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Topic 21: Organic Compounds as Acids and Bases

Note to students: This is a single chapter (or a portion of one) from a textbook that is under construction. Therefore you can ignore references to other textbook sections. In general chemistry you learned that molecules that accept and donate hydrogen ions (acids and bases) are fundamental to many areas of chemistry. The molecule responsible for the tart taste of vinegar is acetic acid. Sodium hydroxide is a powerful base used in common drain cleaners. Hydrogen bonding, a sharing of a hydrogen atom by partial bonds to two other atoms, is controlled by acid and base properties, and is critical to many biological systems such as the DNA double helix. Acids and bases are wide spread in organic molecules as well. In studying organic molecules as acids and bases we will learn some fundamental ideas about how the structure of a molecule controls its acidity or basicity. We will use these fundamental ideas of structural effects on chemical reactivity many times throughout our studies of organic chemistry and beyond, in such areas as biochemistry, drug design and biology.

21.1 Why Should I Study This?


Recall from your previous studies that acids are molecules that give hydrogen ions (H+) to other molecules. Hydronium ion (H3O+) is a typical acid. Bases are molecules that accept hydrogen ions from other molecules. Hydroxide ion (HO-) is a typical base. (Hydrogen ions are often called protons, because H+ is a hydrogen atom minus an electron just a proton is left.) Protons influence a very broad range of phenomena. Proton transfers are among the most important bond change events in all of chemistry and biology. For example they influence the rate of enzyme reactions. Hydrogen bonding (proton sharing, or an incomplete proton transfer) is responsible for the physical and chemical properties of water, and hence life as we know it. Therefore an understanding of the principles that control proton transfers is very fundamental to understanding organic and biological reactions.

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This alone is adequate reason to study this topic. However as we explore more complex reactions and molecules you will often apply the fundamental ideas you discovered in your studies of this simple topic.

21.2 Acid Base Reactions


A. H is for Proton Many textbooks use the notation H+ to mean proton source or proton in water. This may mislead you! H+ looks like a hydrogen atom that has lost one electron. What is left? Just the hydrogen atom nucleus: a naked proton. A naked proton is too unstable to exist on its own (except maybe in interstellar space or a high-energy physics experiment), and it must be bonded to a carrier (the shuttle) of some sort. In aqueous solution, the protons are carried by water to form hydronium ion, H3O+. (Even H3O+ is a misnomer as the proton is shared between many water molecules simultaneously. (H2O)nH+ might be more accurate.) In this text we will avoid H+, and will always show the proton with its shuttle. B. Molecular Collisions and Reactions Think Ahead Question 21.1 Write a balanced equilibrium for the autoionization of water: water becomes hydroxide and hydronium ions. What does this equation tell us about the how-and-why of this reaction: To what extent does water ionize? Why does it ionize in the first place? Answer: In liquid water one water molecule can transfer a proton to another water molecule. This process is called autoionization. It is an equilibrium process, as the wandering proton can get taken away from the H3O+ and eventually returned to HO-.
2 H2O acid and base HO- + H 3O+ base acid

In this balanced equilibrium, one water molecule is the acid (proton donor) while the other is the base (proton acceptor). Hydronium ion is also an acid, because it protonates hydroxide ion (a base). The stoichiometry of the equation reveals that two water molecules gives one hydronium ion and one hydroxide ion, and that one hydronium ion reacts with one hydroxide ion to form two molecules of water. Similarly, it suggests that two moles of water give one mole each of
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hydronium and hydroxide ions. However it tells us nothing about the how-and-why molecular events that cause the ionization to occur in the first place, i.e., why is the proton transferred at all? The equation also tells us nothing about whether the left or right hand side of the equilibrium is favored. In summary, the equilibrium equation reveals very little about the reaction except its stoichiometry. To help answer the question of which side of the equilibrium is favored, it is useful to have a mathematical expression. The equilibrium position is quantified by the equilibrium constant, K eq. Mathematically, Keq is the product of concentrations of all species on the right side of the equilibrium divided by the product of the concentrations of all species on the left. For the autoionization of water:
Keq = [H3O+] [HO-] [H2O]2

The equilibrium constant is therefore influenced by what we choose to write on the left or right side of the equilibrium. Since we started with two molecules of water, these go on the left. The products, hydroxide ion and hydronium ion, are written on the right. Interchanging the left and right halves of the equilibrium changes Keq to 1/Keq. Concept Focus Question 21.1 Write balanced equations and Keq expressions for each of these proton transfer equilibria. Label the acid and base on each side. (a) (b)
H C C H + NH2 C C H + NH3

O CH3O + OCH3 CH3OH +

OCH3

CO2H

CO2 + (CH3CH2)3N + (CH3CH2)3NH CO2

(c)
CO2H

(d)

H2NCH2CO2H

H3NCH2CO2

Recall that molecules must approach each other, and then collide, for a reaction to occur. In the case of two water molecules, the molecules start so far apart (in molecular terms). As the distance between the water molecules decreases, they begin to interact.

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Think Ahead Question 21.2 Make a series of drawings showing how two water molecules might approach each other, leading to autoionization. Start with the two water molecules so far apart, and think about how they might interact as the distance between them falls. Answer: As a metaphor, think about encountering a person as you walk down the street. How do you know this is your friend, someone you want to interact with? You recognize your friend because of their external features: their face, skin or perhaps their favorite hat. Molecules do not have faces and favorite hats, but they do have a "skin" of electron density. This skin is not even: there are areas of greater and lesser electron density. This uneven electron density is caused by electronegativity differences in polar covalent bonds. Also important are regions of high electron density such as pi bonds and lone pairs. Oxygen is more electronegative than hydrogen, so the bonds of water are polarized. The two lone pairs also help make the oxygen appear electron-rich to other molecules.
Lone pairs O !+ H " !+ Polar covalent bonds

Computer software can model the charge distribution more precisely, and to allow its visualization through color. In the diagram below, "cooler" colors represent regions of positive charge (blue means greater ! +), and "hot" colors show regions of negative charge (red means greater ! -). Such diagrams are called electrostatic potential maps.
!-

!+

!+

Polar covalent bonds of water

Electrostatic potential maps of water. Blue = electron poor (!+); red = electron rich (!-)

Electrostatic potential maps are prepared in the computer by moving a positive charge over the surface of the molecule at a fixed difference, and calculating the magnitude of attractive or repulsive force at each point. Red represents points of strong attraction, and blue areas of strong repulsion.

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Considering water molecules as balls of positive and negative charge, how do they approach each other? Recall that opposite electrostatic charges attract, and like charges repel. In the case of water molecules, the !+ region of one water molecule (the hydrogens) is attracted to the !- region (the oxygen with its lone pairs) of another water molecule. This forms a fleeting hydrogen bond between two water molecules as they approach (Step A in the reaction shown).
O !+ H O H !+ Step A " O H O H Step B Ka-Pow!!!! H Collision H Step C H O H " O

!+ H

H !+

As the water molecules get close enough, they collide (Step B), and the proton transfer takes place. In other words, the hydrogen of one water molecule comes within bonding distance of the oxygen atom of the other water molecule. This collision produces the reaction products (Step C).

The O-H bond distance in water is 0.958 .

In General... The majority of organic reactions we will encounter in the future can be thought of as initiated by electrostatic attraction between an electron-rich species and an electron-poor species.

Concept Focus Question 21.2 Make drawings that show how each pair of reactants might approach each other. (a) HO- and H2O (b) NH3 and CH3Cl (c) H2O and (CH3)3C+ (d) BF3 and (CH3CH2)2O (e) CH3O- and H2

Not every collision leads to a reaction, however. There are orientation and energy reasons for this. Orientation: Bond formation during the moment of collision requires orbitals to overlap and mix. Because bonds are strongest when orbital overlap is maximized the molecules need to collide with a specific orientation in order for the reaction to occur.

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Energy: Electron repulsion, plus the instability caused by fleeting partial bonds that exist during the moment of collision must be overcome, so the molecules must collide with sufficient kinetic energy.

