What is multistep synthesis?

Multistep synthesis is the process of taking a readily available compounds (ones you can buy) and converting
them into desired products using known reactions. Multistep syntheses require more than one step, and so
one or more intermediate compounds are formed along the way.

What are multistep synthesis problems

Typical multistep synthesis problems give a starting material and a product and instruct you to devise a route
that takes the starting material into the product. For example, you might be asked to convert starting material
W into product Z using reagents you've learned.

What's an acceptable answer to these problems?

The way to answer these problems is to show the reagents that convert the starting material into the
intermediate compounds, and, finally, into the product. For example, if you were asked to convert compound
W into compound Z, you might convert W into an intermediate compound (X), which could in turn be reacted to
form another intermediate compound (Y), which could be reacted once more to form the product (Z). Note that
no mechanisms (arrow-pushing) are shown for the individual reaction steps, just the reagents and any
intermediate compounds formed along the way.

Six tips for working through multistep synthesis problems:

Multistep syntheses problems can be very challenging. So here are six tips that can aid you in solving these
types of problems.

1. Know the reactions.

This is the basic requirement. No matter how smart you are, you don't stand a chance on synthesis
questions unless you know the reactions. Memorize the reagents, use flash cards, use whatever
techniques you find most helpful, but get the reactions down cold. Since organic chemistry is a
cumulative course, you can't afford to forget any reactions that have been previously covered, so
never throw your stack of old flash cards away, but rather keep adding to the pile (the deck will be
thick by the end of the course). Often, textbooks have end-of-chapter reaction summaries that can be
helpful in making up flash cards.

2. Compare the carbon skeletons.

Compare the carbon skeleton of the starting material to the product. Were any carbons lost or added?
If so, can you identify where they were added or lost? A carbon count of the reactant and the product
doesn't take long, but can help you determine what kind of reactions you are dealing with.

Take the following simple example. The red portion of the molecule identifies where the likely carbon
skeleton of the reactant is found in the product. Doing this allows you to clearly see what portion needs
 to be added or lost during your synthesis (it may seem trivial in this obvious example, but it can be a
quite helpful to organize your thoughts in tougher problems).

3. Work backwards

Ever find it easier to get through a maze starting at the finish and working back to the start? The same thing
applies to multistep synthesis (working backwards like this is a technique termed retrosynthesis). Look at your
product, and think of all the reactions that you know of that could form it, ignoring your starting material.

If your product is an alkene, think potentially of alkene-forming reactions like elimination reactions or the Wittig
reaction. Write all these reactions out and look what reactant would be required for each. Now look at your
starting material. The reaction that most resembles your starting material is probably the best one to select as
a potential candidate.

For example, if you were asked to do the following synthesis:

After completing the first two steps above, you would want to think of ways to make the alkene in the product.
Ignore the starting material for the moment. Just brainstorm all the ways you can think of to make the alkene
and write them down on your scratch paper. You should get something that looks like this:

Now you have three possible routes to choose from. The route to choose is the one that uses a reactant that
most resembles our original starting material. If you did step 2 (accounting for the carbon skeleton), you would
know that the product has one carbon more than the starting material. Only the first reaction, the Wittig
reaction, accounts for this additional carbon, and since the reactant for the Wittig reaction most resembles our
starting material, this would be the reaction to tentatively choose. If it turns out to be wrong, we can always go
back and try another route.
Looking at our reaction scheme, we now have something that looks like this:

Now repeat the same procedure for cyclohexanone, thinking of all the different ways you could make the
ketone. One pointer here is that the closer you get to completing a retrosynthesis, the more you can reference
the starting material in your thinking. At this point, for example, you may want to tune your thinking from "I
need to think of all the ways I can make cyclohexanone" to perhaps something more on the lines of "I need a
reaction that converts an alcohol to a ketone". If you did step one, you would know several ways (different
chromate reagents, KMNO4, Ag2O, etc).

If you get stuck, go back and try one of the other pathways. If the Wittig reaction in our example had let to a
dead end, then we could have gone back and tried one of the elimination reactions. Choosing the correct way
back is often a manner of feel, and that only comes after working a lot of problems (See tip 5).

4. Making your life easier: Sorting your synthetic tools

There are pretty much two types of synthetic tools available to you: (1) carbon-carbon bond forming reactions,
and (2) functional group reactions that convert one functional group into another (like a reaction that converts
an alcohol into a ketone, for example).

You may have noticed that many, many multistep syntheses involve making carbon-carbon bonds (which, in
turn, you will have noticed by comparing the carbon skeleton of the starting material and product as suggested
in a previous tip). In the toolbox of all your reactions, these carbon-carbon bond forming reactions should go
right on the top where they are easy to reach. The functional group transformations are of more secondary
importance and go on the bottom of the toolbox to be dusted off when needed.

