Block 6 Functional Groups 2

CHEM110/Block 6/Functional Groups II/2020 1
CHEM110 2020
CHEMISTRY OF THE LIVING WORLD
BLOCK 6: FUNCTIONAL GROUPS II
Lecturers
Dr Kaitlin Beare (KDB) Prof David Barker (DB)

email: CHEM110@auckland.ac.nz email: d.barker@auckland.ac.nz
Building-Room: 302-847
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to you. Anyone finding this handout should take it to Chemistry Reception, Level 6 of Building
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© School of Chemical Sciences The University of Auckland

The aim of this block is to further extend your knowledge of functional group chemistry by
building on what you learned in block 1 and block 4. You will also see how an understanding of
functional group chemistry can be used to explain the properties and reactivity of important
biological molecules, such as carbohydrates and proteins.
At the end of block 4, you should be able to:
• Recall basic chemical terminology related to oxygen and nitrogen containing functional
groups, carbohydrates, peptides and rad
• Write chemical equations for common reactions of alcohols, ketones/aldehydes and
carboxylic acids/carboxylic acid derivatives, including appropriate reagents.
• Write appropriate mechanisms for nucleophilic addition and nucleophilic acyl substitution
reactions.
• Use mechanistic reasoning to predict/explain regiochemistry or stereochemistry in the
reactions and reaction types mentioned above.
• Suggest routes for synthesising simple organic molecules using the reaction types covered
in both here and in block 4.
• Explain the acid/base behaviour of organic molecules in terms of their structure.
• Apply your knowledge of the chemistry of alcohols and carbonyls to explain the chemical
behaviour of carbohydrates.
• Apply your knowledge of stereochemistry, intermolecular interactions and carbonyl
chemistry to the formation of peptides and proteins.
• Apply your knowledge of resonance to radical species.

UNIT 1 - ALCOHOLS
Pre-Lecture Reading Lecture 1

1.1 INTRODUCTION
Recall from Block 1, Unit 2 that alcohols are named using the suffix -ol. We do not look at
naming compounds where the alcohol group in a substituent in this course. As a result, the
alcohol functional group will always take priority in terms of numbering the parent alkyl chain
(backbone).
Recall also that we classify alcohols as primary (1°), secondary (2°) or tertiary (3°) depend-
ing on how many carbon-carbon bonds there are to the C-OH carbon. This classification will
become important when we look at the reactivity of alcohols.
1.2 PROPERTIES of ALCOHOLS

The alcohol functional group is polar and small alcohols (up to C5) are water soluble. Alcohols
contain an OH group and form hydrogen bonds. The –OH group of an alcohol, under appropriate
conditions, has the ability to react either as an acid or as a base.
CH3CH 2OH + Na +NH 2- CH3CH 2O + Na + + NH 3
O O
CH3CH 2OH + HO S OH CH3CH 2OH + O S OH
O H O
Both the conjugate base (alkoxide) and the conjugate acid (oxonium ion) are important species,
since the formation of one of them is usually the first step in reactions of alcohols.
1.3 PREPARATION of ALCOHOLS

In Block 4 you saw two methods for the preparation of alcohols.
1.3.1 Alkyl Halide Hydrolysis

This is an example of nucleophilic substitution using H2O or HO- as the nucleophile.
Mechanistically, this can be either SN1 or SN2 depending on the substrate and nucleophile.
Refer to Block 4 for more details.
_ _
RX + HO (or H2O) ROH + X (or HX)
1.3.2 (a) Acid Catalysed Addition of H2O to Alkenes

This is an example of electrophilic addition using H2O as the nucleophile and requiring acid
(usually H2SO4) as a catalyst. Remember that for unsymmetrical alkenes, two products are
possible. The major product will be the more substituted alcohol (Markownikoff Addition).
OH
H+ major + OH minor
+ H 2O
Alcohols undergo many of the same types of reactions as alkyl halides. As preparation for
this lecture, please review the nucleophilic substitution (SN1/ SN2) and elimination (E1/E2)
reactions from Block 4.

Practice Questions:
Give the formal chemical names of the alcohols below, and suggest a method for preparing each
of the alcohols above using chemistry you have already seen in this course.
(a)
OH
(b)
OH
Want more practice with these concepts? Try BestChoice modules:

- Block 6 – Alcohol Structure
- Block 4 – All alkenes and alkyl halides modules.
1.3.2 (b) Hydroboration-Oxidation of Alkenes
1. B2H6
CH3CH CH2 _
2. HO H2O2
Mechanism:
Electrophile BH3
Design of a synthetic route – appropriate choice of reagents.

