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The 22 Most Common Errors on Chemistry 232 Exams

J. Wulff
Department of Chemistry
University of Victoria

v. 0.1
July 2011
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Introduction

I taught 2nd year Organic Synthesis for the first time in the Spring of 2010, then taught the course again in
2011. Grading the exams for my second time through the course, I was struck by how many students
made the same few errors again and again – particularly on the synthesis questions at the end of the exam.
Often, the errors took different forms on different questions, such that students might not recognize that
the error they were making on the final exam was the same as one that I had talked about in class,
following the midterm. But perhaps 75% of the mistakes I saw on the last section of the exam could be
grouped into about 20 different “big-picture” problems.

This document is my attempt to spell out for you all of those problems. Think of it as a cheat sheet for my
own exam. I’m telling you most of what you’re likely to get wrong, and I’m telling you ahead of time –
while you can still do something about it. I’m not sure whether putting this on the course website will
dramatically improve everyone’s performance on the final exam, or whether people will just find a way to
invent new, ever more creative errors. Either way, I’ll hopefully have less of the same mistakes to correct
in the future, which would be a win for me.

My intention is for this document to evolve over the next few years (following my return to teaching 2nd
year in 2013), to include more useful content and tips for final exams and midterms. You’ll notice from
the cover page that it’s still in beta, and so you shouldn’t necessarily take what I say here as the final word
on anything. Your textbook provides you with a lot more detail on most reactions than I do here, and my
goal in these pages is not to replace either your coursenotes or your text. On the contrary, I’ve deliberately
refrained from restating things that I’m explicit about in the lecture. The point of these notes is to provide
you with a little bit of extra information so that you can avoid some particularly common errors that have
tripped up students in past years. Once again: if you want to do well in the course, you still need to come
to class every day, and you still need to read your textbook.

I’ve focused on mistakes made in the synthesis questions because: (1) this section is worth the most points
on my exams, and is possibly the most difficult; (2) the diversity of mistakes that people make is
somewhat more limited than in the mechanism questions; (3) there’s a fair amount of “spillover” between
the synthesis questions and other sections of the exam, such that what I tell you here might be useful in
other parts too.

One of the problems with talking about mistakes is that it requires me to write out incorrect reactions, by
way of demonstration. I always worry when I do this, that students will somehow remember the wrong
thing, but not necessarily remember that it’s wrong! To try to make sure this doesn’t happen, I’ve taken
care to indicate incorrect reactions with an angry red X. The corrected forms of these reactions are
designated by a cheerful blue check mark. Hopefully any reactions that stick in your head will do so along
with the appropriate symbol. All of the incorrect responses that I’ve included are taken from answers to
the Spring 2011 final exam (in some cases I’ve simplified the substrates for clarity).

I hope you find this document useful. Please feel free to email me with your comments and suggestions,
as I hope to add more content in the years to come.

J. Wulff
July 2011
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Table of Contents

Problem 1. Acid / Base Errors page 4

Problem 2. Random Functionalization of Alkanes page 6
Problem 3. H3O+ Doesn’t do Everything page 7
Problem 4. Understanding the Difference Between H+ and H– page 7
Problem 5. Chemoselective Brominations page 9
Problem 6. Competing Ester Hydrolysis or Transesterification Reactions page 10
Problem 7. Amines are Nucleophiles – Even When You Don’t Want Them to Be! page 11
Problem 8. Friedel-Crafts Alkylations are Risky page 12
Problem 9. Crazy Reagents page 14
9a. Bifunctional methylenes page 14
9b. Made up electrophiles for Friedel-Crafts chemistry page 14
9c. Protecting groups that aren’t page 15
9d. Self-reacting species page 15
9e. Other reagents that are just too crazy for use page 16
Problem 10. It’s a carbon, not just a stick! page 17
Problem 11. Deoxygenations page 17
Problem 12. Carrying reactive species through multiple steps page 18
Problem 13. Keto-enol equilibria page 19
Problem 14. Friedel-Crafts reactions on saturated systems page 19
Problem 15. Cations on sp2 carbons page 19
Problem 16. Fischer esterifications page 21
Problem 17. The double-addition trap page 21
Problem 18. Mysterious oxidations page 22
Problem 19. Mysterious reductions page 23
Problem 20. Order of reactivities page 23
Problem 21. Poor choice of nucleophile / base page 24
Problem 22. Wishful thinking page 24
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Problem 1. Acid / Base Errors

The most common mistakes on synthesis questions are variations of the acid/base problem, where
people want to use a strong base (or a strong nucleophile, which is ultimately the same thing) in the
presence of an acidic proton. Some examples are shown below.