Synthetic toolbox.

Step 1: Compiling a list of all the carbon-carbon forming reactions you've learned.

Carbon-carbon reactions are your primary tools to build up your molecules, and are perhaps the most
important and valuable reactions to remember. Once you know which carbon-carbon reactions to use to make
the product, the other reactions often seem to magically fall into place.

At first, your list of carbon-carbon forming reactions will be small. But this list will get bigger. At the end of your
first semester, you may have a list that contains some of the following carbon-carbon reactions (and perhaps
others, depending on what material your professor and textbook chooses to cover):

Your most important synthetic tools: Carbon-carbon forming reactions

• Acetylide reactions. These reactions involve use of an acetylide (a deprotonated
terminal alkyne) as a nucleophile. Typically, the acetylide is used to attack a
primary halide (in an SN2 reaction) or a carbonyl group to make an alcohol.

• Cyanide additions to primary halides. Cyanides can be substituted for halides in

a SN2 or SN1 substitution reaction (although I'd recommend you stick with SN2
reactions rather than SN1 reactions in your multistep syntheses).

• The Wittig Reaction. Makes a carbon-carbon double bond starting with a carbonyl
compound phosphonium ylide

• Friedel-Crafts reactions (for aromatic rings). This reaction makes an aromatic-

carbon bond.

• Diels-Alder reaction. This reaction takes a diene and a dienophile to make ringed
and bicyclic products. This reaction makes two new carbon-carbon bonds.
 • Grignard reaction. This reaction adds a halomagnesium reagent (Grignard
reagent) to a carbonyl to make an alcohol.

Some common carbon-carbon forming reactions in first-semester

undergraduate organic chemistry

Later (second semester typically), you may add enolate and enol reactions to the list (like the aldol reaction,
Claisen reaction, Michael reaction, etc).

Tip 4 continued... Adding carbon-carbon forming reactions into your retrosyntheses

All right. You've learned your reactions and organized them into (at least) two categories: functional group
conversions and carbon-carbon bond forming reactions. You've got a fresh synthetic problem in front of you.
So now what?

Now you want to think of which carbon-carbon bonds you have to form to take the starting material into the
product.

Take an example synthesis:

In this example, you can think, "well, if I'm starting with cyclohexane, the carbon-carbon bond I'm going to have
to make connects the cyclohexane ring to the chain containing the carbonyl (C=O) group."
Then you can think "which of the carbon-carbon forming reactions would be useful to make this carbon-carbon
bond?" Then check off the list to see which ones might be used and which can be eliminated from
consideration.

• Acetylide chemistry: This reaction won't work to make this bond. Acetylide reactions work well only
with primary halides. The acetylide chain would have to attack a ring carbon which would be a
secondary carbon. Also, it's not clear how to selectively take the resulting alkyne to the ketone since it
would be an internal alkyne.
• Cyanide addition: This won't work. Cyanides add only one carbon. You need to add three carbons.
• Wittig reaction: This one might work. Of course, Wittig reactions form a carbon-carbon double bond
and you want a carbon-carbon single bond. Probably it's best to see if there's a better route to go
before trying this one.
• Friedel-Crafts: You don't have an aromatic ring in this problem, so this reaction's out of the question.
• Diels-Alder reaction. This won't work. The Diels-Alder reaction forms rings and bicyclic compounds.
You already have the ring in the starting material.
• Grignard reagents. This reaction should work. Of course, a Grignard reagent reacts with a carbonyl
compound to make an alcohol, not a ketone. Fortunately, since you've learned all of your functional
group transformations, you know that it's a straightforward task to take a secondary alcohol into a
ketone. This reaction looks the most promising so try this carbon-carbon bond forming reaction.

Now that you've chosen the carbon-carbon forming reaction, notice how all the other functional group
conversions required to complete the synthesis seem to fall neatly into place. It's usually best to work
backwards (using the retrosynthesis approach I discussed in a previous tip), so do that for this problem.

Since you know the carbon-carbon bond-

forming reaction forms an alcohol, the last
step must convert that alcohol to the ketone
in the product. In this case, a number of
oxidizing reagents could be used. PCC or
Jones' reagent would work just fine here.
(You could use other chromium reagents as
well)

To make this alcohol you use the Grignard

reagent in the carbon-carbon bond-making
step that you decided upon earlier. To make
a secondary alcohol, you must react the
Grignard reagent with an aldehyde. I chose
cyclohexyl magnesium chloride here as the
starting material, but you could just as easily
have gone with cyclohexyl magnesium
bromide (either works fine)
 To make Grignard reagents you add
magnesium turnings to an alkyl halide. Since
I chose in the previous reaction to make a
chloride Grignard reagent, the starting
material I choose in this case is
chlorocyclohexane (it would be
bromocyclohexane if you went with the
bromo Grignard reagent).

