Teaching Mechanisms in Organic Chemistry - American Chemical

In the Classroom

Telling It Like It Is: Teaching Mechanisms in Organic Chemistry Addison Ault Department of Chemistry, Cornell College, Mount Vernon, Iowa 52314 [email protected]

I am inspired by J. Brent Friesen's recent article Saying What You Mean: Teaching Mechanisms in Organic Chemistry (1) to offer some suggestions for ways of doing this. First, I believe that the “story” of a reaction should include both a balanced equation and a reasonable mechanism. However, I also believe that we can tell a better story when we pay more attention to the pH of the solution and to the pKa values of conjugate pairs. When we do this I believe we will make the story both more truthful and easier to understand. Balanced Equation The balanced equation should include representations of all of the starting materials and of all of the products. To be balanced the number of each kind of atom on the two sides of the equation should be the same, but there are different ways of doing this. When I do it, I try to represent each atom in the same way on the two sides of the equation. Thus a hydrogen atom that is implied on the left will be implied on the right, and a hydrogen atom that is explicitly represented on the left will also be explicitly represented on the right. I do this because I believe that this makes it easier to see the relationships between the atoms of the starting materials and the atoms of the products. I also prefer to use the “line” style, and I tell my students that learning this style is part of learning organic chemistry. Finally, and most importantly, the nature of each species should be accurately represented, especially the nature of the actual proton donors and proton acceptors. Because the bare proton is not present in a condensed phase, its representation, Hþ, should not appear in either the balanced equation or the mechanism of the typical organic reaction. As an example, a balanced equation for the hydrolysis of tert-butyl bromide (1) can be written as

to imply that a bromide ion is a stronger base than a water molecule. Study of Reaction Mechanisms The study of reaction mechanisms is the discovery of the rules that govern the behavior of atoms, molecules, and ions as they react. Because, typically, more than half of the steps of a reaction are proton transfers, one must know the two rules for proton transfer. Rule 1: Proton Transfers in Aqueous Acid In aqueous acid, solutions whose pH is near zero, the only kinetically significant proton donor is hydronium ion, and, by the principle of microscopic reversibility, the only significant proton acceptor is water. Rule 2: Proton Transfers in Aqueous Base In aqueous base, solutions whose pH is near 14, the only kinetically significant proton donor is water, and, by the principle of microscopic reversibility, the only significant proton acceptor is hydroxide ion. Specific Acid and Base Catalysis Another way to say this is to say that almost all reactions that take place in aqueous media are subject to specific acid and specific base catalysis. That is, these reactions are specifically catalyzed by hydronium ion or specifically catalyzed by hydroxide ion. The only role for acid, base, or a buffer is to set and maintain the pH of the solution, that is, to set and maintain the hydronium ion and hydroxide ion concentrations. Hydrolysis of Esters Although the examples will be limited to esters, the approach can be applied anywhere.

Reaction Mechanism The mechanism of a reaction is an atomic or molecular description of how the atoms and molecules of the starting materials become the atoms and molecules of the product. A mechanism, then, presupposes a balanced equation. If the balanced equation is wrong, the mechanism will be wrong. Thus an equation that shows HBr to be a product of the hydrolysis of tert-butyl bromide is wrong because the mechanism would have

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Hydrolysis of Ethyl Acetate Ethyl acetate has a half-life of about 90 years in water at a temperature of 25 °C and a pH of 5.5, the pH of the minimum rate of hydrolysis. The reaction, however, is also strongly catalyzed by both acid and base. The half-life for hydrolysis at 25 °C in 1 M aqueous acid is about 2 h, and the half-life for hydrolysis at 25 °C in 1 M aqueous base is about 6 s.

