Chapter 2: Alkanes

Questions
Qu : The structure of EPOTHILONE A, a
compound with anticancer activity similar to
Taxol is shown to the right.
(a) What is the hybridization of the following C
atoms in Epothilone A ?

C1 C8 C12 C14 C17 C19
(b) Arrange the following bonds in Epothilone A
in order of decreasing length:
C14-C15 C15-C17 C17-C18
(c) What type of bonding MOLECULAR orbitals
are involved in the bonds between C3-C4
and C17-C18 ?
(d) What are the oxidation states of the following
C atoms in Epothilone A ?

C1 C8 C12 C14 C17 C19
(e) Identify any C-C s bonds in Epithilone A that
are not between a pair of sp
3
hybridised C
atoms.







Answers

Most of the answers are shown on the structure
of EPOTHILONE A to the right.
(a) The hybridization of the C atoms asked are
indicated in green. If you got them wrong, it may
be because you forgot to account for the CH
bonds that aren't shown.
(b) C14-C15 > C15-C17 > C17-C18. The
hybridization of the C atoms involved in the
various bonds affects the bonds lengths. The
greater the % s character in the hybrids (sp
3
=
25% s, 75% p : sp
2
= 33% s, 67 % p : sp = 50%
s, 50% p), the shorter the bond will be. C14-C15
is sp
3
-sp
3
, C15-C17 is sp
3
-sp
2
and C17-C18 is
sp
2
-sp
2
.
(c) The bonding MOLECULAR orbitals are
indicated in red.
(d) The oxidation states are indicated in black. If
you got them wrong, it may be because you
forgot to account for the CH bonds that aren't
shown.
(e) There are 5 C-C o bonds where at least one C
is not sp
3
hybridised :
C1-C2 is sp
2
-sp
3
, C4-C5 is sp
3
-sp
2
, C5-C6 is sp
2
-
sp
3
, C15-C17 is sp
3
-sp
2
, C18-C19 is sp
2
-sp
2
.











Chapter 15: Alcohols, Diols and Thiols

Alcohols, Diols and Thiols Questions

Qu
1:
How would you prepare 1-propanol from each of the following :

(a) propene (b) ethylene oxide
(c) propanal (d) propanoic acid
(e) methyl propanote

Qu
2:
How would you prepare 2-propanol from each of the following :

(a) propene (b) propanone
(c) ethanal (d) 2-bromopropane
Qu
3:
What are the products of the following reaction sequences ?

(a) cyclohexene + OsO
4
/ tBuO
2
H / tBuOH / NaOH

(b) cyclohexene + CH
3
CO
3
H then NaOH

(c) E-2-butene + OsO
4
/ tBuO
2
H / tBuOH / NaOH

(d) Z-2-butene + OsO
4
/ tBuO
2
H / tBuOH / NaOH

(e) Z-2-butene + CH
3
CO
3
H then NaOH

(f) What is the relationship between the products of the products of (c) and (d) ?
Qu
4:
What are the major products of the following reactions of benzyl alcohol with :

(a) SOCl
2
/ Et
3
N

(b) Na then add CH
3
CH
2
I

(c) NaCrO
4
/ aq. H
2
SO
4


(d) PDC / CH
2
Cl
2


(e) Ethanoic acid / . H
2
SO
4
/ heat
Qu
5:
What carboxylic acid / alcohol combinations are required to prepare the following
esters ?


Qu
6:
What is the product of the reaction of cis-1,2-cyclohexanediol with periodic acid ?
Qu
7:
How would you best prepare the following ethers ?


Alcohols, Diols and Thiols Answers


Qu
1:
(a) Since 1-propanol would be the anti-Markovnikov alcohol, use BH
3
then
H
2
O
2
/ NaOH

(b) Need to add a C, so open epoxide with an organometallic reagent, e.g. CH
3
MgBr
in Et
2
O or THF, followed by an acidic work-up.

(c) Right number of C, so simple reduction using either LiAlH
4
in THF then acidic
work-up or NaBH
4
in EtOH

(d) Right number of C, so simple reduction using LiAlH
4
in THF then acidic work-
up. NaBH
4
will not reduce RCO
2
H

(e) Reduction of a propanoate ester with LiAlH
4
in THF will give the primary
alcohol.
Qu
2:
(a) Since 2-propanol would be the Markovnikov alcohol, use aq. H
2
SO
4
/ heat.

(b) Right number of C, so simple reduction using either LiAlH
4
in THF then acidic
work-up or NaBH
4
in EtOH

(c) Need to add a C, use an organometallic reagent, e.g. CH
3
MgBr in Et
2
O or THF,
followed by an acidic work-up.

(d) Right number of C, just need to change the functional group. Use aq. NaOH.
Qu
3:
(a) cis-1,2-cyclohexanediol

(b) trans-1,2-cyclohexanediol

(c) (R,R)- and (S,S)-2,3-butanediol

(d) meso-2,3-butanediol

(e) (R,R)- and (S,S)-2,3-butanediol. Compare this to reaction (d), changing the
stereochemistry of the overall additon process to anti means that the products will be
diastereomeric with those in (d).

(f) They are diastereomers. Since the addition is syn, the relationship is defined by
the relationship of the alkene starting materials.
Qu
4:
(a) Thionyl chloride converts ROH to RCl, so benzyl chloride, C
6
H
5
CH
2
Cl.

(b) A Williamson ether synthesis, giving C
6
H
5
CH
2
OCH
2
CH
3


(c) Under aqueous, the product will be benzoic acid, C
6
H
5
CO
2
H

(d) With the more selective oxidation conditions, the product will be benzaldehyde,
C
6
H
5
CHO

(e) An ester preparation giving benzyl ethanoate, CH
3
CO
2
CH
2
C
6
H
5

Qu
5:
In each case, disconnect the alcoholic portion from the acid portion:


Qu
6:
Periodic acid, HIO
4
, causes oxidative cleavage of 1,2-diols.