These orientation and energy requirements control the success of bond changes during the moment of collision, and thus the rate of the reaction. This moment of collision is critical for many organic reactions, but as it turns out, we can pretty much ignore it for our simple exploration of acids and bases. This is because the moment of collision controls reaction rates whereas proton transfer reactions are controlled more by thermodynamics (the relative stability of the two sides of the equilibrium). We explore this issue in more depth in Topic 20. C. Proton Transfer Mechanisms Think Ahead Question 21.3 Write a mechanism for the autoionization of water, plus the reverse reaction of hydroxide and hydronium ions. Identify the nucleophiles, electrophiles, Brnsted acids and bases and Lewis acids and bases. Answer: Recall that curved arrows are a very useful bookkeeping method to follow bond changes in a reaction mechanism (Topic 4). The curved arrow starts at the source of the electrons (sigma bond, pi bond or lone pair) and points to the destination of the electrons. A nucleophile (Lewis base) supplies the electron pair to make a new bond, so it always at the start of the curved arrow. An electrophile (Lewis acid) accepts the electron pair, so it always at the pointy end of the curved arrow.
Electrophile H H Nucleophile H O O H H H Electrophile O H ! O Nucleophile

In the forward reaction, one water molecule donates the electron pair that becomes the new sigma bond so it is the nucleophile. The other water molecule accepts the electron pair so it is the electrophile. In the reverse reaction, hydroxide ion is the nucleophile and hydronium ion is the electrophile. Concept Focus Question 21.3 provides more practice with drawing proton transfer mechanisms.

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Concept Focus Question 21.3 Draw the product formed when the base removes the proton in the box. Supply appropriate curved arrows. If the product has more than one resonance contributor, write the mechanism so it leads directly to the most significant contributor. Label each nucleophile and electrophile. (a) (b) (c)
CH3O + H
H2O + H

N(CH2CH3)3
OSO3H

O HO + H

(d)

+ H2 O

D. Brnsted or Lewis? Acid or Electrophile? Base or Nucleophile? Think Ahead Question 21.4 Are all electrophiles acids? Are acids always electrophiles? Answer: "Acid" can mean either "Brnsted acid" (proton donor) or "Lewis acid" (electron pair acceptor). Every Brnsted acid is an electrophile because it must accept an electron pair in order to transfer a proton. However, every Lewis acid is not a Brnsted acid because Lewis acids can accept an electron pair in a wide range of reactions, not just proton transfer. For example, consider CH3CH2+, the ethyl carbocation. It can accept a pair of electrons from Cl- to form a new carbon-chlorine bond (thus behaving as a Lewis acid) without donating a proton (not behaving as a Brnsted acid). On the other hand, it can accept an electron pair at a hydrogen atom (thus acting simultaneously as both a Lewis acid and a Brnsted acid) to form HCl and H2C=CH2.
H H C H H C H Cl H H C H H C Cl H

Ethyl carbocation accepts an electron pair from chlorine at carbon, thus acting as a Lewis acid but not a Brnsted acid.
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H H C H

H C H

Cl

H C H C

H + H Cl H

Ethyl carbocation accepts an electron pair from chlorine at hydrogen, thus acting as both a Lewis acid and a Brnsted acid. Thus, every electrophile and every Brnsted acid is a Lewis acid, but only proton-donor Lewis acids are called Brnsted acids. Similarly, every Brnsted base and every nucleophile is a Lewis base, but not every Lewis base is a Brnsted base. When we discuss a proton transfer reaction, "acid" and "base" mean "Brnsted acid" and "Brnsted base." When we discuss reactions other than proton transfer, we use the terms "nucleophile" (or "Lewis base") and "electrophile" (or "Lewis acid"). Alternately, we can define a Brnsted base as a nucleophile that accepts a proton, and a Brnsted acid as an electrophile that donates a proton. So to answer the Think Ahead Question question, all electrophiles are Lewis acids, but an electrophile is Brnsted acid only when it is donating a proton. All acids (Lewis or Brnsted) are electrophiles, because they all accept an electron pair, regardless of whether the new bond is to a proton or not.

21.3 Position of the Proton Transfer Equilibrium


Just because we can write a reaction does not mean the equilibrium is favorable. For example, we could write:
2 NaCl 2 Na + Cl2

However, we know from our general chemistry studies (and from common sense!) that normal table salt (NaCl) does not spontaneously become sodium metal and chlorine gas. In fact, this equilibrium favors NaCl and Keq is very, very small (Keq ~ 10-282 at 298K!). Salt does not contain any detectable levels of sodium metal or chlorine gas. In principle, every mechanism step and every reaction is in equilibrium. This equilibrium may favor the reactants or products, by a small or a large margin, or it may have an equal concentration of both. In order to understand and manipulate the reaction, we must understand the factors that control the position of the equilibrium. Let
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us start this understanding with proton transfer reactions, perhaps the simplest reactions we will encounter. First we need to quantify the equilibrium position, and later (section 21.5) we will deduce the ways in which molecular structure has a hand in this. Consider the case of acetic acid (CH3CO2H, a simple carboxylic acid), which ionizes to a certain extent when dissolved in water. (Common vinegar is a dilute aqueous acetic acid solution.) Think Ahead Question 21.5 Write the equilibrium reaction with curved arrows for the ionization of CH3CO2H in water. What is the mathematical expression for the equilibrium constant? Answer: The ionization is a proton transfer reaction, in which the water functions as a base to deprotonate the carboxylic acid. (The CO2H functional group is called a carboxylic acid because it gives up its proton so readily.)
O O H OH2 O H O OH2

Recall that the equilibrium constant is the product of the concentrations of the species on the right, divided by the product of the concentration of the species on the left.
Keq = [CH3CO2-] [H3O+] [CH3CO2H] [H 2O]

For the sake of our introductory exploration, let us assume that the concentration of acetic acid and its ionization products are very small. (This is a valid assumption for theoretical purposes, but may not be valid when concentrations are high.) This means the water is almost pure. The activity of pure water is 1, so [H2O] drops out. We can now define a new (and very useful) expression called the acid ionization constant (Ka).
Acid ionization constant = Ka = [CH3CO2-] [H3O+] [CH3CO2H]

Review the idea of activity and its importance in chemical equilibria from your general chemistry textbook.

Like all equilibrium constants, Keq and Ka are unitless.

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Concept Focus Question 21.4 Write the Ka expression for the ionization of these molecules in aqueous solution. Also show the ionization mechanism using curved arrows and water as the base. (a) The O-H bond of formic acid, HCO2H (b) The O-H bond of methanol, CH3OH (c) The N-H bond of trimethylammonium chloride, (CH3)3NH+ Cl-

Think Ahead Question 21.6 What does the magnitude of Ka tell us about the extent of ionization of CH3CO2H in water? Answer: When ionization occurs, [CH3CO2H] decreases, and [CH3CO2-] and [H3O+] both increase. As the extent of ionization increases, [CH3CO2H] becomes smaller, [CH3CO2-][H3O+] increases and K a becomes larger. Thus K a is a measure of the degree of ionization of the acid. For acetic acid Ka = 1.76 x 10-5. This means that acetic acid does not ionize very much in water. Put another way, an aqueous solution of acetic acid contains mostly nonionized CH3CO2H and only small concentrations of CH3CO2- and H3O+. Acetic acid is a weak acid.
CH3CO2H + H2 O Ka = 1.76 x 10-5 CH3CO2- + H 3O+

On the other hand, sulfuric acid (H2SO4) is a very strong acid, whose Ka is about 1010. In water, sulfuric acid is essentially completely ionized into H3O+ and HSO4-. Only a very tiny concentration of nonionized H2SO4 remains (less than 10-5 M).
H2SO 4 + H2 O Ka ~1010 HSO4 - + H3 O+

Any molecule containing hydrogen atoms can, in principle, be an acid. The Ka of methane (CH4) has been estimated at about 10-50 to 10-60. (It is very difficult to measure the acidity of such very weak acids with much certainty.) Using the Ka expression given above, we can estimate that the concentration of CH4 in water would have to be about 1025 to 1030 M (!) in order to produce one CH3- ion in a liter of solution. This is an impossibly high concentration. We would have to dissolve at least a million billion billion kilograms of methane in one liter of water to achieve this concentration!
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CH4 + H2O

CH3- + H3O+

Concept Focus Question 21.5 Rank these molecules from strongest to weakest acid: water (Ka = 1.0 x 10-14), hydrogen chloride (HCl, Ka = 107), acetic acid (CH3CO2H, Ka = 1.8 x 10-5), trichloroacetic acid (Cl3CCO2H, Ka = 3.0 x 10-1), carbonic acid (H2CO3, Ka = 4.3 x 10-7) and methanol (CH3OH, Ka = 3.2 x 10-16).