If the starting material is but-1-ene, depending on whether the required product is butan-1-ol
or butan-2-ol, the reagent(s) choice will be different.

The remaining methods for the preparation of alcohols are concerned with the addi-
tion of a nucleophile to a carbonyl group.
General mechanism for the addition of a nucleophile to a carbonyl group:
C O C O C O
Nu- = H- (hydride anion, from NaBH4 or LiAlH4)

= R- (carbanion, from a Grignard reagent RMgX)
1.3.3 Reduction of Aldehyde, Ketone or Ester

Examples:
Aldehydes give 1° alcohols, ketones give 2° alcohols. 3° alcohols cannot be prepared in this
manner.
1.4.4 Addition of RMgX (Grignard reagent) to an aldehyde, ketone, ester or
acyl chloride.
Recall: Grignard reagents are prepared from the corresponding alkyl halide. (See Block 4)
Mg
RX RMgX
in ether
R = alkyl or aryl
(a) Aldehyde or Ketone - Mechanism covered in Block 6, Unit 2
_ +
1.
(CH3)2CHMgBr
2.

(b) Ester or Acid Chloride - Mechanism covered in Block 6, Unit 4
_ +
1.
(CH3)2CHMgBr
2.
2 Equivalents of Grignard reagent + Ester or Acid Chloride → 3° alcohol.
Practice Question: How would you prepare the following compounds from starting
materials containing no more than three carbon atoms?
1. OH +
H3O
CH3CH2CHCH2CH3
OH
2.
OH
H3O+
CH3CHCH2CH2CH3
OH
3. OH
H3O+
CH3CH2CCH2CH3
CH2CH3
OH

Preparation of Alcohols - Summary
Alcohol Prepared Staring Material Reagent Required
Primary 1° 1° alkyl halide
1-alkene (terminal alkene)
aldehyde
ester
methanal
Secondary 2° 2° alkyl halide
1-alkene (terminal alkene)
internal alkene (eg 2-alkene)
ketone
aldehyde
Tertiary 3° 3° alkyl halide
trisubstituted alkene
ketone

1.5 PHENOLS
Whereas for an alcohol the hydroxyl group is attached to sp3 carbon, in a phenol the hydroxyl
(OH) group is directly bonded to the sp2 carbon of an aromatic ring. Phenols are weekly acidic as
the phenoxide anion (conjugate base) is resonance stabilised. That is, the charge is delocalised
across the molecule.
OH O O O O O
+ H2O +
+ H3O
You saw in Block 4 - Aromatic Substitution that the more delocalised a charge is, the more
stable a molecule is. You also saw in Block 5 that the more stable the conjugate base, the more
acidic the parent acid. You may wish to go back and revise these concepts before moving on.
For substituents on the aromatic ring:
Electron-withdrawing groups increase acidity as they stabilise the phenoxide anion.
Examples include -CHO (aldehyde) -COOR (ester) -X (halide)
Groups that are deactivating towards electrophilic aromatic substitution will be electron-
withdrawing in this context.
Electron-donating groups decrease acidity as they destabilise the phenoxide anion.
Examples include -OH (alcohol) -NH2 (amine).
Groups that are activating towards electrophilic aromatic substitution will be electron-donating
in this context.
CH3
Phenols are named using the root ‘phenol’ adding OH

substituents as required. e.g. m-methylphenol

Practice Question. Draw a second resonance structure of para-substituted phenolate (a) with
the negative charge on an oxygen. Can you draw the equivalent structure for meta-substituted
compound (b)? Which would you predict to be the most acidic?
(a) O (b) O
O
O

- Block 6 – Phenols
1.4 REACTIONS of ALCOHOLS

1.4.1 Nucleophilic Substitution (Recall substitution of alkyl halides, Block 4)
Formation of alkyl halides from alcohols. The reaction of a tertiary alcohol with conc. HCl will
yield the corresponding tertiary alkyl halide.
OH
conc.
CH3CCH2CH3
CH3 HCl
Does the reaction proceed via SN1 OR SN2?: Answer: as for alkyl halides.
For tertiary alcohols, the reaction proceeds via the SN1 mechanism (stable carbocation)
OH
conc.
CH3CCH2CH3
CH3 HCl
Primary alcohols would have to proceed via an SN2 mechanism – too slow!
A more general procedure for converting alcohols to alkyl chlorides by use of thionyl chloride
(sometimes in the presence of pyridine).
In these examples, the alcohol is acting as the electrophile.