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r 2010 American Chemical Society and Division of Chemical Education, Inc. pubs.acs.org/jchemeduc Vol. 87 No. 9 September 2010 10.1021/ed100345k Published on Web 07/14/2010

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Journal of Chemical Education

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In the Classroom

Balanced Equation The products of the hydrolysis of ethyl acetate are acetic acid and ethanol, as indicated by the balanced equation:

Scheme 1. The Addition of Water to the Conjugate Acid of the Ester

Acyl-Oxygen Cleavage or Alkyl-Oxygen Cleavage In principle ethyl acetate could be split upon hydrolysis at either of two nonequivalent points:

Early experiments showed that the hydrolysis of most esters takes place by breaking the bond between the acyl group and the ester oxygen, acyl-oxygen cleavage, rather than breaking the bond between the alkyl group and the ester oxygen, alkyl-oxygen cleavage. Formation and Hydrolysis of Malate Esters One such experiment showed that acetylation and hydrolysis of optically active malic acid regenerated malic acid with the same sign and magnitude of optical rotation as that of the original material indicating, at least in this case, that hydrolysis occurs by acyl-oxygen cleavage:

Because the acetylation reaction takes place by acyl transfer to the alcoholic oxygen without breaking the bond to the chiral center, the hydrolysis of the ester must also take place without breaking the bond to the chiral center. Both reactions involve making or breaking acyl-to-oxygen bonds. 938


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Hydrolysis of 18O Labeled Ethyl Propionate More recent experiments showed that, if ethyl propionate labeled with 18O in the alkyl oxygen is hydrolyzed, the 18O is found only in the ethyl alcohol, another clear indication of acyl-oxygen cleavage.

The Addition Step In solutions with a pH of 0 most esters undergo hydrolysis by an addition-elimination mechanism. The first half of the reaction, the addition, is the addition of water to the conjugate acid of the ester, which is present in equilibrium with the ester, to give an intermediate, the so-called tetrahedral intermediate. Using ethyl acetate the first half of the reaction is shown in Scheme 1. If we estimate the pH of the solution to be 0, and the pKa of the conjugate acid of the ester to be -6, we can then estimate that one part in a million of the ester will be present as its conjugate acid, a much more electrophilic species than the neutral ester molecule. Similarly, if we estimate the pH of the solution to be 0, and the pKa of each of the three conjugate acids of the tetrahedral intermediate to be -2, we can then estimate that one percent of the tetrahedral intermediate will be present as each of its three conjugate acids. Since proton transfers to and from oxygen acids

pubs.acs.org/jchemeduc

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r 2010 American Chemical Society and Division of Chemical Education, Inc.

In the Classroom

Scheme 2. The Elimination of Ethyl Alcohol from the Tetrahedral Intermediate To Give the Carboxylic Acid and the Alcohol

for ester hydrolysis in the presence of acid. In the direction of formation of the ester, the first half of the reaction is the acidcatalyzed addition of alcohol to the carboxylic acid to form the tetrahedral intermediate, and the second half is the acidcatalyzed elimination of water from the intermediate to form the ester. The acid hydrolysis and the Fischer esterification are the same reaction with different positions of equilibrium. The desired outcome, hydrolysis or esterification, is achieved by using water in excess if you want hydrolysis or alcohol in excess if you want esterification. The reason this works is that with an excess of water more carbocations are captured by water to give tetrahedral intermediate 0 rather than 1. Tetrahedral intermediate 0 can go on only to the carboxylic acid, whereas tetrahedral intermediate 1 can give ester as well as carboxylic acid.

With an excess of alcohol more carbocations will be captured by alcohol to give more of tetrahedral intermediates 1 and 2, which have a greater probability of going on to give ester. A Mechanism for the Base-Catalyzed Formation of Esters

are very rapid, the equilibria between these three conjugate acids will be established within microseconds.

The large base-catalytic effect upon ester hydrolysis is explained by proposing that hydroxide ion can react as a nucleophile with the electrophilic carbonyl carbon of the ester to form an intermediate anion. The intermediate anion can then lose ethoxide ion to give the carboxylic acid.

The Elimination Step The second half of the reaction, the elimination, is the elimination of ethyl alcohol from the tetrahedral intermediate to give the carboxylic acid and the alcohol. This reaction takes place by way of the conjugate acid of the intermediate in which a proton is on the “alkyl oxygen”. Ethanol leaves from this species to give, as the immediate product, the conjugate acid of the carboxylic acid, which instantly comes into equilibrium with the solution, whose pH is about 0, by proton transfer to a water molecule to give the carboxylic acid. The second half of the reaction is shown in Scheme 2. Because both the conjugate acid of the ester and the conjugate acid of the carboxylic acid are carbocations, we are not surprised to see that they react by either accepting a nucleophile or eliminating a proton. The relative stability and ease of formation of carbocations such as these can be explained by the unshared pairs of electrons on the adjacent oxygen atoms that can delocalize into the empty p orbital on the electron deficient carbon as implied by the representation as a resonance hybrid: “Resonance implies delocalization implies stabilization.”

