an electrophile. The nucleophile is the atom that provides the electrons
used to form the new bond (shown in red). The electrophile (shown in blue) is receiving the bond-forming electrons (shown in red). The
middle panel shows an example in which a hydroxide ion (OH−) is providing a pair of electrons to form a new bond to an H+ ion (or
proton), resulting in the formation of a water molecule. In this example the oxygen atom in the hydroxide ion is the nucleophile
because it is providing the electron pair that is being used to form the new bond. The proton, on the other hand, is the electrophile
since it is receiving the bond-forming electrons from the oxygen atom. Notice that in this example the nucleophile and electrophile
carry full charges, with the nucleophile being negative and therefore electron-rich, while the electrophile is positive and therefore
electron-poor. The bottom example shows a reaction between ammonia (NH3) and boron trifluoride (BF3). The nitrogen in ammonia is
the nucleophile since it provides the electron pair that is used to form the new bond. In contrast, the boron atom is the electrophile
since it receives the electron pair from the nitrogen. Notice that in this case the nucleophile and electrophile do not carry formal
charges. Nonetheless, the nitrogen is still electron-rich because it carries a partial negative charge due to its polar bonds with
hydrogen. Similarly, the boron, while formally neutral, is electron-poor due to its empty p orbital as well as its polar bonds with fluorine.

Figure F15-7-3. Bond-forming reactions involve a nucleophile and electrophile. The top panel shows a generic example of a
reaction between a nucleophile (Nu, red) and electrophile (E, blue). The middle panel shows an example of a reaction in which a
hydroxide ion (OH−) reacts with a hydrogen ion (proton or H+) to form a water molecule. The oxygen atom in hydroxide is the
nucleophile since it provides the bond-forming electrons, whereas the hydrogen ion is the electrophile since it receives these electrons.
The bottom panel shows another example in which ammonia (NH3) reacts with boron trifluoride (BF3) to form NH3BF3. The nitrogen in
ammonia is the nucleophile since it provides the bond-forming electrons, whereas the boron atom is the electrophile since it receives
these electrons.

Please note that the designations of nucleophile and electrophile are only used in cases where a new bond is formed between
two atoms that were previously unconnected, which means that in Figure F15-7-1 we would not use the terms nucleophile and
electrophile to describe the atoms in the reactions in the bottom row since in that example the atoms were already directly bonded to
one another prior to the reaction.

Many reactions feature a leaving group that detaches from a larger molecule during the reaction

Another concept that is important in understanding reaction mechanisms is the leaving group. This term is used to describe an atom or
portion of a molecule that separates from the molecule as a result of a bond breaking during a reaction. Leaving groups always take
both electrons from the broken bond with them as they depart. Figure F15-7-4 shows an example of a leaving group in the context of a
bond-forming reaction involving a nucleophile and electrophile. In such a case the leaving group is attached to the electrophile, and
upon forming a bond with the nucleophile the bond between the electrophile and leaving group breaks, with the leaving group retaining
the electrons from the bond as a lone pair. The bottom panel of the figure shows a specific example in which an ammonia molecule
(NH3) is acting as a nucleophile that provides a pair of electrons to a hydrogen atom in a water molecule to form a new bond. The
hydrogen atom that receives these electrons is the electrophile. Hydrogen only has enough valence orbitals to form one bond at a
time, so upon forming this new bond with nitrogen, its previous bond with oxygen breaks. The oxygen retains the electron pair from the
broken bond and detaches from the electrophilic hydrogen as a hydroxide ion. This hydroxide ion is the leaving group in this example.
 Figure F15-7-4. Leaving groups detach from a larger molecule during a reaction. Shown on the top row is a generic example of a
leaving group in the context of a nucleophile/electrophile bond-forming reaction. The nucleophile (Nu, red) provides the electrons
needed to form the new bond, while the electrophile (E, blue) receives those electrons. Simultaneously, the leaving group (LG, green)
detaches from the electrophile, taking the pair of electrons from the broken bond with it. The bottom row shows a molecular example in
which a nitrogen atom from an ammonia molecule (NH3) acts as a nucleophile to form a bond to an electrophilic hydrogen atom in a
water molecule. The remainder of the water molecule (the oxygen and other hydrogen) detach from the electrophile, as a leaving
group, to form a hydroxide ion.