In the case of a cyclic diol, this would break the ring. The product here would be
1,6-hexanedial.

Qu
7:
The best method for ether synthesis is the Williamson method from an alcohol and
an alkyl halide.



(a) This is the best
disconnection to a
primary halide
(good SN2) and the
tertiary alcohol.
The tertiary
bromide would be
prone to
elimination.
(b) This is the only
choice since aryl
bromides do not
undergo
substitution, we
must make it the
alcoholic
component.
(c) A symmetrical
cyclic ether so we
can disconnect
either C-O bond, it
makes no
difference.


Ethers, Epoxides and Sulfides Questions


Qu
1:
Identify the products from the reaction of the following ethers with excess HI :




Qu
2:
Design a synthesis of the following dibenzyl ether from toluene as a source of all the
C in the product.





Qu
3:
The base catalysed hydrolysis of a 1,2-chlorohydrin is shown below:

It was found that the product diol had the same configuration as the original
chlorohydrin.
Suggest a mechanism that is consistent with this observation.

Ethers, Epoxides and Sulfides Answers

Qu Ethers are cleaved by strong acids like HBr and HI to give an alcohol and an alkyl
1: halide.

However, in the presence of excess HI, alcohols react to give alkyl iodides.
(a) 2 moles CH
3
CH
2
I
(b) (CH
3
)
3
CI and CH
3
I
(c) I-CH
2
CH
2
CH
2
CH
2
-I
(d) I-CH
2
CH
2
-I



Qu
2:
The challenge is the synthesis of the ether from toluene. First question, how do we
make ethers ?

A Williamson ether synthesis requires and alkoxide and an alkyl halide. In this case,
it is necessary to make the alcohol from the halide by a simple substitution since the
halide can be obtained from the toluene via a radical substituion. The retrosynthesis
and the synthesis are shown below:




Qu
3:
In an SN2 process we normally get inversion, and in SN1 racemisation.

Since we don't have racemisation it can't be SN1, so it must be SN2. In order to get
overall retention, this could indicate 2 sequential SN2 reactions. The process is that
the 1,2-halohydrin forms an epoxide via an intramolecular SN2 displacement of
chloride, followed by ring opening of the epoxide under basic conditions via another
SN2 reaction.



Aldehyde and Ketone Questions


Qu1: Arrange the following in order of relative reactivity towards nucleophilic addition :

(a) (CH
3
)
2
C=O (b) CH
3
CHO (c) H
2
C=O
Qu
2:
What are the major products of reaction of each of the following with (i) propanal
and (ii) propanone ?

(a) LiAlH
4
/ THF then acidic workup (b) PhMgBr then acidic workup
(c) 1,2-ethanediol, H
+
, heat (d) 2,4-dinitrophenylhydrazine
(e) Ph
3
PCHCH
3
(f) NH
2
OH
Qu
3:
Each of the following primary amine derivatives has more than one heteratom, yet
only one product is observed.

rationalize the nucleophilic atom in each case :

hydroxyl amine, NH
2
OH

semicarbazide, NH
2
NHCONH
2


Qu
4:
How can 1-bromopropane be used to prepare each of the following ?

(a) ethanal (b) propanone
(c) propanal (d) 2-butanone
(e) pentanal


Qu
5:
Design efficient synthesis of the following from cyclohexanol:


Aldehyde and Ketone Answers

Qu1
:
Increasing the number of alkyl substituents decreases the electrophilicity of the
carbonyl C due to:

(i) electronic effects (alkyl groups are weak electron donors) and (ii) steric effects
(inhibit Nu approach)
H
2
C=O > CH
3
CHO > (CH
3
)
2
C=O
Qu
2:
Note the very similar nature of the reactions that the aldehyde and ketone undergo:



(a) LiAlH
4
is a hydride reducing agent converting C=O to H-C-OH.
(b) PhMgBr is a Grignard reagent. The Ph adds to the C=O to give Ph-C-OH.
(c) Alcohols react to give acetals, in this case since it is a diol, we get cyclic
acetals.
(d) The arylhydrazine reacts to give the arylhydrazone via addition-elimination.
(e) The ylid undergoes a Wittig reaction generating the alkene.
(f) Hydroxylamine reacts to give the oxime via addition-elimination.
Qu
3:
First step is to recognise what the products are as that defines the nucleophilic atom.

(i) Hydroxyl amine, NH
2
OH , reacts through the N to give an oxime, R
2
C=N-
OH. N is more nucleophilic (better electron donor) than O because the higher
electronegativity of O makes it more difficult to donate its' electrons.
(ii) Semicarbazide, NH
2
NHCONH
2
reacts to give a semicarbazone. This reaction
occurs through the terminal amine type N rather than either of the amide type N
which are less nucleophilic due to the involvement of the electrons in resonance.



Qu
4:
Here is a scheme collecting possible syntheses together (based on the more
important reactions)



(a) Ethanal : we need to lose a C... ozonolysis of an alkene formed by elimination
of the alkyl halide would allow that and give the aldehyde.
(b) Propanone : oxidation of the secondary alcohol to get the ketone requires that
we eliminate then hydrate the alkene in Markovnikov fashion.
(c) Propanal : aldehydes can be obtained by oxidation with the Cr reagents PDC
(pyridinium dichromate) or PCC (pyridinium chlorochromate) in methylene
chloride (aq. conditions result in over oxidation to the carboxylic acid). The
primary alcohol is obtained by substitution.
(d) 2-Butanone : now we need to gain a C. We can do this with Grignard
chemistry by adding MeMgBr to the previous product, propanal, followed by
oxidation of the secondary alcohol.
(e) Pentanal : this time we must add 2 C. Again use a Grignard, but this time add
ethylene oxide to the Grignard of the original halide. Finally, controlled oxidation
(see (c)).

