Organic Chemistry March 2, 2022

QS1. Extracts from the flowering plants of Asteraceae have been used to produce medicine, rubber,
and pesticides. (+)-Carissone, a compound isolated from such extracts, has been found to have
antibacterial properties. During a synthesis of (+)-carissone, a Grignard reaction was used to convert
compound 1 into compound 2, as shown below.

(a) What Grignard reagent is needed for the transformation shown?

(b) Typically, two equivalents of a Grignard reagent are required when reacting with an ester, but in
this case a minimum of three equivalents are required. Explain why a third equivalent is required in
this case. (Hint: What reaction happens first when a Grignard reagent is added to the given starting
material? Consider all of the functional groups that are present.)
(c) Draw a mechanism that uses all three equivalents of the Grignard reagent and generates the diol
product, compound 2 (after neutralization with an aqueous workup).
Answer:
(a) This synthetic transformation converts an ester to an alcohol with the installation of two new
methyl groups. Both methyl groups can be installed in the same Grignard reaction, using CH3MgBr
(MeMgBr), since two equivalents of a Grignard reagent will react with an ester. After the reaction is
complete, an aqueous acidic workup then gives the desired product.

(b) In this case, a third equivalent of the Grignard reagent is required because of the presence of the
alcohol functional group. The acidic proton of the alcohol will react with one equivalent of the
strongly basic Grignard reagent:

(c) In the first step of the mechanism, a proton transfer reaction occurs. One equivalent of the
Grignard reagent (methyl magnesium bromide) functions as a base and removes the proton of the
alcohol. This step requires two curved arrows.

In the second step of the mechanism, a second equivalent of the Grignard reagent functions as a
nucleophile and attacks the electrophilic carbon atom of the carbonyl (C=O) of the ester. This step
requires two curved arrows. The resulting intermediate then ejects a leaving group to give a ketone,

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which also requires two curved arrows. The electrophilic ketone is then further attacked by a third
equivalent of the nucleophilic Grignard reagent. Once again, two curved arrows are used to show the
nucleophilic attack, resulting in a dianion.

Finally, the dianion is then protonated upon treatment with aqueous acid. There are two locations
that are protonated, each of which requires two curved arrows, as shown. Notice that each anion is
protonated in a separate step (this should not be drawn as one step with four curved arrows, because
there are two distinct processes occurring, and it is unlikely that they occur precisely at the same
moment).

QS2. Numerous herbicides and fungicides are known to contain an acetylenic group. For example,
compound A is a pyrimidinone herbicide that functions by inhibiting the accumulation of both
chlorophyll and β-carotene. During a synthesis of A, shown below, an inactive product was also
formed (compound B). The ratio of A:B was 1:4.Compound B, a constitutional isomer of A, also
contains an acetylenic group.

(a) Draw a plausible mechanism for the formation of compound A.

(b) Draw the likely structure of compound B and provide a mechanism for its formation.
(c) Explain why B is favored over A in this process.
Answer:
(a) Sodium methoxide is a strong base, which removes the most acidic proton in the starting material.
The resulting resonance-stabilized anion can then function as a nucleophile and attack 3-bromo-1-
propyne in an SN2 process, giving alkyne A.

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 Organic Chemistry March 2, 2022

(b) As mentioned in the solution to part (a), the anionic intermediate is resonance-stabilized, so we
draw the resonance structures:

Among these resonance structures, the last one is expected to contribute the most character to the
overall resonance hybrid, for two reasons: 1) the negative charge is placed on an oxygen atom (rather
than on the less electronegative nitrogen atoms or carbon atom), and 2) this resonance structure
exhibits a benzene-like ring. In fact, this anionic intermediate is indeed aromatic, and we expect the
oxygen atom to bear the majority of the delocalized negative charge. Based on this, we can propose
the following structure and mechanism of formation for product B:

(c) In addition to the analysis in part (b) that explains why the oxygen atom has more ionic character
than the nitrogen atom (making it more nucleophilic), compound B also has aromatic stabilization
that is absent in A. As such, B is expected to be lower in energy, so the product mixture will have
more of B than A.