The examples in Concept Focus Question 21.5 show that Ka values vary over a very wide range: very strong acids such as H2SO4 (Ka 1010) to very weak acids such as CH4 (K a ~10-50). This Ka range is cumbersome. Can we define a new term related to K a so that acid ionization constants are easier to manipulate? Think Ahead Question 21.7 Recall the mathematical definition of pH , and by analogy, define a more convenient scale for acid ionization constants. Answer: Recall pH = - log [H3O+], so similarly let us define pKa = -log Ka. For CH3CO2H, Ka =1.76 x 10-5 so pKa = 4.78. The pKa of H2SO4 is -10 and the pKa of methane is about 50. (A number range of -10 to 50 is easier to manipulate than a number range of 1010 to 10-50.) On the pKa scale, lower (more negative) pK a value denotes a stronger acid, while a higher (more positive) pK a value denotes a weaker acid. Because this is a log scale, each pK a unit corresponds to a ten-fold change in acid strength. Caution!!! If you study different textbooks, you may find that they seem to disagree on the pKa values for some compounds, such as H2SO4. (The reported pKa values for H2SO4 are -2 to -10.) This is because pK a measurements may have been performed in different solvents. Also, it is difficult to accurately determine pKa values for compounds on the extreme ends of the pKa scale (very strong or very weak acids). The pK a values for many thousands of compounds have been measured. Some of these are gathered together in Appendix XX.
Like Ka, pKa is also unitless.

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Caution!!! It is not necessary to memorize pKa values, but you may manage to commit to memory some of the more important and more common numbers because you use them frequently in problems. Examples include the pK as of H3O+, H2SO4 and H2O. (This might be called "memorization-free memorization.") Concept Focus Question 21.6 Convert the Ka values of Concept Focus Question 21.5 into pKa values. Rank the molecules from weakest acid to strongest acid based on these pKa values.

21.4 Competing Proton Transfers: Estimating Keq


Why is it useful to be able to predict the position of a proton transfer equilibrium? Many reactions (both in the lab and in living organisms) involve one or more proton transfers. Predicting the equilibrium position is vital to determining if the reaction will proceed in the forward direction to give products, or if the reactants will remain unchanged. Think Ahead Question 21.8 When acetic acid and ammonia are mixed, will most of the molecules converted to ammonium acetate, or do most of the reactants remain unchanged? Hint: Consider Keq in terms of pKa values, and use a bit of basic algebra. Answer: In other words, the question asks us to decide if the equilibrium lies to the left or the right. To answer this, start by writing the reaction and its equilibrium constant expression:
CH3CO2H + NH3 CH3CO2 + NH4

Keq =

[CH3CO2-] [+NH 4] [CH3CO2H] [NH3 ]

Substitute with the expressions for the K a of CH3CO2H and the reciprocal of the Ka of +NH4:

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Keq =

[CH3CO2-] [H3O+] [CH3CO2H] Ka CH3 CO2 H Ka +NH4

[+NH4 ] [NH3 ] [H3 O+]

Take the log of both sides to convert Ka values into pKa: log Keq = pKa +NH4 - pKa CH3CO2H Therefore if the difference in pKa values is positive, log Keq > 1 and the equilibrium lies to the right. If the difference in pKa values is negative, Keq < 1 and the equilibrium lies to the left. The pKa difference gives us the magnitude (in terms of powers of ten) of the equilibrium constant. Taking the appropriate numbers from the table of pKa values: log Keq = 9.4 - 4.8 = 4.6 Keq = 104.6 ~ 40,000 In many cases it is sufficient to estimate Keq instead of calculating the precise value. In this case, we can say Keq lies between 10,000 (104) and 100,000 (105), and the equilibrium favors the right side by a significant margin. So the answer to Think Ahead Question 21.8 is that most of the ammonia and acetic acid are converted into ammonium acetate. In General log Keq = pKa of acid on right side of the equilibrium - pKa of acid on left side of the equilibrium If the acid on right side of the equilibrium is weaker (it has a higher pKa), then the equilibrium lies to right. If acid on left is weaker the equilibrium lies to the left. A proton transfer equilibrium favors the side with the weaker acid.

Concept Focus Question 21.7 Use the pKa table (Appendix XX) to decide if these proton transfer equilibria favor the right or left side, and by how much. (a)
H2SO4 + H2O H3O OSO3H

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(b)

O + HO

O + H2O

(c) (d)

(CH3)2CHOH + NH3

(CH3)2CHO + NH4

H3NCH2CO2H

H3NCH2CO2

21.5 How Does Molecular Structure Control Acidity and Basicity?


So far we have seen how to predict the position of the equilibrium when we know the pK a values of the acids involved. The Appendix XX pK a table includes approximately 150 molecules, but not every compound has had its pKa measured. However, more than twenty million organic compounds have been characterized! The compound of interest will often be absent from any pKa table, no matter how extensive. For example, we might need to design a compound with a particular pKa. (This is a very common issue in drug design.) Therefore we need to be able to make some educated guesses concerning the acidity or basicity of unknown compounds. We might make the estimate by comparing with a compound whose pK a is known. Or it might be made based on knowledge of how specific structural features such as functional groups or resonance influence acidity or basicity. We develop these ideas in the next few sections. Think Ahead Question 21.9 Find the pKa of methanol (CH3OH) and ethanol (CH3CH2OH) in Appendix XX. Using these numbers as a guide what is the approximate pKa of propanol (CH3CH2CH2OH)? Answer: Appendix XX gives the pKa values of methanol and ethanol as 15.5 and 16-17, respectively. However, this same table does not include the pKa value for propanol so we have to devise a strategy to approximate it. The given pK a values of methanol and ethanol correspond to loss of the O-H protons. (These are the protons in bold in the pKa table.) Note that the pKa values for these protons are very similar: 15.5 for CH3O H and 16 - 17 for CH3CH2OH. This suggests that the pKa for donation of any alcohol proton should also be in this same range. Examination of the pKa table confirms this idea: all of the alcohols have a pKa of 12 - 19. Therefore we predict that the pKa of propanol should also fall in the 12-19 range.
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Why is this assumption valid? It is no accident that CH3OH, CH3CH2OH and CH3CH2CH2OH have very similar pKa values. In all three cases, the same functional group -- an alcohol -- is donating the proton. We already know that molecules with similar functional groups have many physical, chemical and biological properties in common (Topic 1). Acidity and basicity are certainly chemical properties. In General Similar functional groups give rise to similar pKa values. This is why the pKa table is organized according to functional group. Further examination of the pKa tables shows that while there is some consistency among pK a values for compounds with the same functional group, there is a wide variation in pK a values if the functional groups are different. Compare for example the pK a of a simple alcohol such as ethanol (pKa 16 - 17) with a simple carboxylic acid such as acetic acid (pKa 4.78). This is why the pKa table is organized according to functional group. This leads us to a deeper and very important question: how does a functional group influence pKa? In the following sections we explore several ways in which functional groups and other elements of molecular structure influence acidity and basicity. We will explore this by making comparisons among sets of compounds with similar, but not identical, structures. Concept Focus Question 21.8 The 21 naturally occurring amino acids are the building blocks of proteins and enzymes, molecules of fundamental importance to all organisms. Every amino acid has a carboxylic acid and an amine, but different side chains (the R groups).
H H2 N R Side chain CO2H

Generic amino acid structure The carboxylic acid pKa values fall into a narrow range (that is, their acidities are very similar) because they all have the same functional group (the carboxylic acid), but the pKa values of the R groups vary widely. In an enzyme, these side chains often handle proton transfer tasks. Therefore it is useful to recognize the relative acidity of these side chains. Find the structures of these amino acids in Appendix YY,
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then group them by similar side chain acidity: alanine, aspartic acid, serine, tyrosine, glutamic acid, threonine, asparganine, histidine, valine and glutamine.

The observation that similar functional groups provide similar acid/base properties is true across a very broad spectrum of molecules. But how can we compare when the functional groups are not the same? More directly, what details of molecular structure should we consider when analyzing the acid/base properties of a molecule? Many approaches to this question are valid, but a very useful approach can be developed by ask a slightly different question. Since a pKa value is really just a fancy equilibrium constant, we really need to ask how does the structure of the acid (or base) control the position of the equilibrium? As we will discover in the following sections, electron density (the number of electrons or formal charge per unit of area or volume) is the key to this understanding. Formal charge, resonance, electronegativity, hybridization, atomic size and inductive effects influence electron density.