Qu
5:
In both cases we need to add a C atom so we need nucleophilic C systems which
react with cyclohexanone.

Addition of a Grignard reagent gives the tertiary alcohol, but this can only be
eliminated to give the more highly substituted endocyclic alkene. The Wittig
reaction is ideal for creating the exocyclic alkene since the Wittig reaction
specifically transforms a C=O to C=C at the same location.

Conjugation in Alkadienes and Allylic Systems Questions

Qu 1
The Diels-Alder reaction of furan and cyclopentadiene at 20
o
C yields
product 1, as shown below.

Heating a solution of 1 to 80
o
C for 1 hour gives a mixture containing
a second product 2 (a stereoisomer of 1) in a ratio of 9:1 (2:1).
The reaction of cyclopentadiene and furan at 80
o
C gives the same 9:1
mixture of 2:1.


(a) Which species is the diene and the dienophile in this Diels-Alder
reaction ?

(b) Which of the products is endo and which of the products is exo ?

(c) The sole formation of 1 (and not 2) at 20
o
C is an example of a
reaction under which type of control ?

(d) At 80
o
C, the formation of a 9:1 mixture of 2:1, starting from
cyclopentadiene and furan, is an example of a reaction under which
type of control ?

(e) Is the formation of 90% 2 from 1 (at 80
o
C) likely to be a direct
isomerization of 1 into 2 ?

(f) As previously stated, when 1 was heated to 80
o
C for 1 hour, 90%
of the material was converted into 2. Heating for a further 10 hours
at 80
o
C produced no further change.
Why can we not convert the remaining 10% of 1 into 2 ?

(g) The bimolecular reaction of cyclopentadiene and furan at 20
o
C to
produce 1 is an exothermic reaction. According to the Hammond
postulate what does this imply about the transition-state for this
reaction ?

(h)
Reaction coordinate
diagrams are often used
to illustrate the energy
changes taking place
during chemical
reactions. Indentify the
chemical species that
corresponds to each of
the points indicated by
arrows in the diagram
shown to the left.
Qu 2: What are the product(s) of the following reactions ?

(a)

(b)
Qu 3: What starting materials are required to produce the product shown ?


Qu 4:
Draw in all of the curly arrows to complete the mechanism for the
following reaction scheme:


Qu 5:
(a) Rank the relative reactivity towards 1,3-cyclopentadiene of the
following :



(b) Rate the relative reactivity towards dimethyl cis-butendioate of
the following:



(c) Rate the order of the relative reactivity towards 1-buten-3-one of
the following:




Conjugation in Alkadienes and Allylic Systems Answers

Qu1:
(a) The diene is cyclopentadiene and the
dieonphile is furan.The sole formation of 1 (and
not 2) at 20
o
C is an example of a reaction under
kinetic control.

(b) Product 1 is endo and product 2 is exo. Look
at the relative position of the furan unit with
respect to the bridghead CH
2
unit.

(c) The sole formation of 1 (and not 2) at 20
o
C is
an example of a reaction under kinetic control.

(d) The mixture of 1 and 2 formed at 80
o
C from
cyclopentadiene and furan is an example of a
reaction under thermodynamic control since
heating 1 also provides the same equilibrium
mixture.

(e) No since this would require an inversion of
sp
3
hybridized C atoms.

(f) We can not convert the remaining 10%
of 1 into 2 since the 9:1 ratio represents the
equilibrium mixture.

(g) The Hammond Postulate indicates that the
transition state will be most like the species it is
closest to in energy, so if the reaction is
exothermic it should be the starting materials,
cyclopentadiene and furan.

(h)

Qu 2: (a)

In this Diels-
Alder reaction,
since the
concerted additon
reaction is
stereospecific, the
cis dienophile gives cis products, but since
both faces can be attacked enantiomeric products
are produced. Compare the position of the methyl
group from the diene with the following example.

(b)

In this Diels-
Alder reaction,
since the
concerted additon
reaction is
stereospecific, the
cis dienophile gives cis products, but since
both faces can be attacked enantiomeric products
are produced. Note how the position of the methyl
group has changed in this example.


Qu 3:


First look for the diene of the Diels-Alder
reaction. If you draw the curly arrows for the
retro-Diels-Alder reaction, by starting from the
C=C in the product then the furan diene is readily
revealed and the dienophile must be
MeO
2
CCH=CHCO
2
Me. Given that the product
has the two ester groups trans-, the dienophile
must have also been trans.
Qu 4:

Qu 5: (a)

In the Diels-Alder reaction the dienophile is
usually the electrophile, so electron withdrawing
groups will enhance their reactivity. Since the -
C=O group is electron withdrawing by resonance,
then we get giving iii > ii > i.

(b)

This Diels-Alder reaction requires that the diene
be able to adopt an s-cis conformation. Since
cyclopentadiene is locked in this conformation,
butadiene can achieve it by rotation about the C2-
C3 bond. BUT, (i) is locked in s-trans and so it is
therefore un-reactive. Thus, ii > iii > i.

(c)

We are looking at the diene component of a
Diels-Alder reaction. Benzene does not react like
a diene very easily as it would result in the loss of
aromaticity. Between the 2 substituted
butadienes, thecis methyl groups in iii sterically
destabilize the reactive s-cis conformation making
it less favorable, so ii > iii. Overall, ii > iii > i.




Enol and Enolate
Questions

Q
u1
:
How many o-hydrogens are there
in each of the following aldehydes
and ketones ?