The way to add a chlorine to an alkane is to

chlorinate using free-radical chemistry in the
presence of light.

And that's the retrosynthesis for this molecule. Notice how the steps all seemed to be logical once the carbon-
carbon bond forming reaction was chosen.

5. Check your answer.

Once you have a potential synthesis, go back and make sure all of your reagents are
compatible with the functional groups on your molecule. Make sure, for example, if you are
proposing a Grignard reaction, that there are no alcohols or other incompatible functionalities
on your reagent. Undergraduate organic professors often seem to take delight in creating
challenging (read: tricky) exam questions, giving little partial credit for incorrect answers, so
double check every detail of your synthesis for correctness. Which leads us to the most
important tip at becoming good at multistep synthesis questions, which is:

6. Work lots of problems.

There's no way around it, no magic formula. A good textbook will have plenty of problems to
practice on. Start with easy synthesis problems to get the feel of what is required, then work
your way to harder problems. Get help from a tutor if you need it. If you have a solutions
manual to your text, don't refer to it until after you have completed the problem. Looking at the
solution manual and thinking "yeah, I could do this problem," or "yeah, that looks about right,"
is no substitute for actually doing it. On an exam, the question will never be "Does this look
right to you, check yes or no." So you'll need experience to get the feel of how to work
problems. Get lots of experience. Working in groups can help, but make sure that you do the
work yourself. Don't let someone else do it for you. You're on your own when exam time
comes.

See other tutorials ::

MECHANISMS

Free radical halogenation

 Click here for an animation of the free radical halogenation mechanism of methane (opens in a
popup). Does not show termination steps. Requires the Flash plugin, standard with most new
browsers.

Free radical halogenation is a reaction that substitutes a chlorine or a bromine for a hydrogen on an
alkane. This reaction is a photochemical one. That is, it occurs only when performed in the
presence of uv light (abbreviated hv).

Typically, free radical reactions are described in three steps: initiation steps, propagation steps, and
termination steps (described below). Note the use of a single headed arrow when describing the
movement of a single electron.

Initiation Step:

The reaction begins with an initiation step, which is the separation of the halogen (X2) into two
radicals (atoms with a single unpaired electron) by the addition of uv light. This is called the
initiation step because it initiates the reaction.

Propogation Steps:

The initiation step, or the formation of the chlorine radicals, is immediately followed by the
propogation steps--steps directly involved in the formation of the product. As an example, isobutane
(C4H10) will be used in the chlorination reaction. The first step is the abstraction of the hydrogen
atom from the tertiary carbon (a tertiary carbon is a carbon that is attached to three other carbon
atoms) Note that these are not protons (H+ ions) that are being abstracted, but actual hydrogen
atoms since each hydrogen has one electron. This first propogation step forms the tertiary radical.

In the last step, the tertiary radical then reacts with another one of the chlorine molecules to form
the product. Notice that another chlorine radical is regenerated, so this reaction can, in theory, go
on forever as long as there are reagents. This is called a chain reaction.

A sidenote on free radical stabilities:

Hydrogens attached to more highly substituted carbons (ie. carbons with many carbons attached to
them) are more reactive in free-radical halogenation reactions because the radical they form is
stabilized by neighboring alkyl groups. These neighboring alkyl groups have the ability to donate
some of their electron density to the electron-deficient radical carbon (a radical is short one electron
of filling the atom's valence octet). Thus the hydrogen on the tertiary carbon here is abstracted in
preference to the 9 other hydrogen atoms attached to a primary carbon (a carbon that is attached to
only one other carbon atom) because it forms a more stable radical.

Here, the tertiary radical is stabilized by

electron donation from neighboring
alkyl groups.

Selectivity of free-radical halogenation

A point of note about free radical processes is that the intermediates are so highly reactive and
short lived that usually you obtain a mixture of products, even though there is preference for
forming more highly substituted free radical intermediates. In this example with isobutane, for
instance, there would certainly be some abstraction of hydrogens attached to the primary carbons,
leading to a different product than the above product (can you draw it out?).

Bromine reacts exactly the same way as chlorine; however, it is far more selective. If propane
(CH3CH2CH3), for example, was the substrate, 2-bromopropane would be the dominant product,
and there would be only a small amount of 1-bromopropane. Free radical chlorination, though,
would not be quite as selective, and there would be a greater amount of the chlorination of the
primary carbon than in the bromination reaction.