21.6 Electron Density Effects on Acidity and Basicity


A. Electron Density Think Ahead Question 21.10 Use the pKa table to decide which side of this equilibrium is favored.
CH3CO2H + HO CH3CO2 + H 2O

Describe the molecular structure features of the two bases that account for the equilibrium position. Hint: Drawing appropriate curved arrows may give you some ideas. Answer: This is a good place to remind you of some useful terms you learned in general chemistry. The species that is formed upon deprotonation of an acid is called the conjugate base, because it can function as a base to regenerate the original acid. Similarly, the species formed upon protonation of a base is called the conjugate acid. Water (pKa 15.7) is a much weaker acid than acetic acid (pKa 4.78), so the equilibrium lies to the right with Keq ~ 1011. From these pKa values we can also conclude that hydroxide ion is a stronger base than acetate
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ion. (Recall that stronger acids have weaker conjugate bases.) We can also conclude that " G (CH3CO2- + H2O) < " G (CH3CO2H + HO-), meaning that acetate ion and water (taken together) are "more stable" than acetic acid and hydroxide ion. But what feature of molecule structure explains the relative acidity of acetic acid and water, or the relative basicity of acetate and hydroxide? Does this feature also explain the relative stabilities as well? There are many issues that control "G for each side of the equilibrium, such as the change in bond energies and distributions of charge, to name a few. However, we can greatly simplify the problem by thinking of the equilibrium as a proton tug-of-war between two bases. The base that can most readily take the proton keeps it more often, causing the equilibrium to favor this side. In other words, the equilibrium favors the side in which the strongest base in protonated. (In fact, we already reached this conclusion in section 21.4 when we showed that a proton transfer equilibrium favors the weakest acid.) Acetic acid is a stronger acid than water, so acetate ion is a weaker base than hydroxide ion. What structural feature(s) account for this? The curved arrows provide an important clue.
O O H OH O O H OH

From the curved arrows we can see that the role of the base is to donate the electron pair that becomes the new bond with hydrogen. The base with the stronger drive to share the electron pair takes possession of the hydrogen more often. Any molecule with a lone pair desires to share that pair to form a covalent bond, because electrons are more stable when shared in a bond than when they are alone. Acetate and hydroxide ions both have lone pairs, and both use these lone pairs to form the new bond to hydrogen. Both share this same driving force, so this factor alone does not explain the difference in basicity of acetate and hydroxide ions. We must look elsewhere. Let us examine the structure of these two bases in more detail. Drawing hydroxide ion with three lone pairs and a formal negative charge on oxygen is an adequate description of this ion's structure. Only one structure is possible for hydroxide. However, for acetate ion, we can draw more than one legitimate Lewis structure (that is, it has
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resonance). (Review Topic 5 if you do not see this immediately.) Thus acetate ion is best represented not as a single resonance contributor but rather as the resonance hybrid.
OH X No significant resonance

O O

O O

O !!O

Resonance contributors
This repulsion of like charges the driving force behind a battery. A chemical reaction causes electrons -- negative charge -- to build up at the cathode, so the electrons are driven to leave the cathode and migrate to the anode.

Resonance hybrid

An important feature of acetate ion is the delocalization (distribution) of negative charge over the two oxygen atoms. Compare this with hydroxide ion, in which the negative charge is localized on a single oxygen atom. This is a significant observation: recall from your studies of basic physics that bringing together like charges increases the energy of a system, whereas dispersing like charges decreases energy. (Like charges repel, opposite charges attract.) The electron density of acetate ion -- both the formal negative charge and the electrons -- are more dispersed. Therefore acetate ion has a weaker driving force to share these electrons (to be a base) and disperse the negative charge. The electron density of hydroxide ion is more concentrated, so it has a greater driving force to share electrons with a proton (to be a base). By extension, then, acetic acid is a stronger acid than water because acetate ion is a weaker base than hydroxide ion. We can also say that acetic acid gives up its proton more readily because it can handle the resultant negative charge more effectively than hydroxide ion. We can also consider the situation from the viewpoint of the loss of resonance, a stabilizing feature. Everything else being equal, any molecular change (reaction, conformation change, etc.) is retarded by the loss of resonance and encouraged by the gain of resonance. The loss of resonance suffered by acetate ion upon protonation retards its basicity. Hydroxide ion does not suffer such a loss, so its basicity is not hindered in this way. Similarly, deprotonation of acetic acid (which only has one significant resonance contributor) leads to a conjugate base with two significant resonance contributors, so resonance assists the deprotonation of acetic acid. Water and hydroxide ion both have just one significant resonance contributor, so the deprotonation of water is not assisted by resonance.

_____________________________________________________________ Organic Compounds of Acids and Bases 18

As we continue our exploration of the factors that control acidity and basicity, we will find the most convenient way to analyze any given case is from the viewpoint of the base's ability/desire/driving force to share an electron pair to form the new bond with hydrogen. Thus when asked to analyze acidity, convert the molecule(s) to their conjugate bases, analyze their relative basicities, and then draw a conclusion about the corresponding acids. This approach will provide a standard method for all acid/base cases, and will also assist you when you study the factors that influence the relative strength of nucleophiles in Topic 22. (A base is a just a nucleophile that specializes in sharing its electrons with protons.) In General There are many conceptual patterns like this that weave throughout the fabric of organic chemistry. Work to identify them, and practice applying them. Their existence will greatly facilitate your study of organic chemistry. B. Formal Charge Formal charge notation tells us about the difference between the number of valence electrons in a free atom and the number of electrons located on that atom in a Lewis structure. (Review section 1.xx if you are not confident in your understanding of formal charge.) It makes chemical sense that an atom with a formal positive charge is electron deficient, and of lower electron density than an atom with a formal charge of zero. Similarly, an atom with a formal negative charge has excess (higher) electron density than a neutral atom. For example, the oxygen atom of ethoxide ion (CH3CH2O-) carries a formal negative charge, so it has more valence electron density than the oxygen atom of ethanol (CH3CH2OH) in which oxygen is neutral. The oxygen atom of CH3CH2OH2+ carries a positive formal charge, so it has less valence electron density than the oxygen of ethanol. With this thought in mind, consider the relative basicity of water and hydroxide ion. Think Ahead Question 21.11 Is water a stronger or weaker base than hydroxide ion? (Use Appendix XX.) What feature of molecular structure is responsible? Answer: The pKa table is a list of acid strengths, not basic strengths. However, recall that a stronger base has a weaker conjugate acid. We can therefore analyze basicities by comparing acidities of the
_____________________________________________________________ Organic Compounds of Acids and Bases 19

corresponding conjugate acids. (Lower pKa tells us that the conjugate base is weaker.) The conjugate acid of water is hydronium ion (H3O+), pKa 1.78. The conjugate acid of hydroxide ion is water, pK a 15.7. From these pKa values we conclude hydronium ion is a stronger acid than water, so water must be a weaker base than hydroxide ion. What molecular structure feature is responsible? Expanding on our exploration of acetate ion and water, basicity is controlled by the molecules driving force to share an electron pair with a proton, thereby forming a new bond and dispersing charge. When water or hydroxide ions are acting as bases, they share oxygen lone pairs. The oxygen atom of water has two lone pairs and no formal charge whereas the oxygen atom of hydroxide has three lone pairs and a formal negative charge. Because water has less electron density, its driving force to share electrons with a proton to be a base is less than hydroxide ion. Concept Focus Question 21.9 provides more practice with this electron density effect. Concept Focus Question 21.9 Find the pKa values for ammonia and ammonium ion on the pKa Table (Appendix XX). Which is the stronger acid, and why?

In General Electron density has influences many aspects of structure and reactivity for organic compounds. Get into the habit of using this concept to analyze acid and base properties, as well as many other types of organic chemistry problems. C. Resonance Resonance can also influence electron density. In fact, resonance increases molecular stability by delocalizing electron density. If you do not feel confident in your understanding of resonance or ability to draw resonance contributors, review Topic 5 before starting this section. Think Ahead Question 21.12 Use curved arrows to show how ammonia (NH3) and aniline (C6H5NH2) act as bases to deprotonate hydronium ion. Which of these amines is a weaker base? Use the pKa table to verify your prediction, and then formulate a general rule concerning the effect of resonance on acidity and basicity.

_____________________________________________________________ Organic Compounds of Acids and Bases 20

Answer: Both amines use their nitrogen lone pairs to take a proton from hydronium ion. Ammonia: Aniline:
H3N H OH2 H3N H + OH2

H N H H OH2

H N H H + OH2

Ammonia has no resonance to delocalize the nitrogen lone pair, whereas in aniline the nitrogen lone pair enjoys resonance delocalization onto the benzene ring.
H3N X No significant resonance

NH2

NH2

NH2

NH2

Ammonia: No resonance delocalization of nitrogen lone pair. Electron density (red) concentrated on nitrogen.

Aniline: Resonance delocalizes nitrogen lone pair electron density onto benzene ring carbons. Note less intense red on nitrogen, compared to ammonia.