1.1

1.2

1.3

1.4

None of these reactions will work, because in each case we have a strong base in the presence of an
acidic functional group. Let’s consider these reactions further.

Reaction 1.1: In this reaction, we clearly intend for LDA to remove a proton next to the carbonyl
(pKa ~ 25). But the carboxylic acid (pKa ~ 4.5) is much more acidic! So LDA will only end up
deprotonating the acid to make a salt, and no desired product will be observed.

How can we fix it? An ester is a synthetic equivalent for a carboxylic acid, because the ester can be
hydrolyzed (e.g. KOH, MeOH) to afford the desired acid product. Protons on the carbon next to the ester
function still have a pKa of around 25, but the ester itself does not contain any acidic protons.
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Reaction 1.2: In this reaction, the problem is not with the substrate (cyclopentenone) but with the
electrophile that’s being added to it. This molecule contains an alcohol (pKa ~ 16) which is sufficiently
acidic to react with the enolate of cyclopentanone (pKa ~ 20).

How can we fix it? Putting a protecting group on the alcohol is the easiest way to solve the problem.

Reaction 1.3: Here we’re generating a strong base (a Grignard reagent) in the presence of an acidic
functional group (a phenol; pKa ~ 10). A proton transfer will happen very quickly to quench the Grignard.

How can we fix it? Once again, a protecting group on the alcohol would solve the problem.

Reaction 1.4: In this case, we’re trying to react a Wittig reagent with a ketone. Unfortunately, the ketone
substrate also contains a carboxylic acid function (pKa ~ 4.5). Remember that the Wittig reagent is just a
fancy carbanion, and is therefore quite basic (we generate it with nBuLi, after all!). This means that Wittig
reagents will react with acids, alcohols, or phenols.

How can we fix it? Using an ester in place of the carboxylic acid (as for reaction 1.1) would solve the
problem.
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Problem 2. Random Functionalization of Alkanes

I suspect this is more about wishful thinking on exams than it is about legitimate problems of
understanding, but the sorts of reactions shown below (taken from the 2011 exam responses) are
nonsense.

2.1

2.2

So what will happen in these reactions? The mechanisms for these two reactions are different, but both
will ultimately give a reaction at the benzylic position. Oxidation (SeO2 or KMnO4) will lead to the
installation of an alcohol, ketone or (under more forcing conditions) carboxylic acid at that position, while
radical bromination will result in the installation of a bromine at the same spot on the molecule.

In fact, functionalization of an alkane – in the absence of any other nearby functionality to help control
the reaction – is an enormously difficult problem that’s an area of current interest in the synthetic
literature (google: C-H activation).

This brings up the idea of using synthetic handles to control your chemistry. If you want a carboxylic
acid at the end of your alkyl chain, you really need to have something there first, that you can turn into a
carboxylic acid at the appropriate time (e.g. an ester, or a primary alcohol). Alternatively, you could have
some other functionality present at the next carbon over, which might allow you to brominate controllably
at the desired position.
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Problem 3. H3O+ Doesn’t do Everything

There are a lot of reactions that we see in class (ester formation and hydrolysis, many types of
deprotection reactions, eliminations, etc.) that are catalyzed by acid. And so – while I don’t exactly
condone the practice – I do sort of understand why people write “H3O+” when they can’t think of the right
reagent to use for a reaction.
However, it’s important that you recognize that H3O+ is neither an oxidant nor a reducing agent. So
any reaction that you’re proposing where an oxidation or reduction is taking place cannot be done using
H3O+. Similarly, any reaction involving a carbanion (including a Grignard reagent) or other basic species
had better not involve H3O+, or you’ll just end up protonating your base (see Problem 1, above). Of
course, after you’ve added your Grignard reagent to an electrophile, you often work up the reaction by
adding an acid. It’s important to remember that this is a separate step, and serves to protonate any anionic
groups that are left over at the end of the reaction.