Termination Steps:
Side reactions that can stop the chain reaction are called termination steps. These termination
steps involve the destruction of the free-radical intermediates, typically by two of them coming
together.

Other Halogens?

So why can't the other halogens such as fluorine or iodine be used? Iodine reacts endothermically
(energetically uphill) and too slowly to be of much good in these free radical processes, while
fluorine is at the other pole--it reacts too violently and too quickly to be selective, and can, if
uncontrolled, even break carbon-carbon bonds. To understand why this is so, derive the ∆ H's for
the 4 reactions and compare them (you will find that flourination is highly exothermic, while
iodonation is endothermic; chlorination and bromination, however, are right in the middle).

SN2 Mechanism
Overview:

The general form of the SN2 mechanism is as follows:

nuc: = nucleophile
X = leaving group (usually halide or tosylate)

The SN2 reaction involves displacement of a leaving group (usually a halide or a tosylate), by a
nucleophile. This reaction works the best with methyl and primary halides because bulky alkyl
groups block the backside attack of the nucleophile, but the reaction does work with secondary
halides (although it is usually accompanied by elimination), and will not react at all with tertiary
halides. In the following example, the hydroxide ion is acting as the nucleophile and bromine is the
leaving group:

Because of the backside attack of the nucleophile, inversion of configuration occurs.

Solvents: Protic solvents such as water and alcohols stabilize the nucleophile so much that it won't
react. Therefore, a good polar aprotic solvent is required such as ethers and ketones and
halogenated hydrocarbons.

Nucleophiles: A good nucleophile is required since it is involved in the rate-determining step.

Leaving groups: A good leaving group is required, such as a halide or a tosylate, since it is
involved in the rate-determining step.

SN1 Mechanism
Overview:

The general form of the SN1 mechanism is as follows:

Because the mechanism goes through a carbocation, the leaving group must be attached to either
a tertiary or secondary carbon to stabilize the intermediate. A methyl or primary leaving group will
not form a carbocation. Since it goes through a carbocation intermediate, there are possibilities for
alkyl and hydrogen rearrangements (HINT: In mechanism problems if you see a change in the
carbon skeleton between the reactant and the product, automatically suspect a carbocation
intermediate (ie, E1, Sn1) stabilized by an alkyl or hydrogen rearangement). .

An example ofthe Sn1 Mechanism

Base Strength: Base strength is unimportant, since the base is not involved in the rate determining
step (the formation of the carbocation). .

Leaving groups: A good leaving group is required, such as a halide or a tosylate, since the leaving
group is involved in the rate-determining step.

Notes: Be wary of rearangements that can occur with the SN1 reaction. Because it goes through a
carbocation intermediate, both hydrogen shifts and alkyl shifts can occur!

E1 Mechanism
Overview:

The general form of the E1 mechanism is as follows:

B: = base
X = leaving group (usually halide or tosylate)

In the E1 mechanism, the the first step is the loss of the leaving group, which leaves in a very slow
step, resulting in the formation of a carbocation. The base then attacks a neighboring hydrogen,
forcing the electrons from the hydrogen-carbon bond to make the double bond. Since this
mechanism involves the formation of a carbocation, rearangements can occur.

An example of the E1 reaction:

Base Strength: A strong base not required, since it is not involved in the rate-determining step

Leaving groups: A good leaving group is required, such as a halide or a tosylate, since it is
involved in the rate-determining step.

Rearangements: Since the mechanism goes through a carbocation intermediate, rearangements

can occur.

E2 Mechanism
Overview:

The general form of the E2 mechanism is as follows:

B: = base
X = leaving group (usually halide or tosylate)

In the E2 mechanism, a base abstracts a proton neighboring the leaving group, forcing the
electrons down to make a double bond, and, in so doing, forcing off the leaving group. When
numerous things happen simultaneously in a mechanism, such as the E2 reaction, it is called a
concerted step.

An example of the E2 reaction:

Base Strength: A strong base is required since the base is involved in the rate-determining step.

Leaving groups: A good leaving group is required, such as a halide or a tosylate, since it is
involved in the rate-determining step.

Stereochemistry requirements: Must occur with antiperiplanar stereochemistry.

Electrophilic Addition to Alkenes Mechanism

Overview:

Electrophilic addition to alkenes takes the following general form:

nuc: = nucleophile
E+ = electrophile

Electrophilic addition to alkenes starts with the pi electrons attacking an electrophile, forming a
carbocation on the most stable carbon. A nucleophile then attacks the carbocation to form the
product. There are many different kinds of such addition, including:

• Hydroxylation
• Hydrogenation
• Halogenation
• Oxidative Cleavage
• Hydration
• Epoxidation
• Cyclopropanation
• Halohydrin Formation

Clearly, there are numerous kinds of products that can be formed as a result of this mechanism.