This resonance delocalization reduces the electron density on the nitrogen atom of aniline, so aniline is a poorer base than ammonia. This effect is shown in the electrostatic potential maps. An alternate, and equally valid analysis is to note that protonation of aniline causes the loss of resonance delocalization (stabilization) of the nitrogen lone pair. Protonation of ammonia does not cause a loss of resonance. Therefore aniline does not accept the proton as readily as ammonia, and so aniline is a poorer base than ammonia. By extension, we also predict that the conjugate base of ammonia (ammonium ion, NH4+) has a higher pKa than the conjugate base of aniline (anilinium
_____________________________________________________________ Organic Compounds of Acids and Bases 21

ion, PhNH3+). Examining the pKa table verifies the accuracy of our prediction: the pKa of NH4+ is 9.4 while the pKa of PhNH3+ is 4.6. In General In many (but not all) cases a proton transfer that increases the number of significant resonance contributors is favored more strongly than a similar proton transfer that does not. Resonance enhances acidity if deprotonation increases the number of significant resonance contributors. Resonance enhances basicity if protonation increases the number of significant resonance contributors. Avoid This Common Misconception In most cases you will encounter, resonance enhances acidity and decreases basicity. Avoid the tempting trap of assuming this is true for all cases, and memorize a trend with little understanding. Avoid this by carefully examining every case, applying what you have learned about resonance from the discussions in this section. Concept Focus Question 21.10 For each pair of molecules, draw the conjugate base and all of the important resonance contributors formed when the proton in the box is removed. (If the molecule only has one kind of proton no box is shown.) Then select the most acidic molecule of the pair. (a) (b)
O

Water and sulfuric acid


OH

and
O O

OH

(c)

and
H
O

H
O

(d)

and
H3C OCH3

D. Electronegativity Electronegativity is a measure of how strongly an atom attracts valence electrons. Higher electronegativity means the atom attracts the
_____________________________________________________________ Organic Compounds of Acids and Bases 22

electrons more (the atom is more miserly with its electrons). Lower electronegativity means the atom attracts electrons less strongly (it is more philanthropic with its electrons). Review this topic in your general chemistry textbook if you do not feel confident with this concept. To be a base a molecule shares electrons with a hydrogen atom. It makes sense therefore that electronegativity should influence basicity. Think Ahead Question 21.13 Without recourse to the pKa table, rank the relative basicity of fluoride, hydroxide, amide (H2N-) and methyl carbanion (H3C-). Use Appendix XX to verify your prediction.
F HO

H2N

H3C

Fluoride

Hydroxide

Amide

Methyl carbanion

Answer: Some new vocabulary words will help us focus our discussion of electronegativity and basicity. A molecule with a formal negative charge on carbon is called a carbanion (from carbon anion). Methyl carbanion is also called methanide. Using the same logic, an ion bearing a negative charge on oxygen (such as HO-), is an oxyanion. An ion bearing a negative charge on nitrogen (such as H2N-) is a nitranion. Now on to the question at hand. Before we "reinvent the wheel" let us analyze the situation with the features that we already know can influence basicity: formal charge and resonance. In order to rank the basicities we need to find differences in how these factors apply to the bases in question. There may be similarities as well, but these similarities do not allow us to determine which base is stronger or weaker. Consider formal charge. All of the ions have the same -1 formal charge. While this feature enhances the basicity of each of the ions in question, they all have it, so it does not provide the difference we are looking for. Consider resonance. Fluoride ion has no resonance because it is a single atom! The other ions in question do not enjoy any resonance delocalization of the formal negative charge because the hydrogen atoms cannot accept any addition electron density. Methyl carbanion is a good example.

_____________________________________________________________ Organic Compounds of Acids and Bases 23

C H

C H

Too many electrons on hydrogen!

So the four bases do not differ in their formal charge or resonance, but because the ions are not identical they must have some difference in basicity, even if the difference is minute. Now we must "reinvent the wheel" and start over with our basic (pardon the pun) definition of a base as species that shares an electron pair with a proton.
Base H X Base H

Looking at fluoride, hydroxide, amide and methyl carbanion we see that they differ in the atom that provides the electron pair to form the new bond with hydrogen. How well do fluorine, oxygen nitrogen and carbon share electron density? We know that fluorine is the most "electron greedy" element on the periodic table: it has the highest electronegativity (EN = 4.0 on the Pauling scale). This high electron affinity suggests that fluorine will strongly resist sharing its electron density, something it must do to form a new bond to hydrogen. The other electron-sharing atoms are less electronegative: oxygen EN = 3.5, nitrogen EN = 3.0 and carbon EN = 2.5. This suggests that of the four bases under consideration, fluoride ion is the poorest base, followed in order by hydroxide, amide and methyl anion as the strongest base.

To verify our prediction, we again turn to the pKa table in Appendix XX. We predicted fluoride ion to be the weakest base, so its conjugate acid (hydrogen fluoride, HF) should be the strongest acid of the group. We predicted methyl carbanion to be the strongest base, so methane should be the weakest acid. The actual pKa values from the table verify the accuracy of our prediction. So for the bases F-, HO-, H2N- and H3C-... Electronegativity of atoms sharing e- with H: F (4.0) > O (3.5) > N (3.0) > C (2.5)
_____________________________________________________________ Organic Compounds of Acids and Bases 24

Predicted basicity: F- (weakest base) < HO- < H2N- < H3C- (strongest base) Predicted conjugate acidity: HF (strongest acid) > H2O > H3N > H4C (weakest acid) Actual pKa: HF 3.2 (strongest acid), H2O 15.7, H3N 36 38, H4C 49 - 60 (weakest acid) In General Analysis of many other similar cases reveals a general effect of electronegativity on basicity and acidity. In a base, increasing electronegativity of the atom that shares electron density with the hydrogen decreases basicity. In an acid, increasing the electronegativity of the atom holding the hydrogen to be removed increases acidity. However, as we explore more examples we will find cases where other factors override this general rule. Because carbon is less electronegative than nitrogen or oxygen, CH bonds are often less acidic than N-H or O-H bonds. However, resonance and other factors may change this.

Concept Focus Question 21.11 Select the most acidic molecule is each set, and briefly explain your reasoning. (a) CH3OH, CH3NH2 and CH3CH3 (b) (CH3)2PH and CH3SH
OH
NH2

(c)

and

Concept Focus Question 21.12 When the amino alcohol shown below is reacted with NaOH, which proton is removed first? Draw the product of this deprotonation and the curved arrows to show how it is formed.
OH H3 C C CH3 NH2

_____________________________________________________________ Organic Compounds of Acids and Bases 25

E. Hybridization Covalent bonds are formed by interaction of orbitals, so it is natural to consider them when thinking about features of molecular structure that influence the formation or breaking of bonds to hydrogen. If you are not confident in your understanding of hybrid orbitals, review Topic 3 before reading this section. Think Ahead Question 21.14 Consider the nature of the C-H bonds in ethane, ethylene and acetylene. Which of these hydrocarbons is the strongest acid? Answer: Many organic reactions require deprotonation of a C-H bond, especially reactions in which new carbon-carbon bonds are formed. Therefore issues of C-acidity can be important. Approach the ethane/ethylene/acetylene acidity problem in the usual way. How do the electron densities of the conjugate bases compare?
H H C H C H H
H C C H H

Conjugate base of ethane

Conjugate base of ethylene

Conjugate base of acetylene

None of these conjugate bases has resonance stabilization of the negative charge. The negative charge resides on a carbon in each case, so there is no difference in electronegativity. However, they do differ in the hybridization of the carbon that carries the lone pair. How does this influence electron density? Recall from Topic 3 that hybrid orbitals have characteristics of the atomic orbitals from which they are derived. An s atomic orbital is a sphere in which the electrons are fairly close to the nucleus. A p atomic orbital is more diffuse, and its electron density is further from the nucleus. Electrons in an s orbital are lower energy (or held more tightly) than electrons in a p orbital. We can say that an s orbital is more electronegative than a p orbital. An sp hybrid orbital is more diffuse than a pure s orbital, but is not as diffuse as a pure p orbital. Increasing p character moves the electron density further from the nucleus (held more loosely), and decreases orbital electronegativity. (Review Figure XX of Topic 3.) Thus the electronegativity of carbon depends on hybridization: sp carbon (least p character; most electronegative) > sp2 > sp3 (most p character; least electronegative).
_____________________________________________________________ Organic Compounds of Acids and Bases 26

Now lets apply this idea to Think Ahead Question 21.14. The conjugate base of ethane (in which the lone pair is carried by an sp3 carbon) is stronger than the conjugate base of ethylene (sp2 carbon), because sp3 carbon is less electronegative than sp2 carbon. The conjugate base of acetylene (sp carbon) is least basic. This tells us ethane is the least acidic of these molecules and acetylene is the most acidic. The actual pKa values agree.
H H C
3

H
H

H C sp2 C H

Conjugate bases:

>

>

C sp

H
H C H H
H

sp
H

H C C H

Acids:

C H

<
H

<

pKa 50-62

pKa 36-45

pKa 25

In general we will treat hybridization as a special case of electronegativity. Concept Focus Question 21.13 Identify the most acidic hydrogen in each molecule. (a) (b)
HN NH2
HC C C(CH3)3

H CH3 CH3

F. Atomic Size Think Ahead Question 21.15 Without recourse to the pKa table, rank the relative acidity of hydrogen fluoride (HF), hydrogen chloride (HCl), hydrogen bromide (HBr) and hydrogen iodide (HI). Use the pKa table to verify your prediction.