(a)
(CH
3
)
2
C=O
(b)
CH
3
CHO
(c)
H
2
C=O
(d) PhCHO
(e) 2-
pentanone
(f) 3-
pentanone
Q
u
2:
For each of the following pairs of
compounds, draw their enols
tautomers and choose the one
compound that has the greater
enol content.

(
a
)

(
b
)

(
c
)


Q
u
3:
Draw the stepwise curly arrow
mechanism for the
tautomerisation of propanone with
(i) and acid catalyst, H
3
O
+
and (ii)
a base catalyst, HO
-

Q What are the major products of

u
4:
the reactions of 1-phenylethanone
(acetophenone) with each of the
following:

(a
)
Bromine in
acetic acid

acetophenon
e
(b
)
Iodine in
sodium
hydroxide
solution

(c
)
(i) NaOH
then (ii)
add ethyl
iodide

(d
)
Ethyl
magnesiu
m bromide
followed
by acidic
work up

(e
)
NaOH and
methanal
(f
)
NaOH and
benzaldehy
de


Q
u
5:
What are the major products of
the reactions of 2-cyclohexenone
with each of the following:

(a) NH
3
in water
(b) Ethanethiol
(c)
Lithium diethylcuprate then
acidic work-up
(d)
Ethyl lithium then acidic
work-up







Enol and Enolate Answers


Qu
1:
How many ohydrogens are there in each of the following aldehydes and ketones :

(a) (CH
3
)
2
C=O = 6 (2 x CH
3
)
(b) CH
3
CHO = 3 (1 x CH
3
)
(c) H
2
C=O = 0 (the 2H are attached directly to the carbonyl, not the
adjacent oposition)
(d) PhCHO = 0 (there are no H on the adjacent o-C which is a substituted aromatic
carbon)
(e) 2-pentanone = CH
3
C=OCH
2
CH
2
CH
3
= 5 (1 x CH
3
plus 1 x CH
2
)
(f) 3-pentanone = CH
3
CH
2
C=OCH
2
CH
3
= 4 (2 x CH
2
)
Qu
2:

(a
)

(b
)

(c
)


Qu
3:

MECHANISM OF ACID CATALYSED

TAUTOMERISATION
Step 1:
First, an acid-base reaction. The Lewis basic O atom of
the carbonyl is protonated by the acid catalyst giving an
oxonium ion.

Step 2:
Another acid-base reaction. Removal of an ohydrogen
by a water molecule functioning as a base allows
formation of the C=C and neutralises the positive charge
on the O giving the enol and regenerates the catalyst.

MECHANISM OF BASE CATALYSED
TAUTOMERISATION
Step 1:
First, an acid-base reaction. Hydroxide functions as a
base and removes the acidic ohydrogen giving the
reactive enolate.

Step 2:
The negative charge is resonance stabilized to the more
electronegative O atom.
Step 3:
An acid-base reaction. The alkoxide deprotonates a water
molecule reforming the catalyst hydroxide and the enol

Qu
4:
Acetophenone is a typical ketone.....



Qu
5:
As we have an o,|unsaturated ketone, then there could be both direct (1,2-) or
conjugate (1,4-) addition reactions:



Carboxylic Acid Questions

Qu1: Arrange the following in order of (i) increasing acidity, (ii) increasing pK
a
:

(a) CH
3
CO
2
H (b) CCl
3
CO
2
H
(c) CH
3
CH
2
OH (d) CH
3
CH
2
SH
Qu
2:
What would be the major products of the reactions of (i) butanoic acid and (ii)
benzoic acid with each of the following:

(a) SOCl
2
, Et
3
N (b) LiAlH
4
/ THF then acidic work-up
(c) (CH
3
)
2
CHOH / H
+
/ heat (d) NaOH
Qu
3:
How could you use 1-bromobutane to prepare each of the following carboxylic
acids ?

(a) propanoic acid (b) butanoic acid
(c) pentanoic acid (d) hexanoic acid
Carboxylic Acid Answers

Qu1
:
(i) increasing acidity :

CH
3
CH
2
OH < CH
3
CH
2
SH < CH
3
CO
2
H < CCl
3
CO
2
H
Resonance stabilization in carboxylates makes carboxylic acids more acidic than
alcohols or thiols.
Electron withdrawing groups, here -Cl, increase the acidity due to further
stabilization of the carboxylate.
Thiols are more acidic than alcohols due to weaker X-H bond and the ability of S to
accommodate extra electrons (size).

(ii) increasing pKa :

CCl
3
CO
2
H < CH
3
CO
2
H < CH
3
CH
2
SH < CH
3
CH
2
OH
Remember the lower the pKa the stronger the acid, so once you have part (i), this is
just the opposite.
Tip: When asked about pKa trends, it may be easier to think in terms of acidity then
remember to flip the order.
Qu
2:
Note the identical nature of the reactions that the aliphatic and aromatic acid
undergo:


(a) Thionyl chloride, SOCl
2
, is used to prepare acyl chlorides, the base removes the
HCl by-product.
(b) LiAlH
4
is a hydride reducing agent, acids to primary alcohols.
(c) An alcohol and a carboxylic acid give an ester.
(d) Carboxylic acids react with bases to give carboxylates.

Qu
3:
First, note that we have an homologous series of C3 to C6 acids we are trying to
make.

Here is a scheme collecting possible syntheses together (based on the more
important reactions)


(a) Propanoic acid : need to lose a C from C4. We can do this via ozonolysis of an
alkene, which we can obtain by eliminating the alkyl halide.
(b) Butanoic acid : oxidation of the corresponding alcohol will give the carboxylic
acid, so prepare the alcohol by substitution.
(c) Pentanoic acid : need to gain a C to get C5. One way to do this is via the
reaction of the Grignard reagent with carbon dioxide. Alternatively, substitution
with NaCN then hydrolysis would also work.
(d) Hexanoic acid : need to gain 2C to get C6. Reaction of the Grignard reagent
with ethylene oxide gets the right number of C and a primary alcohol ready for
oxidation to the acid.
Carboxylic Acid Derivative Questions

Qu1:
Arrange the following in order of decreasing reactivity towards hydrolysis using
aqueous NaOH.