Orientation of Addition: Electrophilic Addition adds to give the Markovnikov Product, with the
nucleophile added to the more highly substituted carbon. This is because the carbocation
intermediate is significantly stabilized by alkyl substituents.

Example of electophilic addition to alkenes:

First, formation of the carbocation on the most highly substituted carbon

Followed by attack of chloride on the carbocation to give the addition product

Hydroboration of alkenes
Overview:

The general form of the hydroboration of alkenes mechanism is as follows:

First step is the attack of the alkene on BH3, which then forms a four membered ring intermediate of
partial bonds. It is because of this intermediate that hydroboration forms the anti-Markovnikov
product. The boron atom is highly electrophilic because of its empty p orbital (ie. it wants electrons),
and forms a slight bonding interaction with the pi bond. Since some electron density from the
double bond is going towards bonding with the boron, the carbon opposite the boron is slightly
electron deficient, left with a slightly positive charge. Positive charges are best stabilized by more
highly substituted carbons, so the carbon opposite the boron tends to be the most highly
substituted. Once the transition state breaks down, BH2 is attached to the least substituted carbon.

Peroxide then removes the borane and replaces it with the alcohol to form the anti-markovnikov
product.

An example of the hydroboration mechanism:

Nucleophilic addition to carbonyl groups

Overview:

The general form of the nucleophilic addition to carbonyl group mechanism is as follows:

First step is the attack of the nucleophile on the partially positive carbon to make the tetrahedral
intermediate with the full negatively charged oxygen. The oxygen then becomes protonated to yield
the alcohol.

Variety of nucleophiles:

• Grignard Reagents
• Alcohols
• Amines
• Alkyl Lithium Reagents
• Acetylide Ions

Example of nucleophilic addition to carbonyl groups:

In this case, acetylide anion is acting as the nucleophile

Alcohol dehydration
Overview:

The general form of alcohol dehydrations is as follows:

The first step involves the protonation of the alcohol by an acid, followed by loss of water to give a
carbocation.

Elimination occurs when the acid conjugate base plucks off a hydrogen. Alcohol dehydrations
generally go by the E1 mechanism.

Example of alcohol dehydration:

Fischer esterification mechanism

Overview:

The general form of Fischer esterification mechanism is as follows:

The first step involves protonation of the carbonyl oxygen, followed by the nucleophillic attack of the
alcohol.

Then a loss and regain of a proton,

followed by loss of water as electrons from the alcohol oxygen kick down to form the double bond.
Loss of a proton yields the ester.

Example of fischer esterification:

Williamson ether synthesis

Overview:

The Williamson ether synthesis is a reaction that converts alcohols (R-OH) into ethers (R-O-R). The
first step in this reaction is forming the conjugate base of the alcohol (called an alcoxide) by
reacting the alcohol with sodium metal. This reaction forms hydrogen gas (H2) as a biproduct, so if
you perform this reaction take caution to keep all flame sources away during sodium addition.

The alcoxide can then be added to a suitable alkyl halide (typically a primary halide) to form the
ether via an SN2 mechanism.

Example:

An example of the Williamson ether synthesis to make diethyl ether.

Friedel-Crafts alkylation
Overview:

The general form of the Friedel-Crafts alkylation mechanism is as follows:

Adding an alkyl halide to the Lewis acid aluminum trichloride results in the formation of an organo-
metallic complex. In this complex the carbon attached to the chlorine has a great deal of positive
charge character (in fact, for practical purposes when dealing with this reaction, you can think of the
partially positive charge as a carbocation).

The pi electrons in a benzene ring are mildly electrophilic, and can attack the partially positive
carbon to create a non-aromatic intermediate (note that this intermediate has several resonance
structures, so that it is not as unstable as it might appear). Elimination of a proton re-establishes the
aromaticity of the ring, and the aluminum trichloride catalyst is regenerated along with a molecule of
hydrochloric acid.

A word of caution about this reaction: because the aluminum trichloride generates what can
essentially be thought of as a carbocation, rearrangments can occur to produce a more highly-
substituted carbocation.

For example: Addition of 1-Chloro-2-Methylpropane to benzene with aluminum trichloride results in

the rearranged product, t-butyl benzene, and not the product that you might initially expect (work
out the mechanism if you cannot see how that product is attained).

An example of a Friedel-Crafts alkylation:

Claisen condensation
Overview:

The general form of a Claisen condensation is as follows:

The first step involves adding a strong base to an ester to generate an enolate at the α carbon
(note that the enolate has an additional resonance structure).

The enolate can then add to another ester molecule by attacking the carbonyl to make the
tetrahedral intermediate. The carbonyl reforms with loss of the alcoxy group to make the β -keto
ester.