Because the typical reaction mixture for the hydroxide ioncatalyzed hydrolysis of an ester has a pH of about 14, the carboxylic acid will give a proton to a hydroxide ion,

and the alkoxide ion will take a proton from a water molecule.

A Mechanism for the Acid-Catalyzed Formation of Esters One mechanism for the acid-catalyzed formation of an ester, the Fischer esterification, is the reverse of the mechanism


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When we add the previous two equations, we get the overall equation for the reaction of acetic acid molecules and alkoxide


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In the Classroom

ions with the hydroxide ions and the water molecules of the reaction mixture:

Because only one molecule of acetic acid in a billion will actually be present as an acetic acid molecule, the rest being present as acetate ions, the rate of the reverse reaction will be negligible. Summary of the Base-Catalyzed Hydrolysis of an Ester We can summarize the base-catalyzed hydrolysis of an ester in this way:

We see from the balanced equation that a full equivalent of hydroxide ion is consumed during the base-catalyzed hydrolysis of an ester. In the reaction, the base functions in two ways. The first role for the base is to set the pH of the reaction mixture to 14. This is the catalytic role; this is the “let the equilibrium be established” role. The second role for the base is to convert the carboxylic acid to its conjugate base, thus reducing the rate of the reverse reaction and allowing the forward reaction to predominate; this is the “shift the position of the equilibrium” role. Sufficient base must be used for both roles: enough to set the pH to 14 plus one equivalent to shift the equilibrium. Hydrolysis of Ethyl Acetate: The Reaction at pH = 5.5 With a half-life of about 90 years at a pH of 5.5, the rate of hydrolysis of ethyl acetate at this pH is about 5.6 powers of ten less than the rate at a pH of 0 and about 8.6 powers of ten less than the rate at a pH of 14. Because the concentration of the conjugate acid of ethyl acetate should be 5.5 powers of ten lower at a pH of 5.5 than at a pH of 0, the “traffic” over the acid-catalyzed path to product should be 5.5 powers of ten lower at a pH of 5.5 than at a pH of 0. Similarly, since the concentration of hydroxide is 8.5 powers of ten less at a pH of 5.5 than at a pH of 14, the traffic over the base-catalyzed path to product should be 8.5 powers of ten lower at a pH of 5.5 than at a pH of 14. Thus we can account for the reaction at a pH of 5.5 by saying that half of it is due to traffic over the path of acid catalysis and half of it is due to traffic via the path of base catalysis. Because the rate of hydrolysis at a pH of 5.5, the pH of minimal rate, is completely accounted for by the equal contributions via the acid-catalyzed path and the base-catalyzed path, we conclude that there is no traffic over a third path. Although we do not need additional paths, we can conceive of them, and also see why they carry no traffic. 940


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A Noncatalyzed Path We can conceive of a path that involves the reaction of ethyl acetate as an electrophile with water as the nucleophilic:

Although the concentrations of these species are adequate, their reactivities as electrophile and nucleophile are so low that we see no contribution from their reaction. A Super-Reactive Path We can conceive of a contribution to the hydrolysis by the reaction of the conjugate acid of the ester, a powerful electrophile, with hydroxide ion, a strong base and a good nucleophile:

At a pH of 14 the fraction of the ester that would be present in this form would be only 1 10-20, and so there would be no detectable traffic on this path. At a pH of 13 there would be ten times more electrophile, but only one tenth as much nucleophile. And so on. Summarizing the Mechanism of Hydrolysis of Ethyl Acetate The hydrolysis of ethyl acetate in aqueous solution between a pH of 0 and a pH of 14 is due to the reaction of the conjugate acid of ethyl acetate with water (the acid-catalyzed path) plus the reaction of ethyl acetate with hydroxide ion (the base-catalyzed path). The contribution of each process to the overall reaction depends upon the pH of the solution. When the solution is more acidic than a pH of 5.5, traffic over the acid-catalyzed path predominates, increasing by a factor of 10 for each unit decrease in pH. When the solution is more basic than a pH of 5.5, the traffic over the base-catalyzed path predominates, increasing by a factor of 10 for each unit increase in pH. At a pH of 5.5, the contributions are equal. When the pH differs by more than 1 unit from 5.5, the major path dominates by more than a factor of 10. Summary A good part of the presentation of the mechanism of a reaction is to explicitly point out the rapidly established proton transfer equilibria and to emphasize that the fractional concentrations of the members of a conjugate pair in these equilibria are established quickly, and that their ratio is completely determined by the pH of the solution and the pKa of the pair. In many reactions half or more of the steps are rapid proton transfer reactions, and each of these steps can be treated in this way. We saw in the mechanism of the acid-catalyzed hydrolysis of ethyl acetate, for example, that four of the six steps were proton