(a) CH
3
CO
2
CH
3
(b) CH
3
COCl
(c) CH
3
CON(CH
3
)
2
(d) CH
3
CO
2
COCH
3

Qu
2:
What are the products of the hydrolysis reactions considered in Qu 1 after a dilute
acid work-up ?
Qu
3:
(a) Arrange the following in order of decreasing reactivity towards LiAlH
4
/ THF
followed by dilute acid work-up.



(b) What are the products of each of the reactions in part (a) ?
Qu
4:
What is the product of each of the following reactions ?


Carboxylic Acid Derivative Answers

Qu1
:
Hydrolysis is a nucleophilic acyl substitution reaction, typical of carboxylic acid
derivatives.

First task should be to identify the functional groups in each molecule then use the
reactivity order. It can be rationalized based on (i) the interaction of
the substituent and the carbonyl group, and, (ii) the ability of the substituent to
function as a leaving group.
CH
3
COCl > CH
3
COOCOCH
3
> CH
3
COOCH
3
> CH
3
CON(CH
3
)
2

acid
chloride
anhydride ester amide

Qu2
:
All the carboxylic acids in Qu 1 are derivatives of ethanoic acid, so they all give the
same carboxylic acid...

(a) CH
3
CO
2
H (b) 2 moles CH
3
CO
2
H
(c) CH
3
CO
2
H and CH
3
OH (d) CH
3
CO
2
H and HN(CH
3
)
2

Qu3
:
LiAlH
4
is a source of H
-
(a nucleophile) which functions as a reducing agent.

First task should be to identify the functional groups : carboxylic acid, ketone,
aldehyde, ester.
The aldehyde and ketone will undergo nucleophilic addition, the acid and the ester
nucleophilic acyl substitution.
Consider the electrophilicity of the carbonyl group in each compound in each pair.
Aldehydes are more reactive than ketones (chapter 17) as they are less hindered and
the alkyl group in the ketone is a weak electron donor.
Under the reaction condition s the carboxylic acid will deprotonate to give the
carboxylate which is a very poor electrophile (after all, it has a negative charge !) so
the ester is more reactive than the acid.
Now combine the two pairs. Since the -OR group is a stronger electron donor
(resonance) than the alkyl group of the ketone, the ester is less reactive than the
ketone... so we get :





(b) Each will be reduced to the same product, benzyl alcohol.
Qu4
:
The answers the these questions involve materials from this chapter and review
from chapters 10 and 19




Ester Enolate Questions

Qu1: How many o-hydrogens are there in each of the following ester systems ?

(a) ethyl ethanoate (b) methyl ethanoate (c) methyl methanoate
(d) ethyl benzoate (e) diethyl propanedioate

Qu
2:
What are the major products of the reactions when each of the following esters are
treated with sodium ethoxide:

(a) Ethyl ethanoate

(b) Methyl benzoate

(c) Ethyl propanoate

(d) Diethyl hexanedioate

(e) Diethyl heptanedioate

(f) Ethyl 5-oxohexanoate

Qu
3:
What are the major products of the following reaction sequences ?

(a)


(b)


(c)



Qu
4:
How would you prepare diethyl hexanedioate from cyclohexene ?
Qu
5:
How would you prepare ethyl acetoacetate (ie. ethyl 3-oxobutanoate) ?
Qu
6:
How would you prepare diethyl malonate from malonic acid ?


Ester Enolate Answers

Qu
1:
First step is can you draw the structures ! Maybe you need to review ester
nomenclature ?

The o-hydrogens are those on the carbon adjacent to the carbonyl group, in the first
four examples shown below this is to the left, and in the fifth example between the
two carbonyl groups.
(a)
3 ohydrogens as there is a methyl group attached
to the carbonyl group.
(b)
3 ohydrogens as there is a methyl group attached
to the carbonyl group.
(c)
No ohydrogens as there is no carbon atom
attached to the carbonyl group.
(d)
No ohydrogens as the carbon atom attached to
the carbonyl group does not have a hydrogen
attached to it.
(e)

2 ohydrogens as there is a methylene group (-
CH
2
-) between the 2 carbonyl groups.

Qu
2:

(a)
This is the Claisen condensation reaction. An ester enolate nucleophile attacks a
second molecule of the ester, displacing an ethoxide, that will be protonated giving
the alcohol.
(b)
Transesterification converts the methyl ester to the ethyl ester. There is no
condensation reaction since there are no o-hydrogens.
(c)
This is a Claisen condensation reaction. An ester enolate nucleophile attacks a
second molecule of the ester, displacing the alcohol portion as a leaving group
which will be protonated giving the alcohol.
(d)

This is an intramolecular Claisen known as a Dieckmann condensation.
Numbering the chain helps avoid making the wrong size ring in the product (and
keep track of any substituents if there are any). Form the enolate adjacent to one of
the esters and attack the other. Here, the enolate at C5 is shown attacking the
carbonyl at C1 giving the five membered ring.
(e)

This is another Dieckmann condensation. Here, the enolate at C6 will attack the
carbonyl at C1 giving the cyclohexane derivative.
(f)

This is a condensation of a ketone enolate with an ester. We should form the
enolate adjacent to the ketone, either at C4 or C6. Look for the most stable
product. Here, the enolate at C6 will attack the carbonyl at C1 giving the
cyclohexane derivative in preference to a more strained cyclobutane derivative.

Qu
3:

(a)

An example of an acetoacetic ester synthesis. Alkylation of an active methylene
enolate followed by decarboxylation to give the ketone.