Example of a Claisen condensation:

This is an example of an intramolecular Claisen reaction, called a Dieckmann condensation.

Baeyer-Villiger oxidation
Overview:

Baeyer-Villiger oxidations are a really handy way to make esters from ketones. The general form of
this reaction is as follows:

Under basic conditions, a peroxide can be deprotonated. This nucleophilic species can then attack
a carbonyl group to form a tetrahedral intermediate. Once the tetrahedral intermediate collapses,
instead of kicking the peroxide back off, the more highly substituted alkyl substituent makes a
sigmatropic shift to the oxygen, kicking off the alcoxide as the leaving group, forming the ester.

Example of a Baeyer-Villiger oxidation:

Here the common MCPBA (m-chloroperoxybenzoic acid) is used as the peroxide. It is one of the
most common peroxides because it is cheap and crystalline, and can be used in stoichiometric
quantities.

Diels-Alder Reaction
Overview:

The Diels-Alder reaction combines a diene (a molecule with two alternating double bonds) and a
dienophile (an alkene) to make rings and bicyclic compounds. The three double bonds in the two
starting materials are converted into two new single bonds and one new double bond. Since this
reaction forms two new carbon-carbon bonds in a single step, it is a very useful and powerful
reaction (one which earned Otto Diels and Kurt Alder a Nobel prize in chemistry for discovering it).

Typically, the Diels-Alder reaction works best when either the diene is substituted with electron
donating groups (like -OR, -NR2, etc) or when the dienophile is substituted with electron-
withdrawing groups (like -NO2, -CN, -COR, etc).

Conformational requirements of the diene

One quirk of the Diels-Alder reaction is that the diene is required to be in the s-cis conformation in
order for the Diels-Alder reaction to work. The s-cis conformation has both of the double bonds
pointing on the same side of the carbon-carbon single bond that connects them. In solution, the
carbon-carbon single bond in the diene that connects the two alkenes is constantly rotating, so at
equilibrium there is usually some mixture of dienes in the s-trans conformation and some in the s-
cis conformation. The ones that are at that moment in the s-trans conformation do not react, while
the ones in the s-cis conformation can go on to react.

Because of the Diels-Alder's requirement for having the diene in a s-cis conformation, dienes in
rings react particularly rapidly because they are "locked" in the s-cis conformation. Unlike dienes in
open chains in which there is usually some proportion of the diene in the unreactive s-trans
conformation, dienes in rings are held in the reactive conformation at all times by the constraints of
the ring, making them react faster.

Stereochemistry of Diels-Alder reaction

What about the stereochemistry of the Diels-Alder reaction? If your dienophile is disubstituted
(substituted twice), there is the possibility for stereochemistry in the product. In the Diels-Alder
reaction, you end up with the stereochemistry that you started with. In other words, if the
substituents started cis (on the same side) on the dienophile, they end up cis in the product. If they
started trans (opposite sides) on the dienophile, they end up trans in the product.

Formation of bicyclo products.

When the diene is in a ring, the product of the Diels-Alder reaction is a bicyclo ring system (which
can be somewhat intimidating to draw at first). A bicyclo ring system is a compound in which two
rings share more than two carbons. There are two main bicyclo ring systems that you typically have
to deal with, and these are the ones that come from the diene being in a five-membered ring
system and the diene being in a six-membered ring system. (The nomenclature of bicyclic alkanes
can be found elsewhere).

When you make bicyclic products (that is, when the diene is in a ring), and you have a dienophile
that is substituted, there are two possible products that you can form from the Diels-Alder reaction--
the endo product, in which the substituent points down from the top of the bicyclic molecule, and
the exo product, where the substituent points towards the top of the bicyclic molecule. In general,
you form the endo product preferentially over the exo product in the Diels-Alder reaction.
Example of the Diels-Alder reaction

In this example, since the diene is in a six-membered ring, you make a bicyclo product. Since the
dienophile is cis disubstituted, you get the endo stereochemistry with the two cyano (CN)
substituents pointing away from the top of the bicyclo compound.

PRACTICE TESTS
Introduction to organic chemistry test
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Difficulty Rating:
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1. What is the hybridization of the carbon atom in Urea?

 Sp

Sp2

Sp3

Sp4

2. Which of the following compounds are not consistent with

valence rules?