Problem 4. Understanding the Difference Between H+ and H–

This really shouldn’t be an issue by the time you get to 235, but some people still insist on using H + as
a reducing agent, or otherwise mix up the functions of these two very different species. To make sure this
never happens again, I will briefly summarize their roles here.

H+ is an acid, which means that it’s also an electrophile. It will react with nucleophiles (bases) by
accepting electron density. In our curvy arrow formalism, the arrow always flows toward the H+.

In elimination reactions, the proton is effectively lost as H+.

H– is not really encountered as a discrete species, but can be invoked (somewhat informally) to
explain the function of reducing agents like LiAlH4 or NaBH4. It is fundamentally a nucleophile, and
reacts with carbonyls. In our curvy arrow formalism, the arrow always flows from the H–.
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In principle, H– can (like any nucleophile) act as a base as well. In fact, this can be a pretty big
problem when you’re trying to reduce carboxylic acids, since the first equivalent of “H–” (e.g. LiAlH4)
will react with the acid to make an equivalent of hydrogen gas. Once that happens, your substrate
becomes a negatively charged carboxylate which reacts very sluggishly with further equivalents of
LiAlH4. To put this in perspective, the reduction of carboxylic acids requires relatively high temperatures
(refluxing THF or dioxane) and long reaction times (usually 24 hours or so) to go to completion. By
contrast, esters (which lack an acidic proton) can be reduced in a few minutes at room temperature or
below.

In practice, reagents like LiAlH4 or NaBH4 aren’t very useful as sources of “basic H–”, because both
these reagents tend to function preferentially as nucleophiles (and therefore reducing agents). LiAlH4 is a
particularly vigorous reducing agent!
However, sodium hydride (NaH), because it is insoluble in many organic solvents, is not very good at
donating H– as a nucleophile. The corollary is that this reagent is quite useful as a base, removing a
proton from an acidic functional group (alcohol, ketone, etc.) to generate an anion. Once again, your
arrow should flow from the H–.

Because the pKa of hydrogen gas (H2) is very high (~40, depending on who you ask), forming the
conjugate base (H–) is almost never going to be thermodynamically favourable. This means that you
should never use H– as a leaving group in a mechanism!

As a result, the reaction above (conversion of an alkoxide to a ketone) is nonsense, since it would
require a loss of H–. Note that I haven’t actually drawn in this problematic hydrogen atom – a big part of
watching out for these types of mistakes involves keeping a careful count of how many hydrogens are on
each of your carbon atoms.
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Problem 5. Chemoselective Brominations

Certain types of reactions that accomplish similar end goals (but with different mechanism and
different regiochemical outcomes) lead to confusion. Bromination reactions – perhaps because they’re
discussed in different parts of the course – seem particularly problematic. To see the difference between
the various brominations we discuss in class, consider the following three reactions:

Note that for each of these three reactions, the bromine ends up in a different place on the molecule.
That’s a good thing, because it allows you to make lots of different types of products. But it’s also a bad
thing, in that you have to understand how you get each one.
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Problem 6. Competing Ester Hydrolysis or Transesterification Reactions

In a lot of carbonyl addition reactions (aldols, Claisens, etc.) with esters, you’ve probably noticed that
the base is the same as the ester group. In almost all the examples in my lecture notes, this takes the form
of an ethyl ester reacting with sodium ethoxide. There’s a good reason for this! It means that
transesterification reactions don’t lead to mixtures of different esters. To see what I mean by this, consider
the following reactions:

This problem is fairly easy to see, but it gets more tricky when you’ve assembled a good part of your
molecule together through an ester linkage. The following reaction, for example, would not be a good
idea:

Not only would you end up doing a lot of transesterification at the phenolic ester linkage (in fact,
phenolates are better leaving groups than alkoxides, so this would be a particularly efficient process), but
you’d also get a lot of self-condensation of the acetaldehyde under these conditions. There’s also a
problem with the positions next to both carbonyls being deprotonated under these conditions, leading to a
regioisomeric mixture of products.
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How can we fix it? There’s always going to be a problem with using an unsymmetrical diester, since
you’re never going to have control over which ester you’re deprotonating next to. But you can at least fix
the transesterification problem by quantitatively deprotonating with a strong base (either LDA or NaH).
Once the enolate is formed, you can add the aldehyde to get the desired product.