_____________________________________________________________ Organic Compounds of Acids and Bases 27

Avoid This Common Misconception HCl is hydrogen chloride, a very noxious and highly corrosive gas. Hydrochloric acid is a solution of hydrogen chloride gas in water, and is best described as H3O+ Cl-. In this text "HCl" will denote anhydrous HCl gas, whereas hydrochloric acid will be denoted as "HCl (aq.)" or HCl/H2O. Answer: As we have seen before, acidity is conveniently predicted by examining the strengths of the corresponding conjugate bases.
Acid: Conjugate base: H F F H Cl Cl H Br Br H I I

Now we can examine the structural features that influence each base's ability or drive to share electron density. Each has the same -1 formal charge. None of the bases enjoy resonance delocalization of their electron density, as each is a single atom. However, fluorine is highly electronegative (EN = 4.0), thus preferring to keeps its electrons to itself. Iodine is of lower electronegativity (EN = 2.5), and thus more willing to share its electrons with a proton. Continuing this trend suggests this order of basicity: F- (most electronegative; weakest base) < Cl- < Br- < I- (Least electronegative; strongest base) We can verify the accuracy of our prediction by examining the pKa of the conjugate acids (the original goal of the exercise!). Remember once again that the correlation between base and acid strength is an inverse one. Predicted basicity: F- (weakest) < Cl- < Br- < I- (strongest) Predicted acidity: HF (strongest) > HCl > HBr > HI (weakest) Actual pKa data: HF 3.2 (weakest acid) > HCl -7 > HBr -9 > HI 10 (strongest acid) Our prediction was wrong! The predicted acidity ranking does not agree with the empirical data (the pKa values). This failure of our prediction suggests that some undiscovered factor is at work here. What structural difference do these ions have that we
_____________________________________________________________ Organic Compounds of Acids and Bases 28

have not yet explored, but may influence their drive to share electron density with a proton? One obvious difference is atomic size. For atoms of equal formal charge, the charge is more concentrated in smaller atoms (smaller volume or smaller surface area). Of the halogen anions, fluoride is the smallest (it is in the second row of the periodic table). Atomic radius increases as we descend the family (column) of the periodic table, with iodide the largest of the bases under consideration. Ion Periodic table row Ionic radius, F2nd 1.33 Cl3rd 1.81 Br4th 1.96 I5th 2.20

Fluoride has the most concentrated negative charge and therefore the greatest drive to share its electron density with a proton. Based on this idea, and ignoring (for the moment) other factors, this is consistent with the observation that fluoride (smaller ion) is a stronger base than iodide (larger ion). If we include electronegativity a paradox emerges. Predicted basicity based on electronegativity gives one result, whereas predicted basicity based on atomic radius gives the opposite result. Basicity based on electronegativity: F- (weakest base) < Cl- < Br- < I(strongest base). But... Basicity based on atomic radius: F- (strongest base) > Cl- > Br- > I(weakest base). Which is correct? The pKa values tell us fluoride ion is in fact the strongest base (HF is the weakest acid). This suggests that the atomic size effect is more influential than the electronegativity effect. Atomic radius increases as we descend a column (family) of the periodic table. In our studies of organic chemistry we will encounter this size effect in the halogen family (F, Cl, Br and I) as well as the oxygen and nitrogen families. Atomic radii also change within a row (period) of the periodic table, but this size change is outweighed by electronegativity differences. This concept is summarized below for the elements important to introductory organic chemistry.
_____________________________________________________________ Organic Compounds of Acids and Bases 29

Increasing EN Decreasing basicity C N P O S F Cl Br I Increasing atomic radius Decreasing basicity

In General Basicity is inversely proportional to the atomic radius of the atom sharing electrons to form the new bond to a proton. Smaller atoms enhance basicity and larger atoms inhibit basicity. Stronger bases have weaker conjugate acids so acidity is enhanced when the atom bearing the proton to be donated is large, and decreased when this atom is small. This effect is apparent when comparing atoms in the same family of the periodic table, but is outweighed by electronegativity effects when comparing atoms in the same period. Concept Focus Question 21.14 Select the strongest acid in each set. (a) CH3CH2OH and CH3CH2SH (b) CH3NH2 and CH3PH2 (c) ICH2CO2H and FCH2CO2H

H. Inductive Effects How do we compare the acidity or basicities of molecules when the portion of the structure that is involved with the capture or release of the hydrogen atom is the same? For example, how do we compare the acidities of two carboxylic acid protons? In these cases we must consider the effect of the more remote portions of the molecule on the electron density at the business end of the acid or base in question. Think Ahead Question 21.16 Using Appendix XX, rank these carboxylic acids according to their relative acidity: acetic acid (CH3CO2H), chloroacetic acid (ClCH2CO2H) and fluoroacetic acid (FCH2CO2H). What specific molecular features account for this trend? Answer: Consulting Appendix XX, we can rank these carboxylic acids in order of increasing acidity (decreasing pKa): acetic acid (pKa 4.78) < chloroacetic acid (pKa 2.8) < fluoroacetic acid (pKa 2.7). Resonance effects cannot account for the pKa differences, as each conjugate base
_____________________________________________________________ Organic Compounds of Acids and Bases 30

(RCO2-) has the same resonance contributors and resonance hybrid. Electronegativity and atomic size effects cannot account for the difference, as each conjugate base carries its negative charge on identical (oxygen) atoms. In other words, the only difference in these three molecules is the atom attached to the sp3 carbon: hydrogen, chlorine or fluorine. Changing the nature of this substituent does not alter the resonance, electronegativity or atomic size effects of the oxygen atoms that share electron density with the proton.
X O O X Base O O X O O

X = H, Acetic acid X = Cl, Chloroacetic acid X = F, Fluoroacetic acid

X does not influence resonance, atomic size or electronegativity at CO2 H group.

None of the structural features we discussed previously explain the relative acidity of these carboxylic acids so it is once again time to "reinvent the wheel". Acidity is a measure of the acid's ability to give up a proton. This is controlled by the stability of the conjugate base. Alternately, we can compare acidity by considering the ability or drive of the conjugate base to share electron density to form the new bond to a proton. The same fundamental feature controls both viewpoints: electron density. How does the nature of the substituent influence the electron density at the carboxylate groups? Consider the case of fluoroacetic acid, which differs from acetic acid by substitution of one methyl group hydrogen atom by a fluorine atom. Does fluorine influence the electron density at the carboxylate group? When we think of fluorine, its high electronegativity comes to mind. Because of this high electronegativity, fluorine is taking electron density from the neighboring atoms, including the carboxylate group. The carboxylate group of FCH2CO2- has less electron density than the carboxylate group of CH3CO2-. This reduced electron density makes FCH2CO2- a weaker base than CH3CO2-, and so FCH2CO2H is a stronger acid than CH3CO2H. Acetate ion: Hydrogen does not influence electron density at the CO2- group. Fluoroacetate ion: Fluorine has strong electron withdrawing influence on CO2- group.
H H C H C O O

_____________________________________________________________ Organic Compounds of Acids and Bases 31

Chloroacetate: Chlorine has weaker electron withdrawing effect on CO2- group. Chlorine is also a highly electronegative atom, and so a similar effect is predicted. ClCH2CO2- is a weaker base than CH3CO2-, and ClCH2CO2H is therefore a stronger acid than CH3CO2H. Chlorine is not as electronegative as fluorine, so we predict that the basicity of ClCH2CO2- is not decreased as much as the basicity of FCH2CO2-. Along the same lines, we predict CH3CO2H to be a weaker acid than ClCH2CO2H. The pKa data verify this prediction. What we have discovered here is the effect that one portion of the molecule has on the electron density at another site in the molecule. This is called an inductive effect, and can occur through the bond framework of the molecule or through space. Inductive effects can be electron withdrawing in nature (as we have seen here) or electron donating. The same inductive effect that decreases the electron density on the CO2- group also causes all the hydrogens of acetic acid to bear a ! + charge, and consequently to be a hydrogen bond donor. Consider the influence of inductive effect on pKa with Concept Focus Questions 21.15 and 21.16. Concept Focus Question 21.15 Rank the acidity of these molecules: HCF3, HCCl3, HCBr3 and HCI3. Concept Focus Question 21.16 Which alcohol is most acidic, CH3CH2CH2OH, H2NCH2CH2OH or CH3OCH2CH2OH?