(b)

An example of an acetoacetic ester synthesis applied to a cyclic system. Alkylation
of an active methylene enolate followed by decarboxylation to give the cyclic
ketone.
(c)
First part of a malonic ester synthesis, alkylation of the active methylene enolate
giving the alkylated diester.


Qu
4:
This question reviews some material from previous chapters.....


Cyclohexene can be cleaved by either ozonolysis (or by oxidative cleavage of a
diol). Oxidation of the dialdehyde gives the dicarboxylic acid which can be
converted into the diester by Fischer esterification.
Qu
5:

The most likely method is via a Claisen condensation reaction of ethyl
ethanoate. An ester enolate nucleophile attacks a second molecule of the ester,
displacing an ethoxide, that will be protonated giving the alcohol.
Qu
6:
Esters are typically made from the parent carboxylic acid by the Fischer
esterification.






Amine Questions

Qu1:
For each of the following series of compounds, arrange the molecules in order of
decreasing basicity (most basic to least basic):

(a)
(b)
(c)
(d)
Qu
2:
What would be the major products of the following reactions:


Qu
3:
Design syntheses of the following amines using ethene as the only source of carbon
atoms:

1-aminoethane, 1-aminopropane, 1-aminobutane
Qu What would be the major products of the reactions of cyclohexylamine with each
4: of the following:

(a) ethanoyl chloride / Et
3
N (b) hydrogen bromide
(c) cyclohexanone in an acidic
buffer
(d) ethylene oxide followed by dilute
acid work-up.
(e) excess ethyl iodide
(f) excess methyl iodide then Ag
2
O /
H
2
O / heat
Qu
5:
What would be the major products of the reactions of piperidine (see right) with
each of the following:

(a) benzoyl chloride / Et
3
N (b) hydrogen bromide

(c) cyclohexanone in an acidic
buffer
(d) ethylene oxide followed by
dilute acid work-up.
(e) benzyl chloride
(f) excess methyl iodide then
Ag
2
O / H
2
O / heat

Qu
6:
Design an efficient synthesis of the following starting from benzene and any
inorganic reagents.

(a) 1-bromo-3-iodobenzene (b) N,N-dimethyl benzamide
(c) phenol (d) 4-bromoaniline
Amine Answers

Qu
1:
(a)





Use the Lewis base definition to start and try to look at the lone pair availability
(more available = stronger base). Each system in N centered, so we can ignore that as
a factor.
The amide ion is the strongest base since it has two pairs of non-bonding electrons
(more electron-electron repulsion) compared to ammonia which only has one.
Ammonium is not basic since it has no lone pair to donate as a base.
(b)



Amines are stronger bases than alcohols. Again we can use lone pair availability.... N
is less electronegative than O so it is a better electron donor. What about the alcohol
and the thiol ? Acidity increases down a group, so the thiol is a worse base than the
alcohol.... larger atoms tend to form weaker bonds with the small proton.
(c)








Since these are all substituted anilines, we need to look at the role of
the substituent (after all, it is the only thing changing across the series). Substituents
that are electron donors will make the N lone pair more available (electron donating
ability -OCH
3
> -CH
3
) , whereas electron withdrawing groups will make the N lone
pair less available (electron withdrawing ability -NO
2
> Cl)
(d)











We can still use lone pair availability.
Piperidine is the most basic (conjugate acid pKa = 11.2). The lone pair is in an
sp
3
hybrid orbital and there is no resonance (no t system).
In pyridine (conjugate acid pKa = 5.2) the N lone pair is in an sp
2
hybrid orbital but
is not part of the 6t electron aromatic system nor is it involved in any resonance
(perpendicular). The sp
2
hybrid is smaller than the sp
3
hybrid, so there is a stronger
attraction to the nucleus, so less basic.
In aniline (conjugate acid pKa = 5.2), the N lone pair can interact with the tsystem
of the aromatic ring which makes them less available for donation .
In pyrrole is a very weak base (conjugate acid pKa = -4). The N lone pair is
involved in the 6t electron aromatic system. Protonation will destroy the aromaticity
of the 6t electron aromatic system and this makes it an unfavourable process.
Qu
2:


Nitriles, R-CN, are reduced to 1
o
amines by conversion of the R-CN to R-CH
2
-
NH
2
so the product would be 1-aminopentane.


Benzyl bromide is an alkyl halide and will therefore undergo nucleophilic
substitution by the nucleophilic N of ammonia giving benzylamine.


Toluene undergoes nitration to give mainly para-nitrotoluene. Reduction of the
nitro group gives the amine, para-aminotoluene (or para-methylaniline if you
prefer).


Cyclohexanone, a ketone, will react with a secondary amine to give an enamine
(more stable alkene preferred) which on catalytic hydrogenation reduces to the
tertiary amine, N,N-dimethylaminocyclohexane.
Qu
3:
First, note that we have a homologous series of C2 to C4 amines we are trying to
make.

Here is a scheme collecting possible syntheses together. These are based on
important reactions and to be short syntheses.



(a) 1-aminoethane : we can't add NH
3
directly to the alkene, so introduce a halogen,
bromide is a good choice as it is a good leaving group then substitute using excess
ammonia.
(b) 1-aminopropane : we need to add a C atom to get from C2 to C3. For an amine a
good way to do that is via the nitrile. So after preparing ethyl bromide, nucleophilic
substitution with NaCN ( in a polar aprotic solvent such as DMSO) will give the
nitrile which can be reduced to the amine.
(c) 1-aminobutane : now we need to add 2C to get to C4.... addition of the Grignard
ethyl magnesium bromide to ethylene oxide gives 1-butanol. Ammonia will not react
with an alcohol to give substitution (poor leaving group), our best choice here is
either to convert the alcohol to the bromide or we could use a tosylate (both better
leaving groups) then substitute with the ammonia.
Qu
4:
In each of the reactions the primary amine is the nucleophilic species reacting with a
variety of electrophiles.....