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In the Classroom

transfers (Schemes 1 and 2), and only two steps involved a change in bonding between a pair of heavy atoms. The most important overall idea is that a reaction involves a set of equilibria, some established quickly (proton transfers) and some more slowly (the rate limiting steps). We need to help our students visualize these equilibria just as we help them visualize the atoms, molecules, and ions that participate in the equilibria. We should also point out those occasions when a species is present that is not on the path to the product under consideration. If we do not do this, students are rightfully mystified by the apparent ability of protons to go on and off when and where we want them to. They might wonder, for example, about the “other” conjugate acid of an ester, the one that could be formed by proton transfer to the “alkyl oxygen”. After students know the rules for proton transfers and can estimate the relative concentrations of members of conjugate pairs, we can focus our attention on the slower steps, the steps in which the bonds between the heavy atoms are made and broken, the steps in which electrophile meets nucleophile to make a new bond or a leaving group departs from an electrophile to break an old bond. Here the rules are not so clear, and the story is more subtle than it is with proton transfers. The Bottom Line: Telling It Like It Is Telling it like it is for reactions that take place in aqueous solutions requires that we invoke only hydronium ion and water as proton donors, and only water and hydroxide ion as proton acceptors. We should never show HCl or HBr or any other strong acid as the proton donor in a reaction that takes place in an aqueous solution. A strong acid will already have donated its most acidic proton to a water molecule. The real proton donor will be H3Oþ. Similarly, we should never invoke Cl- or Br- or the conjugate base of any strong acid as a proton acceptor in aqueous solution. The proton will have gone onto either hydroxide ion or water.

Some Final Comments Being more clear about the presence and concentrations of members of conjugate pairs of acids and bases is part of a larger effort, which is to be more clear about what is “really there” in a reaction mixture. We know what the label on the bottle says, but that does not tell us what is “really there” when the material in the bottle is added to the reaction mixture. A conjugate acid, or a conjugate base, or some of both may also be present, and the reaction may take place, depending upon the pH of the solution, via one or the other of these species. Showing that the concentrations of conjugate forms is dependent upon pH illustrates the fact that proton transfer is not an all-or-nothing phenomenon, but is a matter of degree. We rightly emphasize that solubility is not an all-or-nothing phenomenon but is a matter of degree. We should do the same with proton transfer. Finally, we can see that an overall chemical reaction involves attainment of a series of equililbria, some of which are established more quickly, such as proton transfers, and some more slowly, such as changes in the bonding of heavy atoms. Literature Cited

Are We Making It Too Simple? According to Einstein, “Things should be made as simple as possible but no simpler.” Have we made things too simple? For


reactions that take place in an aqueous solution at a pH near 0 or 14 the answer is no. Most reactions in aqueous solution are subject to specific catalysis, not general catalysis. Furthermore, because general catalysis is proportional to acidic or basic strength, catalysis by acids other than hydronium or bases other than hydroxide will be undetectable at high concentrations of hydronium or hydroxide ions (2). For reactions taking place under physiological conditions, when both hydronium and hydroxide ion concentrations are low, providing paths that involve general catalysis is one way in which enzymes provide new, lower energy, paths for reactions (3).

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1. Friesen, J. Brent. J. Chem. Educ. 2008, 85, 1515–1518. 2. Ault, A. J. Chem. Educ.. 2007, 84, 38–39. 3. Weiss, H. J. Chem. Educ. 2007, 84, 440–442.


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Teaching Mechanisms in Organic Chemistry - American Chemical

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