Problem 7. Amines are Nucleophiles – Even When You Don’t Want Them to Be!
We need to be particularly careful about using electrophiles in the presence of amines, since the latter
are good nucleophiles. Anilines are less nucleophilic than other amines, but they’re still good enough to
cause problems in Friedel-Crafts reactions.

7.1

7.2

There are actually two problems with these reactions. The first is that the nitrogen tends to bind the
aluminum as a ligand, removing electron density from the nitrogen (and thus from the benzene ring) and
making any kind of subsequent electrophilic aromatic substitution reaction less likely. But the second
problem (which is more important, particularly with alkylations) is that the amine will react with the
electrophilic alkyl or acyl cations that are formed in the reaction mixture. Both of these problems can
solved by protecting the nitrogen as an acetamide (or benzamide). This leaves the ring quite electron rich,
but tempers the nucleophilicity of the nitrogen considerably. The Friedel-Crafts alkylation is still a bit
sketchy, but I wouldn’t mark it wrong.
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Problem 8. Friedel-Crafts Alkylations are Risky

I sometimes feel that we shouldn’t even cover these reactions in 235, since they’re so plagued by
competing rearrangement reactions and other problems. But they’re useful in certain (fairly limited)
applications synthetically, and turn out to be quite important industrially as well. So we need to talk about
them. If you want to use them, however, you need to be aware of what kinds of reactions will work for
you, and what kind of reactions will cause problems.
The first kind of problematic reaction is discussed in the previous section. Don’t try to do a Friedel-
Crafts alkylation in the presence of a nucleophilic amine or alcohol. To some extent, these problems can
be avoided through the use of protecting groups (as discussed above).

8.1

8.2

8.3

The second problem happens when you try to use an electrophile that can rearrange.

8.4

The problem with reaction 8.4 is that you’re trying to form a primary (n-propyl) cation. While methyl
or ethyl cations can be OK (try as hard as you like, you won’t be able to rearrange an ethyl cation into
anything more stable than the same ethyl cation), this n-propyl cation can rearrange to give a more stable
2° carbocation.
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The third problem happens when you try to selectively mono-alkylate a benzene ring using a Friedel-
Crafts reaction. Because the alkyl group that you just added is an electron-donating group, it speeds up
subsequent Friedel-Crafts alkylations, resulting in the formation of di-alkylated product. You can
sometimes fix this by using a very large excess of the benzene substrate, relative to the electrophile. Note
that this is not a problem for Friedel-Crafts acylation reactions, since the group that you’re adding in this
case is deactivating. So in many cases it’s better to perform a nicely controllable acylation reaction, then
convert the product of that reaction into your desired alkylated product – either through deoxygenation or
some other reaction at the carbonyl group.

The fourth problem happens with electron-poor benzene rings. Friedel-Crafts alkylations are very
sluggish, and so don’t work well with substrates that are less electron-rich than benzene itself. Generally
speaking, if you’re considering using a meta-directing group to control a Friedel-Crafts alkylation, there’s
going to be a problem.

So what to do? Friedel-Crafts alkylations can be useful reactions if (1) your substrate aromatic is
electron rich; (2) your substrate already has a good-size donor substituent, such that your alkylation will
take place selectively at the para position, and the ortho position will be relatively unreactive; (3) the
substrate contains no nucleophilic amines, free alcohols, carboxylic acids, etc.; (4) the electrophile is of a
relatively simple structure, and cannot rearrange to a more stable cationic intermediate.
If one of these is not true, you might want to consider performing a more-easily-controllable Friedel-
Crafts acylation, then removing the superfluous carbonyl group through either a Wolff-Kishner reduction
or a Clemmensen reduction. You can even do Friedel-Crafts acylations on somewhat electron-deficient
benzene rings, though of course your free heteroatoms will need to be protected (as discussed above).
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Problem 9. Crazy Reagents

People often come up with crazy reagents under the pressure of an exam. Often these take the form of
coupounds that – even if they could be generated – would react with themselves. Here are some classics:

9a. Bifunctional methylenes

9.1

The problem here is that the electrophile being used is something that really isn’t isolable. You should
recognize this as a chlorohydrin (or bromohydrin) and recall from your course notes that these revert back
to the parent aldehyde as soon as they have a chance to do so.