In Block 4 we also saw alcohols and more often alkoxides acting as nucleophiles in a substitu-
tion reaction to give an ether.
-
O + CH3Br OCH3 + Br
1.4.2 Elimination (Recall elimination of alkyl halides, Block 4)

Alcohols eliminate water when reacted with conc. H2SO4 and heat, forming an alkene. Tertiary
alcohols proceed via E1 mechanism (stable carbocation).
conc. H2SO4
C C
H OH heat
Primary alcohols proceed via E2 mechanism.
Secondary alcohols proceed via either E1 or E2 mechanisms.
As with alkyl halides, the Zaitsev (Saytzeff) rule applies in the elimination of alcohols. Where
more than one elimination product is possible, the more substituted alkene will form as the
major product.
Example:
OH
CH3
conc. H2SO4
heat

1.4.3 Oxidation
Oxidation in organic chemistry refers to processes by which carbon gains bonds to more
electronegative atoms (usually oxygen). For alcohols, the process involves breaking carbon-
hydrogen bonds and forming carbon-oxygen bonds.
OH [O] O O
[O]
R H
R H R OH
H
Note: For oxidation to occur, there must be at least one hydrogen attached to the carbon to be
oxidised – so primary and secondary alcohols can be oxidised, as can aldehydes but tertiary
alcohols can’t react in this way.
(a) Primary alcohol to an aldehyde (or carboxylic acid)
H2CrO4
CH3CH2OH
whereas:
CH3CH2OH
(b) Secondary alcohol to a ketone
Ketones do not undergo further oxidation.
In summary:
Primary alcohol + mild oxidising agent (PCC) gives:
Primary alcohol + strong oxidising agent (H2CrO4) gives:
Secondary alcohol + strong oxidising agent (H2CrO4) gives:
Tertiary alcohols cannot be oxidised.

UNIT 2 - ALDEHYDES and KETONES
2.1 INTRODUCTION
The chemistry of aldehydes and ketones is governed by two factors. The polarised C=O bond,
and the presence of lone pairs on the C=O oxygen.
C O
In addition the carbon of the C=O is sp2 hybridised - that is, flat.
Aldehydes are named using the suffix -al. Ketones are named using the suffix -one. Refer to
Block 1, Unit 2 for further details.
2.2 PREPARATION OF ALDEHYDES and KETONES

2.2.1 Oxidation of Alcohols
We have just seen that aldehydes and ketones can be prepared from the corresponding alcohols.
The ONLY method for the preparation of aliphatic aldehydes you will see in this course is
oxidation of primary alcohols using PCC.
The ONLY method for the preparation of aliphatic ketones you will see in this course is oxidation
of secondary alcohols using H2CrO4.
2.2.2 Friedel-Crafts Acylation of an Aromatic Ring

In Block 4 you also saw one method for preparing aromatic ketones.
AlCl3
+ CH3COCl
Challenge Question. How could you prepare pentanal from butan-1-ol? (Hint: work backwards)

2.3 REACTIONS OF ALDEHYDES and KETONES
Aldehydes can be oxidised to carboxylic acids in the presence of a strong oxidant (H2CrO4).
Ketones cannot be oxidised as there is no hydrogen on the C=O carbon to remove.
However, the principle class of reactions that is available to aldehydes and ketones is the
nucleophilic addition reaction.
2.3.1 Nucleophilic Addition - General Mechanisms
Mechanistically these are either:

(i)
R1 R1 R1
C O R2 R2
R2
or
(ii)
R1 R1 R1 R1
C O C OH
R2 R2 R2 R2
Note that type (ii) is only possible where the nucleophile is ‘available’ in the presence of an acid.
Consider nucleophilic attack at a carbonyl carbon in aldehydes and ketones. The relative rates
of nucleophile attack decrease down the table as shown.
R1 R2 Compound
H H methanal
H R aldehyde
R R ketone