QS3. DCC can be used to form a peptide bond. We explored the mechanism, and we saw that DCC
activates the COOH group so that it readily undergoes nucleophilic acyl substitution. An alternative
method for activating a COOH group involves converting it into an activated ester, such as a para-
nitrophenyl ester:

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 Organic Chemistry March 2, 2022

The activated ester is readily attacked by a suitably protected amino acid to form a peptide bond:

(a) Explain how the p-nitrophenyl ester activates the carbonyl group toward nucleophilic acyl
substitution.
(b) What is the function of the nitro group?
(c) A meta-nitrophenyl ester is less activating than a para-nitrophenyl ester. Explain.
Answer:
(a) The COOH group does not readily undergo nucleophilic acyl substitution because the OH group
is a relatively poor leaving group, and it donates electron density to the carbonyl group (making it
more electron-rich). By converting the COOH group into an ester with an attached electron-
withdrawing group, the compound is now activated toward nucleophilic acyl substitution for two
reasons: 1) it has a good leaving group because the negative charge is stabilized by resonance, and 2)
the electron-withdrawing group makes the carbonyl carbon more electron-deficient and therefore
more electrophilic.
(b) The nitro group stabilizes the leaving group via resonance. As described in Chapter 18, the
electronwithdrawing nitro group serves as a reservoir for electron density:

(c) The nitro group must be in the ortho or para position in order to stabilize the negative charge via
resonance (as shown above). If the nitro group is in the meta position, the negative charge cannot be
pushed onto the nitro group.
QS4. The aroma, taste, and general quality of wine are tied closely to the stage of development of the
grapes from which it is made. In order to develop a molecular- level understanding of this
phenomenon, the volatile components of cabernet sauvignon grapes were tested throughout their
growth period. Among the many molecules detected, the concentration of (E)-2-hexenal was found
to increase slowly for eight weeks from the flowering of the vine, then to spike for four weeks before
decreasing again, propose a synthesis of (E)-2-hexenal starting from 1,1-dibromopentane.

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 Organic Chemistry March 2, 2022

Answer:
Installing the alkene group by elimination turns out to be a viable approach in this case, as described
below. The figure below outlines a retrosynthetic analysis for our target molecule. An explanation of
each of the steps (a-f) follows.

a. The target compound can be made via dehydration of the alcohol under acidic conditions.
b. The aldehyde can be made by ozonolysis of the corresponding alkene. Note that the required
alkene has only one C=C double bond, so we avoid the problem described above with ozonolysis of
a diene.
c. The alkene can be made by partial reduction of the corresponding alkyne.
d. A disconnection at the C–C bond adjacent to the triple bond leads to an acetylide ion nucleophile
and the aldehyde shown as the electrophile (see problem 11.34).
e. The aldehyde is made from anti-Markovnikov addition of water to 1-pentyne.
f. 1-Pentyne is made from 1,1-dibromopentane (the given starting material) by double elimination.

Now let’s draw the forward scheme. 1,1-Dibromopentane is converted to 1-pentyne by reaction with
excess sodium amide (double E2 elimination), followed by treatment with water to protonate the
terminal alkynide ion. 1-Pentyne is converted to the aldehyde via hydroboration-oxidation. Reaction
of the aldehyde with sodium acetylide, followed by treatment with water to protonate the resulting
alkoxide intermediate, forms a new C–C bond, and gives an alkynyl alcohol product. Reduction with
H2 and Lindlar’s catalyst converts the alkyne group to an alkene group, and ozonolysis then converts
the alkene to an aldehyde. Finally, treatment with concentrated acid and heat causes dehydration of
the alcohol (E1 process), producing the target compound.