Technically speaking, you could protect the alcohol, but this is making more work for yourself. What
you want to do here is just use formaldehyde as your electrophile. This brings up a larger point – often the
best way to make substituted alcohols is to add nucleophiles to carbonyl compounds.

9b. Made up electrophiles for Friedel-Crafts chemistry

9.2

Just… no.
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9c. Protecting groups that aren’t

You know that acetals and ketals are useful as protected forms of aldehydes and ketones, and so
there’s a temptation (again, under pressure) to try to do the same thing with esters, acids, amides, acid
chlorides, etc. This doesn’t work.

9d. Self-reacting species

9.3

9.4

9.5

Although these reactions are related thematically, they’re all a little different mechanistically, so it’s
worth going through them individually.

Reaction 9.3: The problem here is with the electrophile being used in the attempted Friedel-Crafts
acylation. It has an electrophilic portion (the acid chloride side of the molecule) which becomes even
more electrophilic when it encounters the catalyst (at which time the chloride is pulled away by the
aluminum, at least partially). But it also has a nucleophilic part in the form of the OH, which is probably
made even more nucleophilic by loss of a proton. So one molecule will add to another, then another, then
another, until you make polycarbonate. Polycarbonates can be useful plastics, but that’s probably not what
you’re going for here.
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The solution is to use a synthetic equivalent. For example, you might consider doing a Friedel-Crafts
reaction with formyl chloride, after which you could oxidize the resulting aldehyde up to the desired
carboxylic acid.

In practice, formyl chloride is not very stable, and so is usually generated in situ from carbon
monoxide and HCl (google: Gattermann–Koch reaction). But that’s a fairly minor issue that you probably
don’t need to concern yourself with at this stage.

Reaction 9.4: In this homologation reaction, the problem is that there’s something else for the
Grignard reagent to do, once it is formed. It will most likely undergo self-reaction with the nearby ketone,
to produce an undesired product.

These kinds of problems are difficult to see coming, since you really need to evaluate the whole
molecule (and indeed all the molecules in the flask) for potential side reactions. The ability to see these
sorts of problems is one of the hallmarks of a good synthetic chemist.
In this case, of course, the problem could be taken care of by using a protective group for the ketone.

Reaction 9.5: This is another type of self-reaction problem, this time associated with the electrophile.
Always remember when trying to do a Friedel-Crafts alkylation that you’re forming a carbocation from
the electrophilic coupling partner. We’ve already seen how carbocations can rearrange, but of course they
can react in other ways too, if nucleophilic bits are present on the same molecule.

9e. Other reagents that are just too crazy for use

9.6

I see these kinds of strategies fairly often on exams, but that double-Grignard thing is not very likely.
Instead, as soon as you form the first Grignard, the substrate will tend to decompose into a carbene. This
is not something that you want to happen.
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Problem 10. It’s a carbon, not just a stick!

10.1

Variations on this sort of thing appear with surprising frequency in exam answers, and presumably
arise from the fact that our “stick diagram” representations of molecules make it easy to (perhaps
optimistically) avoid thinking about all the carbons. But of course if you draw out the structures in more
detail, you’ll see that one of the carbon atoms has been lost.

Another surprisingly popular answer to a question from the spring 2011 exam is shown below. Clearly
this does not make any sense, and could be avoided by considering the nature of the reactants more
carefully.

10.2

The bottom line here is that if you want to avoid these kinds of trivial errors: count your carbons!
Counting your hydrogens is not a bad idea either, since it will keep you out of some of the “H – as leaving
group” problems that are discussed above, and will likewise keep you from doing unreasonable oxidations
(loss of hydrogen) or reductions (gain of hydrogen).

Problem 11. Deoxygenations

Although it’s not particularly “elegant” in a synthesis, burning off a carbonyl group can be a helpful
way of controlling functionality in a molecule. However, keep in mind that these kinds of reactions only
work for ketones and aldehydes, which can’t do nucleophilic substitution reactions. For substrates that
can participate in nucleophilic acyl substitution (acids, acid chlorides, amides, etc.) unwanted products
will result.

11.1

11.2

11.3

Fortunately, you don’t need these reactions, because the substrates can be easily reduced.
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Other problems with deoxygenations stem from the fact that the reagents used (hydrazine in the Wolff
Kishner reduction, zinc in the Clemmensen reduction, Raney nickel for desulfurization of thioketals) can
also react with other functionality in your molecule. Be on the lookout for these (probably unwanted)
reactions if you’re going to make use of a deoxygenation step.