There is no pre-reading for lecture 3. Go over lecture 2 and make sure you are comfortable with
the two mechanisms by which nucleophilic addition can occur.
Today’s practice question requires you to think about the mechanism of the reaction and what
that means for stereochemistry. You may wish to go back to Block 1, Unit 3 to revise the terms
chiral, achiral, enantiomer, and racimic mixture.
Practice Question: Draw the products of the following reactions and state whether the product
is a single enantiomer, a racemic mixture or achiral.
H3C
1. NaBH4
C O
2. H3O+
H3C
H 3C 1. NaBH4
C O
H3CH2C 2. H3O+
H 3C
CH3MgBr
C O
2. H3O+
H3CH2C
2.3.2 Reduction to an Alcohol with NaBH4 or LiAlH4

(Nucleophile: H- , followed by H3O+)
Example:
1.
CH CH CHO
2.
This reaction does not change the number of C-C bonds. Aldehydes are reduced to primary
alcohols, ketones are reduced to secondary alcohols.
Mechanism:
R1 R1 R1
(i) C O
R2 R2 R2
2.3.3 Addition of a Grignard Reagent (RMgX)

(Nucleophile: R- , followed by H3O+)
Increases the number of C-C bonds (to the carbonyl carbon) by 1, so:
Methanal (HCHO) gives primary alcohol
Other Aldehydes give secondary alcohols
Ketone gives teritary alcohol
Mechanism:
R1 R1 R1
(i) C O
R2 R2 R2
2.3.4 Addition of Cyanide
(Nucleophile: NC- , followed by H3O+)
Mechanism:
(i)
R1 R1 R1 R1
C O
R2 R2 R2 R2
2.3.5 Addition of Oxygen Nucleophiles

Ketones and aldehydes react with two molar equivalents of an alcohol in the presence of an
acid catalyst to yield an acetal.
R1 R1
C O R2
R2
aldehyde or ketone
Mechanism:
(ii) R1 R1
R1 R1
C O C OH R2 R2
R2 R2
Addition initially yields a hydroxy ether called a hemiacetal (both -OH and -OR bonded to the
same carbon atom), which then reacts with a second equivalent of the alcohol. This second
step is a substitution reaction - but we will not teach this part of the mechanism formally in this
course.
R1 R1 R1
C O R2 R2
R2

2.3.6 Addition of Nitrogen Nucleophiles
Ammonia and primary amines react with an aldehyde or ketone by addition followed by
elimination (of water), to yield an imine.
R1 R1 R1
C O R2 R2
R2
Nitrogen is a better nucleophile than oxygen (lone pairs are more available), so this reaction
does not require the addition of acid as a catalyst.
Imines formed from simple aldehydes and ketones with NH3 are unstable, but are common
intermediates in numerous biological pathways.
Other nitrogen nulceophiles react in the same manner. Oximes and hydrazones (imine
derivatives) are prepared by treatment of the aldehyde or ketone with special amine derivatives
(hydroxyl amine and hydrazines respectively).
C O + C + H2O
aldehyde or ketone
G Reagent Compound Formed
-R NH2R imine
(amine)
-OH NH2OH oxime

(hydroxyl amine)
-NH2 NH2NH2 hydrazone

(hydrazine)
2.3.7 Summarising:

Practice Question. Give the product of the reaction of propanone with the following
nucleophiles.
excess CH3CH 2OH
O
NH 2CH3
1. PhMgBr
2. H 3O+
An Aside: Changing the Carbon Skeleton

In this course, most of the functional group chemistry that we study looks at changing the
functional groups on a molecule.
For example: alkene to alcohol to ketone.
However, we have also looked at a small number of reactions that can change the carbon
skeleton of the molecule.
Grignard addition is the main method you have seen for altering the carbon backbone of a
molecule (ie making C-C single bonds).
Recall: Grignard reagents are made from alkyl halides and added to carbonyl containing
compounds (nucleophilic addition) to give alcohols.
Mg,
ether
(CH3)2CHBr (CH3)2CHMgBr
Addition of the cyanide anion or alkylidine anion to a carbonyl

(nucleophilic addition) or alkyl halide (nucleophilic substitution) will also generate new C-C
single bonds.
CH3
Br C CCH3
-
O
+
Br CN CN H3O
OH
Can you think of any C-C single bond forming reactions?
Looking for changes to the carbon skeleton can help you narrow down your options when
tackling difficult synthesis problems.

UNIT 3 - CARBOHYDRATES
Pre-Lecture Reading - Lecture 4
Carbohydrates are a class of compounds of tremendous biological and commercial importance.