In the previous section we saw that the magnitude of the inductive effect is controlled by the relative electronegativity of the atoms involved. What happens if the number of electron withdrawing or donating groups is increased? Think of this as an issue of quality versus quantity. Think Ahead Question 21.17 Why is chloroacetic acid (ClCH2CO2H, pKa 2.8) a weaker acid than dichloroacetic acid (Cl2CHCO2H, pKa 1.3)? Use a different set of carboxylic acid pKa values from Appendix XX as evidence of your rationale.
_____________________________________________________________ Organic Compounds of Acids and Bases 32

Answer: The difference between these molecules (and hence the answer to the difference in their pKa values) is the number of chlorine atoms. We know from the previous discussion that chlorine enhances acidity due to the inductive effect. Extending this idea, we can conclude that two electron-withdrawing groups (Cl2CHCO2H) enhance the acidity more than just one electron-withdrawing group (ClCH2CO2H). Support for this idea comes from comparing the pKa of a molecule with two electron-withdrawing groups with a similar carboxylic acid having three electron-withdrawing groups. Dichloroacetic acid (Cl2CHCO2H, pKa 1.3) is a weaker acid than trichloroacetic acid (Cl3CO2H, pKa 0.64). Concept Focus Question 21.17 Find the pK a values for acetic, fluoroacetic, trifluoroacetic and iodoacetic acids in Appendix XX. (a) Rank these carboxylic acids from strongest to weakest acid, and explain the trend. (b) Estimate the pKa of F2CHCO2H. (c) Based on this data, make a prediction about the pK a of triiodoacetic acid. Concept Focus Question 21.18 Without looking at Appendix XX, decide if Cl3CCO2H or F2CHCO2H is the stronger acid. Then find their pK a values, and verify your assumption. Concept Focus Question 21.19 The acidity of phenols depends upon the groups attached to the benzene ring. Consider the case of a substituent X para to the OH (located across the ring):
HO X

(a) Which of these structural features of X influence the acidity of the OH group: resonance, electronegativity, atomic size and inductive effect? (b) Briefly explain how resonance and inductive effects operate when X = nitro, nitrile, ketone, alkyl and ether. Draw all of the important resonance contributors for the conjugate base. Label the net effect of each of the X groups as electron withdrawing or electron donating. Use the data in Appendix XX to verify your labels.

_____________________________________________________________ Organic Compounds of Acids and Bases 33

In our exploration of the inductive effect, we have considered the effects of electronegativity and quantity, but does distance play any role? Think Ahead Question 21.18 What do the pKa values of chloroacetic acid, 2-chloropropanoic acid and 3-chloropropanoic acid suggest about the effect of distance between the acidic proton and the electron-withdrawing group? Use a different set of carboxylic acid pKa values as evidence of your rationale. Answer: The pK a values for the carboxylic acids of Think Ahead Question 21.18 are:
H Cl C H CO2H

H Cl H C H C H CO2H
Cl

H C H

H C H CO2H

Chloroacetic acid pKa 2.8

2-Chloropropanoic acid pKa 2.83

3-Chloropropanoic acid pKa 3.98

Comparing chloroacetic acid and 2-chloropropanoic acid we see that the pK a values are similar when the chlorine atoms are immediately adjacent to the carboxylic acid group. Comparing 2-chloropropanoic acid and 3-chloropropanoic acid we see that the pKa increases as the chlorine atom is further away from the acidic proton. The same effect can be seen in the first pK a values (pK a1) of the dicarboxylic acids. (A carboxylic acid group withdraws electron density by the inductive effect because it contains two highly electronegative oxygen atoms.) Acidity drops as the number of carbons between the two CO2H groups increases. HO2CCO2H (oxalic acid), pKa 1.2 HO2CCH2CO2H (malonic acid), pKa 2.9 HO2C(CH2)2CO2H (succinic acid), pKa 4.2 HO2C(CH2)3CO2H (glutaric acid), pKa 4.3
Increasing distance between CO2H

In General Inductive groups can be electron withdrawing or electron donating in effect. Increasing the number of inductive groups amplifies the inductive effect. Moving the inductive group further away reduces the inductive effect.

_____________________________________________________________ Organic Compounds of Acids and Bases 34

Increasing acidity

Concept Focus Question 21.20 Find the pK a values of acetic acid and benzoic acid (C6H5CO2H or PhCO2H) in Appendix XX. (a) Use this data to decide if the inductive effect of a phenyl group (C6H5 or Ph) electron donating or electron withdrawing. (b) Assign the pK a values of 4.66 and 4.31 to PhCH2CO2H and PhCH2CH2CO2H. (c) Estimate the pKa value of PhCH2CH2CH2CO2H. Concept Focus Question 21.21 Select the more acidic carboxylic acid isomer in each set.
CO2H NO2
CO2H

(a)

and

NO2

Cl

(b)
CO2H
CO2H

and

Cl

CO2H

CO2H

(c)
OH

and

OH
CO2H F

CO2H Cl

(d)

and

Cl

Think Ahead Question 21.19 Why, when comparing acidity or basicity of two molecules with the same functional group, such as two carboxylic acids or two amines, we can usually focus the analysis just on inductive effects? Answer: As we have seen, acidity and basicity are controlled by electron density. Electron density is a function of molecular structure, and is influenced by various structural features such as resonance, electronegativity, atomic size and inductive effects. Two identical functional groups have the same atoms in the same positions, so the
_____________________________________________________________ Organic Compounds of Acids and Bases 35

functional groups structural features that influence acidity or basicity (resonance, atomic size and electronegativity) are also the same. Atoms that are not directly part of the functional group influence its electron density through the inductive effect. Therefore when comparing acidity or basicity of two molecules with the same functional group, we expect resonance, atomic size and electronegativity effects to be identical, but inductive effects to differ. This concept is illustrated below with a carboxylic acid, but it applies to any acid or base.
O H O R Inductive effects arise from the R group, not the CO2 H group.

Resonance, atomic size and electronegativity effects arise from the CO2H group, not the R group.

In General When comparing acidity or basicity of two molecules with the same functional group, resonance, atomic size and electronegativity effects are equal, so you can skip right to inductive effects. There are exceptions to this General Rule, especially when the functional group in question is directly bonded to a benzene ring (aniline, phenol, etc.). H. Other Factors Explaining the relative acidity or basicity of organic molecules is really an analysis of an equilibrium (proton transfer). Many factors (both significant and subtle) can influence the relative stability of the acids and bases and hence the position of the equilibrium. For example we have not explored entropy ("S) effects or the nature of the solvent in which the pKa is measured. For acids stronger than water but weaker than H3O+, water can be used as the solvent. Dimethyl sulfoxide (DMSO) is another solvent commonly used to measure pKa values, especially for acids weaker than water. We leave these topics for a more advanced course, or for you to ponder on your own.

21.7 Relative Influence of Factors


We have explored five general structural features that can influence the acidity or basicity of a molecule: formal charge, resonance, electronegativity, atomic size and the inductive effect. In some cases consideration of one of these structural features may cause us to
_____________________________________________________________ Organic Compounds of Acids and Bases 36

conclude that a certain molecule is more basic, whereas consideration of a different feature leads to a different conclusion. Only one of these predictions can be accurate, so how do we know which structural features have the greatest influence on acidity and basicity? We already have some idea about this. Recall our prediction concerning the relative acidity of HF, HCl, HBr and HI. Here we discovered that electronegativity and atomic size both play a role, but atomic size had the dominant influence. But is this always the case? Consider, for example, relative acidity of acetic acid, ethanol and ethanethiol. Think Ahead Question 21.20 What are the pK a values of acetic acid, ethanol (CH3CH2OH) and ethanethiol (CH3CH2SH)? What do these numbers suggest about the relative influence of resonance and atomic size on acidity? Answer: The pKa values for acetic acid, ethanol and ethanethiol are given below. Now apply our usual procedure to compare acidity: convert to the conjugate bases and see how the factors in question influence the bases electron density. Acids (pKa): Acetic acid (4.78)
O O H

Ethanol (16 17)


O H

Ethanethiol (10.5)
S H

Conjugate bases: Acetate ion


O O

Ethoxide ion
O

Ethanethiolate ion
S

Compared to ethoxide, acetate ion is stabilized by resonance whereas the basicity of ethanethiolate is influenced by atomic size (oxygen is smaller than sulfur). The pKa difference due to resonance (16 17 for ethanol versus 4.78 for acetic acid) is larger than the pK a difference due to the atomic size effect (16 17 for ethanol versus 10.5 for ethanethiol). If we assume this pKa difference is an acceptable measure of the relative magnitude of these two effects, then we conclude that resonance has a greater influence than atomic size. Similar comparison of other pKa values verifies that resonance usually is more influential than atomic size.