Qu
5:
In each of the reactions the secondary amine is the nucleophilic species reacting with
a variety of electrophiles.....


Qu
6:
These examples reveal some of the interesting aspects involving amines and
aromatic compounds......
(a)






In order to get the two ortho- / para- directing halogens meta- to each other we need
to utilise the chemistry of diazonium salts by introducing the first halogen at the nitro
stage. This route is especially useful for getting the iodide substitutent.

(b)







To prepare an amide we need to plan to get the carboxylic acid and the amine. We
can prepare the acid by the reaction of carbon dioxide with the Grignard of
bromobenzene. Alternative routes to the acid could be the oxidation of an alkyl
benzene prepared by alkylation (not shown).

(c)







A good route to phenols is via the hydrolysis of the diazonium salt prepared via the
conversion of the nitro group to aniline.

(d)






In order to limit the reaction to monobromination, we first prepare the less reactive
amide, then brominate, then hydrolyse the amide to the required aniline.
Aryl Halides Questions

Qu1: How could you prepare the following aryl halides from benzene ?

(a) chlorobenzene (b) fluorobenzene
(c) iodobenzene (d) 1-bromo-3-chlorobenzene
(e) 1,4-dibromobenzene (f) 1,3,5 tribromobenzene
Qu
2:
Identify the major products formed by the reaction of bromobenzene with each of
the following :

(a) HNO
3
/ H
2
SO
4
/ heat (b) Br
2
/ FeBr
3

(c) CH
3
CH
2
Cl / AlCl
3
/ heat (d) H
2
SO
4
/ heat
(e) CH
3
CH
2
COCl / AlCl
3
/
heat
(f) Mg / THF then CO
2
followed by aq. acid
work-up
Qu
3:
What are the major products of the reactions of each of the following with phenyl
magnesium bromide followed by a regular acidic work-up ?

(a) CH
3
CH
2
CHO (b) C
6
H
5
CHO (benzaldehyde)
(c) CH
3
COCH
3
(propanone) (d) D
2
O
(e) C
6
H
5
CO
2
CH
3
(f) C
6
H
5
CO
2
H
(g) CH
3
CH
2
OH (h) C
6
H
5
CN
Qu
4:
Based on the definitions discussed in Chapter 11, is benzyne an aromatic
compound ?
Qu
5:
What is the product of the reaction of benzyne with each of the following:

(a) 1,3-butadiene (b) furan
(c) H
2
O (d) NH
3

Aryl Halides Answers

Qu
1:
(a)



Chlorine atoms can be introduced fairly
simply by treating benzene with chlorine in
the presence of a Lewis acid catalyst like
iron (III) chloride.
(b)




The most common method for introducing fluorine is via the Schiemann reaction of
the diazonium salt using HBF
4
. Diazonium salts are obtained from anilines.
(c)





The most common method for introducing iodine is again via the diazonium salt , by
treating it with potassium iodide.
(d)


Since both -Cl and -Br are ortho- / para- directing, we cannot just introduce them
using the halogen and iron (III) trihalide method. The alternative is via the diazonium
reactions and a Sandmeyer reaction. This also means we can use the nitro- group to
set up the required meta arrangement.

(e)







Since bromine is an ortho / para director but the large size of the bromine to some
degree sterically inhibits ortho substitution, 1,4-dibromobenzene can be obtained by
treating benzene with excess Br
2
and the Lewis acid catalyst iron (III) bromide.
(f)









In order to complete this synthesis, we need to use aniline.... this powerful activating
group allows for the introduction of 3 bromines in the correct arrangement (in fact it
is so reactive, a catalyst is not even needed, and the reaction is almost instantaneous
at room temperature), then the amino group, -NH
2
, can be removed by diazotisation
and the introduction of a H.
Qu
2:
Since the bromine is an ortho- / para- director, but is fairly large, the major product
of these reactions will be the para- isomers.



Qu
3:
A collection of reactions of an aryl Grignard reactions.... you should compare them
with those of ethyl magnesium bromide (see chapter 14 questions). In each case
remember that there is a aqueous acid work-up.



Qu
4:
Yes benzyne is aromatic..... it has a cyclic, planar, conjugated, 6t electron system.

Note that the second t bond (shown as the blue orbitals in the
diagram to the right) of the triple bond is perpendicular and
therefore cannot overlap with the aromatic t system (shown as
cyan orbitals). This means that the two electrons associated with
this bond are not part of the conjugated system.
Benzyne is very reactive due to the strain of the triple bond due to
its incorporation into the six membered ring.
Qu
5:
Benzyne has a reactive triple bond undergoing addition reactions, including the
Diels-Alder reaction:



Phenol Questions

Qu1:
For each of the following series of compounds, arrange the molecules in order of
decreasing acidity (most acidic to least acidic):





Qu Identify the major products formed by the reaction of phenol with each of the
2: following :

(a) HNO
3
/ CH
3
CO
2
H / heat (b) Br
2

(c) CH
3
CH
2
Cl / AlCl
3
/ heat (d) H
2
SO
4
/ heat
(e) CH
3
CH
2
COCl / AlCl
3
/ heat (f) CH
3
CH
2
COCl
(g) Na then add benzyl chloride (h) HBr
Qu
3:
Identify the major products formed by the reaction of methoxybenzene with each of
the following :

(a) HNO
3
/ CH
3
CO
2
H / heat (b) Br
2

(c) CH
3
CH
2
Cl / AlCl
3
/ heat (d) H
2
SO
4
/ heat
(e) CH
3
CH
2
COCl / AlCl
3
/ heat