They occur in every living organism and are essential to life. The starch and sugar in food, and
the cellulose in wood and cotton are almost pure carbohydrate. Carbohydrates are found in
DNA which carries genetic information and some are used as medicines.
The term carbohydrate translates to “hydrates of carbon”. Glucose, the first simple carbohydrate
to be purified, has the molecular formula C6H12O6 which can be written as C6(H2O)6. Despite
the fact that not all carbohydrates can be represented in this way, the term persists and is used
to refer to the broad class of polyhydroxylated aldehydes and ketones known commonly as
sugars or saccharides [Latin saccharum for sugar.]
Carbohydrates are made by green plants during photosynthesis:
sunlight
6CO2 + 6H2O 6O2 + C6H12O6 cellulose, starch .
glucose
When eaten, and then metabolised, carbohydrates provide the major source of energy required
by organisms.
3.1 CLASSIFICATION OF CARBOHYDRATES

Carbohydrates are classified into two groups, complex or simple.
3.1.1 Complex Carbohydrates

Complex carbohydrates consist of two or more simple sugars (monosaccharides) that
joined together. Hydrolysis of complex carbohydrates (disaccharides and polysaccharides)
breaks them down into the constituent monosaccharide units. So on hydrolysis (using acid)
disaccharides would be broken down into two monosaccharides and polysaccharides would
be broken down into three or more monosaccharides.
Examples:
sucrose hydrolyses to 1 glucose + 1 fructose
cellulose hydrolyses to ~3000 glucose
HO OH OH
HO OH OH
HO O HO OH
O OH +
O HO O
HO O HO
OH OH
OH OH OH
lactose galactose glucose

3.1.2 Classification of Simple Carbohydrates
Monosaccharides consist of a single carbon chain (usually three to six carbons long), with one
carbonyl group (either an aldehyde or ketone functional group) with hydroxy groups attached
to the remaining carbons.
Monosaccharides can be classified as aldoses (contain an aldehyde) or ketoses (contain a

ketone).
ketone
aldehyde =
= ketose
OH O aldose OH O
HO (b) OH
(a) H HO
OH OH OH
Here ‘ose’ denotes sugar. They are also classified by the number of carbons in the chain using the
prefix ‘tri’, ‘tetra’, ‘pent’, ‘hex’....
e.g. (a) has a 4-carbon backbone and is thus classified as an aldotetrose

(b) has a 6-carbobn backbone and is thus classifies as a ketohexose.
You are NOT expected to know the names of the various monosaccharides, but you are expected
to be able to classify them.
Practice Question: Classify the following monosaccharides.
OH O O
(a) HO H (b) HO OH
OH OH

3.2 CONFIGURATION OF MONOSACCHARIDES
3.2.1 Stereoisomerism in Monosaccharides
All carbohydrates have stereogenic centres (carbon atoms with four different atoms or groups
attached).
Recall from Block 1:

Stereoisomers: have the same molecular formula and same connectivity, but a different
arrangement in space. Interconversion between stereoisomers requires bond breaking and
bond forming.
Enantiomers: stereoisomers that are also mirror images of each other.
Diastereomers: stereoisomers that are NOT mirror images of each other.
For a compound with multiple stereocentres, ALL stereocentres must be reversed to generate
the enantiomer. Reversing some, but not all stereocentres in the molecule gives a diastereomer.
OH O OH O OH O
(a) HO OH OH OH
(b) HO (c) HO
OH OH OH OH OH OH
For example, (a) and (b) above are enaniomers. (a) and (c) are diastereomers, as are (b) and
(c).
Consider aldoses as an example.
O OH O OH O OH OH O
HO HO
HO H H HO H H
OH OH OH OH OH OH
triose tetrose pentose hexose
There are:
Aldose stereocentres stereoisomers pairs of enantiomers
aldotriose
aldotetrose
aldopentose
aldohexose
Mathematically, the relationship between the number of stereocentres and number of

stereoisomers is:

3.2.2 D/L-Sugars
Historically the designation of sugars as D or L arose from the fact that (R) glyceraldehyde was
found to dextrorotatory (that is it rotated plane-polarized light in a clockwise direction) and
was referred to as D-glyceraldehyde. On the other hand its enantiomer (S)-glyceraldehyde was
found to be laevorotatory (that is it rotated plane-polarized light in an anticlockwise direction)
and was referred to as L-glyceraldehyde. Most naturally occurring monosaccharides are D
sugars.
O
D,L notation is still in common usuage for sugars. For sugars
HO H
containing multiple stereocentres, D/L notation is determined by the
OH
stereochemistry of the centre furthest from the C=O group. For
D-sugars, this stereocentre is (R). For L-sugars it is (S). D-glyceraldehyde
Note: D/L notation is usually related to the position configuration of this stereocentre as
depicted in a Fischer projection. This method of showing stereochemtistry is still commonly
used in biochemistry. However, it has become increasingly rare in chemistry and we will not
cover Fischer projections in this course.
Practice Question: How many stereoisomers are possible for the sugar below? How many
pairs of enantiomers? Draw one pair of enatiomers.
OH O
OH
HO
OH OH
Challenge: Label your each of enantiomers as ‘D’ or ‘L’
3.3 CYCLIC STRUCTURE OF MONOSACCHARIDES

Sugars contain both a carbonyl group (aldheyde or ketone) and alcohol group. We saw in the
previous unit that aldehydes and ketones can react with alcohols to form hemiacetals (and
acetals). For sugars, this can happen internally - one of the alcohol groups can react with the
aldehyde or ketone to form a cyclic hemiacetal.
OH
OH OH O
O
HO HO OH
H
OH OH OH
OH
Although most sugars have multiple alcohol groups, which could, in theory, be involved in
hemiacetal formation, only five- and six-membered cyclic hemiacetals form easily. The size of
the ring depends on the relative stabilities of the possibilities.
Therefore many carbohydrates exist in an equilibrium between open-chain and cyclic forms.
Glucose, for example, exists in aqueous solution mainly in the six-membered, pyranose form
resulting from the intramolecular nucleophilic addition of the OH group at C5 to the C1 aldehyde
group.
We know from Block 6 that the most stable form for a 6-membered ring is the chair conformer.
Just like cyclohexane, when a sugar forms a 6-membered cyclic hemiacetal, two chair forms are
possible. Just like we saw for substituted cyclohexanes, you can assess the relative stability of
the two chairs based on whether the majority of groups are in the axial or equatorial positions
(equatorial is more stable). There are some exceptions to this rule for sugars, but that is beyond
the scope of this course.
3.3.1 Anomers
Looking more closely at the formation of a cyclic hemiacetal we can see that the stereochemistry
at each of the chiral centres remains unchanged.
OH
OH OH O
O
HO HO OH
H
OH OH OH
OH
However, at C-1 in the cyclic form, a new stereocentre has been formed.
OH OH OH
O OH O
HO HO HO OH
H
OH OH O OH
OH OH OH OH
The two hemiacetal forms of a sugar are diastereomers. Diastereomers that differ only in
configuration at only one asymmetric carbon are referred to as anomers. To differentiate
between the two anomers of a cyclic sugar, they are classified as:
the α-anomer when the C1 OH group and C5 CH2OH are trans

the β-anomer when the C1 OH group and C5 CH2OH are cis
The system is in equilibrium, so the amount of each form depends on the relative stability of
α- and β-anomers - keeping in mind that each anomer has two potential chair conformers. That
gives a total of 4 chair structures that need to be compared for stability.
3.3.2 Monosaccharide Anomers and Mutorotation
D-Glucose cyclises reversibly in aqueous solution to a 36:64 mixture of the α:β anomers.
Both anomers of D-glucopyranose can be crystallized and obtained in pure form.
The specific rotation [α]D = +113° for α-D-glucopyranose
= +19° for β-D-glucopyranose
When a sample of either pure anomer is dissolved in water the optical rotation slowly changes
to +53°. This change in optical rotation is due to the conversion of either anomer to the 36:64
equilibrium mixture of anomers. This equilibration occurs by reversible ring opening to the
open chain aldehyde form, followed by reclosure. At neutral pH equilibration is slow – it is
catalysed by acid and base. This equilibration, or ‘scrambling’ of the anomeric stereocentre is
referred to as mutorotation.
Mutorotation: spontaneous change in optical rotation observed when a pure anomer of a
sugar is dissolved in water and equilibrates to an equilibrium mixture of anomers.