Likewise, be aware that the strongly basic conditions required for the Wolff Kishner reduction may
trigger elimination reactions, if some part of your molecule may be prone to elimination (e.g. alkyl
halides, ether functions that are beta to carbonyls, etc.), while the strongly acidic conditions required for a
Clemmensen reduction will likely remove ketal groups that you might be using to protect other latent
carbonyl functions elsewhere in your structure. The takehome message here is: be very careful in
selecting the correct deoxygenation conditions!

Problem 12. Carrying reactive species through multiple steps

Compounds like diazonium salts are very useful in synthesis by virtue of their high potential energy –
they really want to react, which means that you can turn them into all kinds of useful products. But this
comes with a downside too. Highly reactive species will often undergo unwanted reactions. For this
reason, diazonium salts – as well as acid chlorides or anhydrides (highly electrophilic), carboxylic acids
(prone to deprotonation), and even alkyl aldehydes (prone to self-condensation) should be used in the very
next step after they’re generated. Don’t carry reactive species through multiple steps of a synthesis.
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Problem 13. Keto-enol equilibria

The tautomerization from an enol to the corresponding ketone (or aldehyde, ester, etc.) is a very fast
process, and will be catalyzed by minute traces of acids or bases. Commercial solvents, the surface of
laboratory glassware, and pretty much anything else that your molecule comes into contact with will be
sufficient to make this reaction happen nearly instantaneously. That means that if you generate an enol in
your reaction (for example, by adding water across a triple bond), you’ve for all practical purposes made
the ketone. Don’t try to somehow carry the enol onto the next stage of the synthesis (you could trap the
enol with a silyl protecting group, but that’s a whole other story). Similarly, the enol cannot be used as
some sort of protected form of a ketone.

Problem 14. Friedel-Crafts reactions on saturated systems

14.1

One might argue that the enol form of the ketone substrate in reaction 14.1 might intercept the
carbocation to produced the intended product – but this is probably not the best way to do this.
Deprotonation to form the enolate will provide a more reliable reaction with the electrophile. No AlCl3
required.
Though there are a few exceptions (none of which pertain to Chem 235) you should consider Friedel-
Crafts reactions as something that doesn’t work on saturated hydrocarbons.

Problem 15. Cations on sp2 carbons

I spend quite a bit of time on this in class, but some people still insist in using vinyl halides or aryl
halides in Friedel-Crafts and related reactions.

15.1

15.2

15.3

15.4

The problem in the first two reactions here is subtly different from the problem in the second two
reactions, so let’s address these separately.
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Reactions 15.1 and 15.2: Always keep in mind that sp2–hybridized carbons cannot easily support a
positive charge. Because a carbocation is required for Friedel-Crafts reactions to occur, these really can’t
be done with aryl or vinyl halides. In later courses, you’ll learn that other types of coupling reactions
(using palladium catalysts) allow you to couple two sp2 centres very effectively – but that will have to
keep for another day.

Reactions 15.3 and 15.4: As you recall from Chem 231, addition reactions to alkyl halides can be
divided into SN1 reactions (proceeding through a carbocation intermediate) and SN2 reactions (requiring
attack from the “back” of the alkyl halide.

Neither of these pathways are open to vinyl or aryl halides. In the case of a putative SN1 reaction, the
required carbocation is too high in energy, as discussed above. Since you can’t form the intermediate, you
can’t get to the product.
In the case of a putative SN2 reaction, the reaction is prohibited on geometric grounds. Unlike with an
alkyl halide (see above), in the case of a vinyl or aryl halide the incoming nucleophile can’t attack from
the “back side” of the halide because there are atoms in the way. More subtle molecular orbital factors
also disfavor a direct SN2 displacement of a vinyl or aryl halide.
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Problem 16. Fischer esterifications

Fischer esterifications are often great reactions, but it’s important to remember that they are
fundamentally reversible. In order to drive the equilibrium toward products, one must either use the
alcohol as the solvent (so that at least 10 equivalents of one reactant are present) or have the alcohol and
acid functions tethered together, so that the local concentration will be very high.

So if you’re making a methyl ester or an ethyl ester, a Fischer esterification is for you! But for
coupling together two high-value pieces, this would not work.