3. Label the strongest Bronsted-Lowry acid in the following

equation:
(see here for explanation)

D
4. Assuming equal concentrations of the acid and base, the equilibrium for the
reaction from question 3:
(see here for explanation)

Favors the Products

Is approximately 1

Favors the Reactants

Cannot be determined

5. Which of the following acids will be almost completely deprotonated

by NaOH?

phenol pKa = 10.0

Ethanol CH3-CH2-OH pKa = 16.0

Water HOH pKa = 15.7

Both Ethanol and Water

6. This compound has the following functional groups:

ketone, alkene, carboxylic acid, ester

alkyne, ester, carboxylic acid, aldehyde

carboxylic acid, alkene, ketone, ester

ester, aldehyde, carboxylic acid, alkene

7. What is the structure of trans-decalin

8. How many quaternary carbons are on the following molecule:

9. What is the IUPAC name of the following molecule:

(see here for explanation)

Bicyclo [2,2,1] heptane

Bicyclo [2,2,2] heptane

Bicyclo [1,2,1] heptane

Bicyclo [2,2,1] pentane

10. The following compound is:

A ketone

An amine

A ketone and an amine

A lactam

Alkyl halides test

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1. Which of the following alkyl bromides will undergo the Sn2

reaction the fastest?
(see here for explanation)

2. Rank the following carbocations in order of increasing

stability (least stable to most stable)

1 2 3

1, 3, 2

1, 2, 3

3, 2, 1

2, 1, 3

2, 3, 1

3. Of the carbocations in question 2, which ones are prone to

rearangement?

1 and 2

1 only

2 only

2 and 3

None of them will rearange

4. What is a product of the following reaction:

5. What is the major product of the following reaction?

None of the Above

6. Which is the major product of the following reaction?

7. How many potential E2 elimination products can form from the addition of NaOH to the following:
(free hint: trans-decalin cannot undergo a ring flip)

No Elimination Products are Possible

8. Which of the following alkyl halides will react more quickly

in the E1 reaction
(see here for more)

9. Free radical chlorination (Cl2, hv) is not very selective. Which of the following compounds will give
the most selective mono-chlorination (ie. only one product)?
10. What compound could not be a product of the following reaction?

All can be products

Stereochemistry test
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1. Optically active molecules which rotate plane-polarized light in a counterclockwise direction are
said to be:

levorotary

of R configuration

dextrorotary

of S configuration

2. The specific rotation of a compound is denoted by the symbol:

R
 S

3. Assign R or S configuration to the chiral carbon marked with an asterisk

4. Assign the correct term describing the relationship to the following two isomers:

enantiomers

diastereomers

identical

5. How many stereoisomers of S-Adenosylmethionone are possible in principle (Free Hint: there are 5
stereogenic centers):

16
 32

None of the Above

6. (R)-(+)-Glyceraldehyde:

is levorotary

rotates plane-polarized light in a counterclockwise direction

rotates plane-polarized light in a clockwise direction

is racemic

7. What is the stereochemistry of the following compound:

Meso

Not Chiral

8. Would the following compound have an enantiomer:

(See explanation)

Yes

No
9. Is the following compound meso:

Yes

No

10. Does the following compound rotate plane-polarized light:

Yes

No

Alkenes test
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1. Calculate the degree of unsaturation in Testosterone,

C19H26O2
(See explanation)

None of these
2.

Both B and C

None of the Above

3.

4. What is the product of the addition of MCPBA to styrene?

 None of the Above

5. Choose the best reagent from the list below to do the

following conversion:

1. O3 2. Zn, H3O+

KMnO4, Acid

1. OsO4 2. NaHSO3, H20

CH2I2, Zn(Cu)

6. Rank the following substituents by the Cahn-Ingold-Prelog sequence rules and put them in
decreasing order (from the highest priority substituent to the lowest priority substituent)

1, 3, 4, 2

4, 1, 2, 3

1, 3, 2, 4

3, 1, 2, 4

None of the Above

7. 8. What would probably not be a product of the following

reaction:
8. One of the following cycloboranes undergoes elimination
much faster than the other. Which one is it?

9. What is the most stable conformation of cis-

1,4 di t-butylcyclohexane?

None of these are the most stable

10. What is the major product of the following reaction:

 No reaction

Alkynes Test
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1. What is the structure of ethynylcyclohexane?

None of the Above

2. What is the common name of ethyne?

Acetone

Acetylene

Angstrom

Agriculture

3. Which of the following bases is the weakest base?

4. What is the product of the following reaction:

None of the above

5. What is the product of the following reaction:

 None of the Above

6. Which of the following bases are strong enough to deprotonate acetylene?

Concentrated H2SO4

NaNH2

CH3-CH2:- Li+

Both B and C

7. Which of the following reagents will best convert methyl acetylene to acetone?

H2SO4, H20, HgSO4

1. BH3, THF 2. HOOH

H2, Lindlar

1. HCl 2. NaNH2, NH3

8. What is the major product(s) of the following reaction:

Both the first and third choice (A and C)

No Reaction
9. What is the major product of the following reaction:

None of these

10. What is the major product of the following reaction :

None of the Above

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Alcohols test
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1. Rank the following alcohols from most acidic to least acidic in

ascending order (least acidic to most acidic):

A, B, C,

C, B, A

B, C, A

A, C, B

2. For questions 2 and 3, consider the following transformation:

What reagents from the list below would best accomplish the
above transformation?