3.4 REACTIONS OF MONOSACCHARIDES
3.4.1 Ester and Ether Formation
The –OH groups present in carbohydrates, including the anomeric one, can be converted into
esters and ethers.
CH2OH
O
HO
HO OH O
HO O CH2OCCH3
CH2OCH3 CH3CO O
O CH3CO
CH3O OCCH3
CH3O OCH3 O CH3CO O
CH3O O
You saw ether formation in Block 6 unit 1 (and also in Block 4), although the conditions are
slightly different here. You will see ester formation in unit 5 of this block.
In addition to these ‘global’ reactions, which affect all the free -OH groups in the molecule,
the -OH of the hemiacetal can react selectively to form an acetal. Just like in the previous unit
of this block, reacting a hemiacetal with an alcohol in the presence of an acid catalyst yields
an acetal in which the anomeric OH group has been replaced by an OR group. The acetal of a
sugar is called a glycoside.
Glycosides (like all acetals) are stable to water and are not in equilibrium with an open chain
form. They do not show –
Glycosides are converted to the free monosaccharide by treatment with aqueous acid
CH2OH CH2OH
HO O HO O
HO OH HO OCH3
HO HO
hemiacetal acetal
[methyl -D-glucopyranoside]
3.4.2 Polysaccharide Formation
When the acetal is formed with the –OH of a second sugar acting as the alcohol, a disaccharide
is formed. One example is sucrose (table sugar) which is formed between glucose and fructose.
Other examples are lactose and maltose. The glycoside bonds can form between the anomeric
carbon on one sugar and any of the hydroxyl groups on other sugars so there is an almost
infinite number of possible carbohydrates that can be formed.
CH2OH CH2OH
H O H CH2OH H H O H
H O H+
+ OH H CH2OH
OH H H OH H
OH OH HO CH2OH OH O H O
H OH OH H
H OH OH H
HO
Glucose Fructose Sucrose
H CH2OH
Many biologically active molecules contain glycosidic linkages – for example digoxin, which is
used to treat various heart conditions.
REVISION EXERCISES FOR BLOCK 6 Units 1 - 3
1. Arrange the following compounds in order of decreasing acid strength.

OH OH OH
CH3CH2CH2CH2OH
NO2 CH3

2. Draw and name the eight isomeric alcohols having the molecular formula C5H12O.
3. Draw structures for the alcohols produced by the reaction of B2H6, followed by
treatment with H2O2/HO−, with the following alkenes. Label the products as major or
minor, as appropriate.
a) 2-methylprop-1-ene b) 1-methylcyclohexene c) 3-phenylbut-1-ene
4. Draw structures for the alcohols produced from Q3 a) – c) by treatment of the alkene
with aqueous sulfuric acid. Label the products as major or minor, as appropriate.
5. Give the structural formulae of the products of the following reactions:

O
1. NaBH4 1. NaBH4
a) CH3CH2CH2CHO b) CCH3
2. H3O+ 2. H3O+

6. What would be the product of the reaction of the following compounds with 2 propyl
magnesium bromide after treatment with aqueous acid?
a) propanone b) methanal c) ethyl methanoate
7. Given that one reactant is 1-butylmagnesium bromide give the other reactants neces
sary for the preparation of:
a) pentan-1-ol b) 2-methylhexan-2-ol c) heptan-3-ol
8. Illustrate how methanol can act as either an acid or a base by writing equations for its
reaction with a strong base (NaH) and a strong acid (H2SO4).
9. Write equations for the following reactions. (Indicate major and minor products as ap
propriate.)
a) hexan-3-ol + SOCl2 c) 2-methylpropan-2-ol + conc. HBr (25 °C)
b) cyclohexanol + conc. H2SO4/heat d) 3-methylpentan-3-ol + conc. H2SO4/heat
10. Which of the eight alcohols drawn in Q2 would react with H2CrO4 ?
Where a reaction would occur, give the product which would be formed.
11. Give the structural formula of the product of each of the following reactions.