16.1

A much better idea would be to convert the carboxylic acid to an acid chloride prior to reaction with
the phenol. Another option is to use a peptide coupling reagent like dicyclohexylcarbodiimide (DCC).
These work for esterifications as well as amidations – to make them go at a reasonable rate, it’s helpful to
also add a nucleophilic catalyst like N,N-dimethylpyridine (DMAP).

Problem 17. The double-addition trap

When adding two new groups to a benzene ring that contains a meta-director, it’s tempting to put both
new substituents at the two meta positions.

17.1

I chalk this one up to either exam pressure or wishful thinking. Of course, the first iodide substituent
will appear meta to the carboxylic acid. But then you need to remember that when adding to a
disubstituted benzene ring, it’s the strongest donor group that controls the position of the next substituent.
So the second substituent will appear ortho or para to the first.
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Problem 18. Mysterious oxidations

It’s fairly common in exam responses to see reactions with aldehydes leading to ketone products. It’s
never clear whether the respondent has just forgotten to include the oxidation step, or whether the
implication is that the hydride has somehow acted as a leaving group. Either way, it’s wrong.

18.1

It’s likewise not uncommon for me to see deprotonations somehow lead to oxidation. Presumably this
is intended to proceed through loss of H– ? But of course H– cannot be a leaving group, as was discussed
at length above.

18.2

To avoid making errors like the one in reaction 18.2, it’s useful to evaluate any reaction that you want
to do in a synthesis as to whether it is an oxidation or reduction. This is actually the reason that I include a
question early on in the exam where you’re asked to assign reactions as oxidations, reductions, or neither
– it’s supposed to get you on track for the synthesis questions at the end.
If a reaction is an oxidation (as is transformation shown in 18.2; note the loss of two hydrogen atoms),
then you need an oxidant (note: bases like t-BuOK are never oxidants). Likewise, if the reaction you want
to do is a reduction, you require some kind of reducing agent to make it happen.
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Problem 19. Mysterious reductions

Sometimes your molecule ends up over-functionalized relative to what you’re targeting. In these
cases, there is often a temptation to just “wish away” the offending functional group. But of course
functional groups don’t just go away. In many cases, these would be (formally, at least) reduction steps.
Once again, if you can get in the habit of evaluating whether a proposed transformation is an oxidation or
reduction, you can often save yourself a lot of trouble.

19.1

For example, in reaction 19.1 the addition of HCN to a ketone should afford a cyanohydrin. The
nitrile compound that is shown as the product would therefore require a (formal) reduction step. In reality,
this direct reduction would be impractical. A much better way to access the target nitrile would be to do
the reduction first, then install the nitrile group through routine functional group manipulations.

Problem 20. Order of reactivities

You can save yourself a lot of trouble on exams by committing to heart the order of reactivities for
carbonyl compounds with nucleophiles. This is in your notes (along with an explanation for the trend),
but I’ll reproduce it here for convenience.

That means that ketones will not react before aldehydes, even if you really want them to.

20.1
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Problem 21. Poor choice of nucleophile / base

This is another area that separates those who really understand the chemistry from those who have
merely memorized reactions. It’s good to be in the former camp.

21.1

The problem with reaction 21.1 is that the base being used (NaOEt) is also a very good nucleophile,
and so will react with the benzyl bromide. A better strategy would be to use a non-nucleophilic base like
NaH. Alternatively, you could quantitatively deprotonate the malonate with LDA.

Problem 22. Wishful thinking

Many of the problems discussed above are probably attributable to wishful thinking on exams. But
these two incorrect responses stand out as particularly strong examples.

22.1

22.2

In reaction 22.1, the problem is that KI is a nucleophilic source of iodine (i.e. K+I-). In an electrophilic
aromatic substitution reaction, the benzene ring is the nucleophile, and the group being added must be
electrophilic. So you want some kind of source of “ I+ ”. The one I suggest in my course notes is ICl.
In reaction 22.2, it is unrealistic to expect that the magnesium can insert into the Ar-Br bond, but not
into either of the Ar-I bonds (if anything, it will react faster with the iodides, but you probably still won’t
get good selectivity). So this reaction will not work. The solution here is to form your Grignard reagent
and add it to whatever electrophile you have in mind before adding the iodide groups.