Phenol Answers

Qu
1:

In order to establish acidity, it is often a good idea to consider the simple acidity
equilibria, HA <=> H
+
+ A
-

and look for factors that stabilize the conjugate base, A
-
since that implies that HA is
a stronger acid....
(a
)







Carboxylic acids (pK
a
~5) are more acidic than phenols (pK
a
~10) which in turn are
more acidic than simple alcohols (pK
a
~16 - 20). The carboxylate anion is stabilized
by resonance that allows the negative charge to be delocalised onto a second
electronegative oxygen atom. The phenolate ion can also be stabilized by resonance
but the charge ends up on C atoms. In contrast, the alkoxide ion has no resonance
stabilization since there is no t system.
(
b)















All these structures are p-substituted phenols, so the substituent must be the
controlling factor. The effect the substituent exerts on the benzene ring will
influence the stability of the phenolate ion. A strong electron withdrawing group
will stabilize the phenolate making the phenol more acidic whereas a strong electron
donor will destabilize the phenolate making the phenol less acidic. A nitro group is
strongly withdrawing due to resonance, a chloro group is weakly electron
withdrawing due to inductive effects, a methyl group is a weak electron donor and a
methoxy group a strong electron donor due to resonance.








(c
)










All nitrophenols. As we saw in part (b) nitro groups stabilize the phenolate ion by
resonance electron withdrawal that allows the negative charge to be moved to an
electronegative oxygen atom in the nitro group when the nitro group is ortho-
or para- to the -OH group. The more nitro groups there are in these positions, the
greater the stabilization of the phenolate and the more acidic the phenol.

Qu
2:
In each of the reactions the phenol is the nucleophile, either the aromatic ring or at
the oxygen atom:





Qu
3:
The aromatic ring of methoxybenzene undergoes similar reactions to those of phenol
discussed above:






Carbohydrate Questions

Qu
1:
What type of stereochemical representation of glyceraldehyde is shown below ?


Qu
2:
Assign the configuration of the molecule of glyceraldehyde shown above as R or S
and D or L.
Qu
3:
Assign the configuration of the molecule of glyceraldehyde shown above as R or S
and D or L.


Qu
4:
How are the following 2 structures related ? (be as specific as you can !)



Qu
5:
For each of the following structures:

(i) identify the anomeric center (ii) identify it as a hemi-acetal, acetal, kemi-ketal or
ketal and (iii) a furanose or a pyranose.



(a) (b) (c)

Qu
6:
For each of the following structures decide whether the carbohydrate is:

(i) an aldose or ketose, and (ii) a tetrose, pentose or hexose




(a) (b) (c)

Qu
7:
Which of the following sugars are reducing sugars ?




(a) (b) (c)
Carbohydrate Answers

Qu1: This is a Fischer projection.
Qu
2:
In a Fischer projection the horizontal bonds are towards you, the vertical away as
shown below:

=
To assign the R / S configuration, need to assign the priorities of the groups at the
chirality center.
HO > CH=O > CH2OH > H. Now with the lowest priority group away, the sense
of rotation of highest to lowest priority is counter-clockwise, so this is the S
stereoisomer. Review this ?
To assign the D / L configuration, need to remember that in the Fischer projection
the -OH group is on the left in the L stereoisomer.
Qu
3:
This is the mirror image of that in qu2, so this is the R- or D-glyceraldehyde.

Note how important it is to remember that the Fischer diagram of sugars needs to be
drawn with the carbonyl (oxidised) end uppermost.
Qu
4:

Both are Fischer projections, drawn the same way up, so a straight comparison can
be made. The systems are isomers, differing only in the arrangement of the groups
at one of the two chirality centers. So they are stereoisomers,
specifically diastereomers.
Qu
5:
In each case, the anomeric center has been indicated by * . It is important that you
can recognise this center... you need it for part (ii)

(a)

A hemi-acetal, pyranose
The -OH group at the anomeric center indicates
the hemi-.
The -H group (not shown) at the anomeric carbon
implies the structure is based on an aldehyde, so
we have an acetal.
The cyclic unit is 6 atoms so it is a pyranose.
(b))

A hemi-ketal, furanose
The -OH group at the anomeric center indicates
the hemi-.
The anomeric carbon is attached to 2 other C
atoms so the structure is based on a ketone so we
have an ketal.
The cyclic unit is 5 atoms so it is a furanose.
(c)

A hemi-acetal, pyranose
The -OH group at the anomeric center indicates
the hemi-.
The -H group (not shown) at the anomeric center
implies the structure is based on an aldehyde so
we have an acetal.
The cyclic unit is 6 atoms so it is a pyranose.

Qu
6:
In each case the anomeric center / carbonyl group has been indicated by * . It is
important that you can recognise this center... you need it for part (i)

(a)

The anomeric carbon is only attached to one other C
atom, so it corresponds to an aldehyde. Hence, the
carbohydrate is an aldose. The carbohydrate contains 6
C atoms, so it is a hexose.

(b)

The carbonyl carbon is attached to two other C atoms,
so it is a ketone. Hence, the carbohydrate is a ketose.
The carbohydrate contains 6 C atoms, so it is a hexose.
(c)

The carbonyl carbon is attached to only one other C
atom, so it is a aldehyde. Hence, the carbohydrate is
an aldose. The carbohydrate contains 4 C atoms, so it is
a tetrose.

Qu
7:
A reducing sugar needs to have an aldehyde, a hemi-acetal group or be a ketose that
can tautomerise to a aldose.

(a) is not a reducing sugar as there is not an -OH at the anomeric center.
(b) Sucrose is not a reducing sugar as both anomeric centers are glycosides
(i.e. acetals) not hemi-acetals.
(c) Glucose is a reducing sugar, here the aldehyde group is obvious.