1. OsO4, pyridine 2. NaHSO3, H2O

1. Hg(OAc)2, H20 2. NaBH4

1. RCO3H, CHCL2 2 H30+

1. BH3, THF 2. H2O2, OH-

3. For the reaction in question 2, the alcohol product is classified as a:

Primary Alcohol

Secondary Alcohol

Tertiary Alcohol

Quaternary Alcohol

4. What is the product of the following reaction:

5. What is the major product of the following reaction:

None of the Above

6. Choose the best reagents to carry out the following reaction:

D2, Pt

1. Mg, Ether
2. D20

D2SO4, D20,

D3O+, Acetone,

7. What is the major product of the following reaction:

 No reaction

8. Disregarding elimination products, what is the major product

of the following reaction:

None of the Above

9. What reagent would undergo the following reaction the

quickest:
10. The product of the following reaction immediately undergoes a
dimerization at room temp (Diels-Alder reaction). To regain its normal
monomer state, it must be heated. What is the structure of the dimer?

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Grading Scale
A 80-100 Outstanding
B 70-79 Very Good
C 60-69 Average
D 50-59 Below Average
F Below 50 Failing
Conjugated systems and aromatics test
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For Questions 1 and 2, refer to the following reaction:

1. The kinetically controlled product in the above reaction
is:

3-Chloro-1-Butene

1-Chloro-2-Butene

2. For the reaction in Question 1, which one is the result

of 1,4-addition?

3-Chloro-1-Butene

1-Chloro-2-Butene

3. What is the major product of the following reaction:

None of the Above

4. Which of the following compounds have no conjugated

portions?
5. For a diene to undergo Diels-Alder reaction it must:

be substituted with electron-withdawing groups.

be able to adopt an s-trans conformation

be substituted with electron-donating groups

be able to adopt the s-cis conformation

6. Which of the following would have the longest

wavelength absorption in its UV spectrum.

7. Which of the following are aromatic:

 Both A and D
8. Indicate which spectral technique would best be used
to distinguish between the following compounds:

and

1H NMR

IR Spectroscopy

Mass Spectrometry

UV Spectroscopy

9. Which of the following are antiaromatic:

Both A and B

Both C and D

10. What is the major product of the following

reaction:
 No Reaction

Ketones & aldehydes test

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1. What is the IUPAC name of the following compound:

Diphenyl Ketone

Benzophenone

Dibenzyl Ketone

1,1-Diphenylmethanone

2. What is the correct structure for 2-Hydroxyacetophenone:

3. What is the product of the following reaction:

 None of the Above

4. What is the structure of Benzaldehyde (Oil of Bitter

Almonds)?

None of the Above

5. Choose the best reagent(s) from the list to do the following

conversion:
 H2/Ni (R)

Hg(OAc)2, H30+

1. BH3, THF
2. H2O2, NaOH

NaBH4, THF

6. What is the product of the following reaction:

None of the Above

7. One of the following dioxanes is potentially explosive.

Which one is it?

8. What is the major product of the following reaction:

 None of the Above

9. What is the major product of the following reaction:

No Reaction

10. Which of the following would give a positive Tollens

Test:

CH3CH2COCH3

CH3CH=CH-CH=CH-OH

CH3CH2CHO

Both B and C
Amines test
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1. Classify the following amine:

Primary Amine

Secondary Amine

Tertiary Amine

Quaternary Ammonium Salt

2. What is the name of the following amine:

Pyrrole

Pyridine

Pyrimadine

Piperdine

3. Which of the following amines is more basic:

B
4. What is the major product of the following reaction:

None of the Above

5. Which of the following amines can be resolved into

enantiomers:

ethyl amine

N, N-Dimethylaniline

1-Methylpiperdine

6. Tell whether the products or reactants are favored in

the following acid-base reaction:

Reactants

Products
7. What would not be a product of the following
reaction:

Br-

8. What is the major product of the following reaction:

No Reaction

9. What is the major product of the following reaction:

 None of the Above

10. What is the major product of the following

reaction:

It forms a tosyl amide

No Reaction

**Note: Grader will only explain incorrect answers**

Grading Scale
A 80-100 Outstanding
B 70-79 Very Good
C 60-69 Average
D 50-59 Below Average
F Below 50 Failing