_____________________________________________________________ Organic Compounds of Acids and Bases 37

What is the relative influence of other factors, such as electronegativity and formal charge? Think Ahead Question 21.21 Find the pKa values for HF, H2O and NH4+. What is the relative influence of electronegativity and formal charge on the basicity of fluoride ion, hydroxide ion and ammonia? Answer: The pK a values of the conjugate acids reveal the relative basicity of the three molecules in question. Base: Conjugate acid (pKa): Relative basicity: FHF (3.2) Weakest HOH2O (15.7) Strongest NH3 NH4+ (9.4) Intermediate

Of the three conjugate acids, HF is the strongest and H2O the weakest, so F- is the weakest base and HO- is the strongest base. Fluoride is a weaker base than ammonia because fluorine is more electronegative than nitrogen. However, fluoride bears a formal negative charge whereas ammonia does not. As we have seen earlier, a formal negative charge enhances basicity. This comparison suggests electronegativity has a greater influence on basicity than formal charge. Comparison of hydroxide with ammonia contradicts this! Oxygen is more electronegative than nitrogen, and we saw previously that electronegativity has more influence than formal charge. This suggests that hydroxide should be a poorer base than ammonia. The pKa data for water and ammonium ion suggest just the opposite: in this case formal charge has more influence than electronegativity. Analysis of the relative acidity or basicity of many other sets of compounds reveals formal charge does not consistently have more influence than electronegativity, or vice versa. Comparison of dozens of compounds in the same manner Think Ahead Questions 21.20 and 21.21 reveals a very useful General Rule concerning the relative influence of the five structural features we have explored.

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In General When comparing acidity, basicity (or any other phenomenon that is controlled by electron density) the order of influence of structural features is:
Resonance Atomic size Electronegativity Inductive effect Increasing influence on pKa and electron density

The relative influence of formal charge is inconsistent, so it must be considered on a case-by-cases basis. There are exceptions to this order of influence, but if you consider these structural factors in the order given, your predictions concerning acidity or basicity will be accurate most of the time. (Most of the time is not a bad accuracy rate for such a simple analysis!) Concept Focus Question 21.22 Select the boxed site of the molecule that is most basic.
CF3

(a)
H2N OH

NH2

(b)

Concept Focus Question 21.23 Select the boxed proton that is most acidic.
O

(a)
H3C

NH2

(b)
Cl O
NH3

(c)

H2N

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21.8 In The Real World: Acidity and Drug Design


Sulfa drugs are among the first antibiotics developed for use in humans and animals. They work by mimicking para-aminobenzoic acid (PABA) and inhibiting an enzyme that bacteria use to synthesize folic acid, a molecule necessary for normal cell growth and maintenance. Mammals do not synthesize folic acid (we get it from our diet), so sulfa drugs generally have low mammalian toxicity. All sulfa drugs have certain structural features in common, and other portions that are varied to give the highest effect against the specific infection being treated.
"2!
!"2

"! ! # "!

#
# #"

HO2C

!"

CO2H

Para-aminobenzoic acid (PABA)

Folic acid

When designing a drug, many factors must be considered. The drugs pKa is often critical. Lower pKa results in a greater extent of ionization in an aqueous environment. The average human physiological pH is 7.4, so a drug whose pKa is 7.4 is half ionized and half nonionized in the body. In the case of sulfa drugs, ionization and solubility are critical. If the pKa is too high, too much of the drug is nonionized, and it may precipitate. This is especially problematic in the kidneys where accumulation of undissolved drug can lead to renal failure. The sulfa drugs with the most potent antibiotic action have a sulfonamide proton (SO2NH) whose pKa is in the range of 5-11. The structure and pKa for some important sulfa drugs are listed in Table 21-1.

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Table 21-1: Some Important Sulfa Drugs


R
O H2N S O NH2

O H2N S O N H

N R

Sulfanilamide (pKa 10.5)

Sulfadiazine (R = H, pKa 6.5) Sulfamethazine (R = CH3, pKa 7.4)


OCH3 O N N H OCH3 N

O H2N S O N H CH3O

N N
H2 N

S O

OCH3

Sulfadoxine (pKa 5.5)


O H2N S O N H H3C CH3 O N

Sulfadimethoxine (pKa 6.1)


O H2N S O N H N S

Sulfisoxazole (pKa 6.1)

Sulfathiazole (pKa 7.1)

Gerhard Domagk was awarded the 1939 Nobel Prize for Physiology or Medicine for the discovery of the antibiotic effects of prontosil, the first sulfa drug. (For more information, explore www.nobel.se.) Sulfa drug use has decreased significantly in recent years, due to the introduction of better antibiotics, and the emergence of sulfa-resistant bacteria. Concept Focus Question 21.24 Briefly discuss how each structural feature indicated causes sulfamethazine to be more acidic than sulfanilamide.
Nitrogen O H2N S O N H N CH3 N Pyrimidine ring CH3 Methyl group

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Summary
21.1 Why Should I Study This? Acid/base reactions are wide spread in organic chemistry and biology. They are equilibria in which a base (Lewis base, nucleophile) shares a pair of electrons with a hydrogen atom of the acid (Lewis acid, electrophile). Curved arrows are convenient way to represent this bonding change. 21.2 Acid Base Reactions A. H is for Proton Acid-base reactions involve transfer of a hydrogen atom (H+; also called a proton). B. Molecular Collisions and Reactions Reactions are often initiated by the electrostatic attraction, then collision, of two species with opposite charges. C. Proton Transfer Mechanisms Curved arrows can represent the bond changes in a proton transfer mechanism. Bases are nucleophiles and acids are electrophiles. D. Brnsted or Lewis? Acid or Electrophile? Base or Nucleophile? Reactants can be classified as Brnsted acids (proton donors), Brnsted bases (proton acceptors), Lewis acids (electron pair acceptors) or Lewis bases () electron pair donors). Every Brnsted acid (base) is a Lewis acid (base), but every Lewis acid (base) is not a Brnsted acid (base). 21.3 Position of the Proton Transfer Equilibrium The position of a proton transfer equilibrium is quantified by its acid ionization constant or Ka. For the ionization of HA in water, Ka = ([A-][H3O+])/[HA]. Weaker acids have smaller Ka values. A more convenient number is pKa. pKa = -log Ka. Weaker acids have higher pKa values. Appendix XX is a table of useful pKa values. 21.4 Competing Proton Transfers: Estimating Keq A proton transfer equilibrium favors the weakest acid (lowest pKa). The equilibrium constant can be estimated in this way: log Keq = pKa of acid on right pKa of acid on left. 21.5 How Does Molecular Structure Control Acidity and Basicity? It can be useful to determine the relative acidity or basicity of organic molecules. A. Electron Density Basicity is proportional to the bases electron density. Acidity can also be explored by considering the electron density of the corresponding conjugate base. B. Formal Charge A negative formal charge enhances basicity. A positive formal charge enhances acidity.
_____________________________________________________________ Organic Compounds of Acids and Bases 42

C. Resonance If resonance delocalization decreases electron density at the atom(s) that share electron density with a proton then basicity is decreased. D. Electronegativity Increasing the electronegativity of the atom that shares electrons with the proton decreases basicity. E. Hybridization Hybridization can be treated as a special case of electronegativity. Increasing s character increases electronegativity. F. Atomic Size Increasing the atomic radius of the atom that shares electrons with the proton decreases basicity. G. Inductive Effects When one portion of a molecule influences the electron density at another portion of the molecule to which it is not directly bonded is called the inductive effect. Electron withdrawing groups decrease basicity. Electron donating groups enhance basicity. Increasing the number of inductive groups or decreasing their separation from the rest of the molecule enhances the magnitude of the inductive effect. H. Other Factors Factors other than those explored in sections 21.6A G may also influence acid/base properties. 21.7 Relative Influence of Factors Resonance > Atomic radius > Electronegativity > Inductive effect. The relative influence of formal charge varies. 21.8 In the Real World: Acidity and Drug Design Sulfa drugs are antibiotics whose activity is influenced by the pKa of the sulfonamide proton (SO2NH). This pKa is influenced by the substituents on the sulfonamide nitrogen atom.

New Terms
Electrostatic potential map (page 4) Acid ionization constant, Ka (page 9) pKa (page 11) Carbanion (page 23) Oxyanion (page 23) Nitranion (page 23) Orbital electronegativity (page 26) Inductive effect (page 32) Sulfa drug (page 40)
_____________________________________________________________ Organic Compounds of Acids and Bases 43