QS5. The bengamides are a series of natural products that have shown inhibitory effects on the
enzyme methionine aminopeptidase, which plays a key role in the growth of new blood vessels, a
necessary
process for the progression of diseases such as solid tumor cancers and rheumatoid arthritis. During
the synthesis of bengamides, it is often required to use protecting groups that convert OH groups into

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other, less reactive functional groups. For example, the alcohol 1 is protected upon treatment with
compound 2 in the presence of compound 4. 17 First, 1 reacts with 2 to give intermediate 3, which is
then deprotonated by 4 to give 5:
(a) Draw the structure of 5 and show a mechanism for its formation from 3.
(b) Use pKa values to verify that 4 is an appropriate base for this transformation.
(c) Explain how you would use IR spectroscopy to verify the conversion of 1 to 5.

Answer:
(a) The lone pair in compound 4 functions as a base and deprotonates intermediate 3. This requires
two curved arrows, as shown:

(b) If we consult Table 3.1, we find the following entries to be used for reference:

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 Organic Chemistry March 2, 2022

Notice that the first cation (an oxonium ion) has a pKa value of -1.74, while the second cation (a
pyridinium ion) has a pKa value of 5.3. The difference between them is seven pKa units. In other
words, an oxonium ion is approximately 107 (or 10,000,000) times more acidic than a pyridinium
ion. Since a proton transfer step will proceed in the direction that favors the weaker acid, we expect
compound 4 to be successful in deprotonating intermediate 3 to give compound 5.
(c) The conversion of 1 to 5 involves the loss of an alcohol O-H bond. That is, the IR spectrum of
compound 1 should exhibit a broad signal between 3200 and 3600 cm-1, due to the O-H stretching
vibration. This signal is expected to be absent in the IR spectrum of compound 5, which lacks an O-
H bond. This can be used to verify that the desired reaction has occurred. Specifically, the
disappearance of the O-H signal indicates the conversion of 1 to 5.
QS6. Cyclopropyl chloride (1) cannot generally be converted into cyclopropanol (4) through a direct
substitution reaction, because undesired, ring- opening reactions occur. The following represents an
alternative method for preparing cyclopropanol.

(a) Compound 2 is a powerful nucleophile, and for our purposes, we will treat MgCl+ as a
counterion. The transformation of 2 into 3 is accomplished via an SN2-type process. Draw a
mechanism for this process and identify the leaving group.
(b) Explain why the conversion of 2 to 3 is an irreversible process.
(c) Under aqueous acidic conditions, 3 can be converted into 4 either via an SN1 process or via an
SN2 process. Draw a complete mechanism for each of these pathways.
(d) During conversion of 3 to 4, another alcohol (ROH) is formed as a by- product. Draw the
structure of this alcohol.
Answer:
(a) Compound 2 functions as a nucleophile, which means that the lone pair on the carbon atom will
attack the substrate in an SN2-type process. Based on the structure of the product (3), we can deduce
that the oxygen atom attached to the tert-butyl group is attacked by the nucleophile. The leaving
group is a resonance-stabilized anion (an acetate ion).

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 Organic Chemistry March 2, 2022

(b) The reverse process would involve an acetate ion functioning as a nucleophile and the expulsion
of 2 as a leaving group. That is extremely unlikely to occur, because 2 is not a good leaving group. It
is a very strong base, because its conjugate acid is an alkane, which is an extremely weak acid
(compare pKa values of alkanes with other organic acids). Since 2 is not a stable, weak base, it
cannot function as a leaving group. And as a result, the reaction is irreversible.
(c) Since an alkoxide group (RO¯) is a strong base and therefore a very poor leaving group, it must
be protonated first, in either pathway. The SN2 pathway involves a simultaneous nucleophilic attack
and loss of a leaving group. This step is then followed by deprotonation to give the product. As
expected for an SN2 process, the nucleophilic attack occurs at the secondary position, rather than the
sterically crowded tertiary position.

The SN1 pathway also begins with protonation of the oxygen atom to produce a better leaving group.
But in this pathway, the leaving group first leaves to generate a carbocation, and only then does the
nucleophile attack. As expected for an SN1 process, loss of the leaving group generates a tertiary
carbocation, rather than a secondary carbocation. In this case, the leaving group is the product
(cyclopropanol).

(d) As seen in both the SN1 and SN2 pathways, the by-product is tert-butanol.

END