Note that the term leaving group applies whenever a group of atoms detaches from a larger molecule and takes the pair of
electrons from the broken bond with it. This means that the use of this term is not limited to bond-forming reactions that feature a
nucleophile and electrophile. For example, in the top row of Figure F15-7-1, the bromide ion in the product would be considered a
leaving group. In that same figure the oxygen atom in the example on the third row would not be considered a leaving group since in
the product it remains bound to the carbon atom.

Some reactions occur in multiple steps and must be represented by multiple arrow pushing mechanisms

So far, we have largely looked at simple, straightforward reaction mechanisms that require only one or two arrows to represent. Many
reactions, however, occur in multiple steps, which require multiple arrow pushing mechanisms to fully describe (with one set of arrows
per step). Figure F15-7-5 shows an example of such a mechanism. The reaction shown here takes place in two discrete steps, each
represented with its own arrow pushing mechanism. In the first step we see an enolate ion (bottom reactant in step one) reacting with
an acid chloride molecule (top reactant in step one). When analyzing a mechanism that contains multiple arrows, it is best to start at
the initial source of electrons, which in this case is the lone pair on the bottom-left oxygen. The arrow that originates from this lone pair
points to the bond with the adjacent carbon, meaning that the lone pair will be added to the bond, increasing the bond order by one
and creating a double bond. This double bond can be seen in the ketone functional group seen in the product of this step. The next
arrow, which points from the double bond to the carbonyl carbon, is a little more difficult to interpret. This bond is showing that a pair of
electrons from the double bond is going to be used to form a new bond to the carbonyl carbon. The difficult part of interpreting this
arrow comes from deciding which one of the atoms in the double bond is going to form the new bond to the carbonyl carbon. We can
decide this by considering the previous arrow, which told us that the oxygen was forming a double bond to the left carbon in the double
bond. The formation of this new double bond would give that central carbon a total of five bonds, which would cause it to exceed its
octet. Therefore, this left carbon needs one less bond, and when the carbon-carbon double bond breaks, the left carbon will lose
access to those electrons. The right carbon in the double bond, however, still needs to form four bonds to maintain its octet, so this
right carbon becomes the nucleophile. The right carbon in the double bond takes the pair of electrons that it used to share with the left
carbon and uses them to form a new bond to the electrophilic carbonyl carbon. The final arrow in step 1 shows a pair of electrons from
the carbonyl becoming a lone pair on the oxygen, resulting in a single bond and a negative charge on the oxygen. The chemical
structure produced during step 1 is known as an intermediate, a chemical species produced during one step of a chemical reaction
and consumed in a later step.
 Figure F15-7-5. Arrow pushing mechanism for the reaction of an enolate ion with an acid chloride molecule. Shown is the two-
step arrow pushing mechanism as an enolate ion reacts with an acid chloride molecule to form a ketone product.

Step 2 in F15-7-5 shows the arrow pushing mechanism by which the intermediate is consumed and converted to a product. Let
us look first at the arrow that points from oxygen’s lone pair to the carbon-oxygen bond. This arrow signifies that the lone pair is being
added to the bond, raising its bond order to create a double bond. Forming this additional bond to the carbon would give the carbon
five bonds, which is not possible since carbon does not have the capacity to exceed an octet. Therefore, in order to form a new bond,
this carbon must lose one of its previous bonds. The second arrow, which points from the carbon-chlorine bond to the chlorine atom,
tells us that the carbon-chlorine bond is breaking, and chlorine is gaining the electrons as a lone pair. The chloride ion that detaches
from the structure is a leaving group in this reaction.