CH2OH CH2OH OH
a) PCC b) H CrO c) H CrO4
2 4 CH3CHCH2CH3 2

12. Give reaction schemes for the preparation of butanone from each of the following.
OH
(a) (b) (c)
13. Give the structure of the product of the reaction of propanal with each of the following
reagents.
+ +
a) CH3CH2OH + H (heat) b) CH3CH2MgBr followed by H3O
14. Explain why the behaviour of CH3CH2CHO and CH3COCH3 with oxidising agents
would allow the two compounds to be distinguished from one another.
15. Some monosaccharides are shown below.

a) Classify each as aldose/ketose and as tri/tetra/pent/hex.
b) How many stereocentres are present in each?
c) How many stereoisomers are possible?
d) How many pairs of enantiomers?
OH O OH O
b. c.
HO H HO OH HO H
OH OH O
OH O
16. Draw the enantiomer and one diasteriomer of the sugar shown
right. HO H
OH OH
17. Draw the C-1 anomer of the cyclic sugar below and label each as α- or β-. Draw the
second chair form of each anomer and make a prediction as to the most stable.
OH OH
HO
OH
OH
18. a) For each of the following transformations state the reagent(s) which would be
appropriate.
b) Circle and label a hemiacetal and an acetal group.
CH2OH
O
HO
HO OH
HO
CH2OH
O HO O
O CH2OCCH3 HO OCH2CH3
CH3CO O
HO
CH3CO OCCH3
O CH3CO O CH2OCH2CH3
CH3CH2O O
O
CH3CH2O OCH2CH3
CH3CH2O
UNIT 4 - CARBOXYLIC ACIDS and DERIVATIVES

All carboxylic acids and their derivatives have the general formula:
Nomenclature summary
Y Functional Group Nomenclature

prefix stem suffix
-OH carboxylic acid alkan oic acid
-OR carboxylic ester alkyl alkan oate
-Cl acyl (acid) chloride alkan oyl chloride
-OCOR acid anhydride alkan oic anhydride
-NH2, -NHR, -NR2 amide alkan amide
Examples: O
O
C
CH3COH OH CH3CH 2CH 2CH 2COOH
ethanoic acid benzoic acid butanoic acid

pentanoic acid
(acetic acid)
O
O
C
OCH 2CH3 CH3CH 2CH 2CH 2COCH3
ethyl
ethylbenzanoate
benzoate methylbutanoate
methyl pentanoate
O
O C O O
Cl C C
CH3CCl
H 3C O CH3
ethanoyl chloride ethanoic anhydride
benzoyl chloride
(acetyl chloride) (acetic anhydide)
O O
CH3CNH 2 CH3CH 2CN(CH3) 2
ethanamide N,N-dimethyl propanamide
(acetamide)
At this stage, you need to be able to name carboxylic acids, esters, acyl halides and simple
(primary) amides.

4.1 PROPERTIES OF CARBOXYLIC ACIDS

One of the key physical properties of carboxylic acids is their acidity and they are moderately
weak acids.
An equation representing their acidity is shown below.
O O O
+
H + H2 O H3 O +
R O R O R O
resonance stablised
carboxylate anion
The ability to delocalize the negative charge in carboxylate anions makes these anions more
stable than alkoxides (deprotonated alcohols). Therefore, carboxylic acids are more acidic than
alcohols. Recall that phenols are more acidic than alcohols because the phenolate (phenoxide)
anion that is formed is stabilised by the adjacent aromatic ring, which is not possible in alkyl
alcohols. However, the stabilisation that occurs in carboxylate ions is greater than that found in
phenoxides, therefore deprotonation of carboxylic acids is more favourable.
So overall the acidity of organic compound containing an –OH group follow the order:
Carboxylic acids > phenols > alcohols
Practice Question: Draw the structure of 2-bromo-3-methyl-penantoyl chloride.

- Block 6 – Carboxylic Acid Structure 1/2
4.1.1 Acidity and Structure in Carboxylic Acids

For substituents directly attached to COOH in aliphatic acids, or ortho or para to –COOH in
aromatic acids, the acidity (pKa) correlates with the electron donating or withdrawing effect of
the substituents. These groups either stabilise (withdrawing groups) or destabilise (donating
groups) the carboxylate ion formed upon deprotonation. Increased stability correlates with
increased acidity. The same effect was seen for phenols (Block 6, Unit 1).
Electron-donating substituents decrease acid Electron-withdrawing substituents increase

strength (increase pKa). acid strength (decrease pKa).
HCOOH 3.75 Cl3CCOOH 0.7
CH3COOH 4.75 Cl2HCOOH 2.85
CH3CH2COOH 4.88 CH3COOH 4.75

Consider:
O2 N CO2H CO2H MeO CO2H
pKa 3.41 4.19 4.46
Practice Question: Rank the following compounds in order of increasing (lowest to highest)
pKa.
4.2 PREPARATION OF CARBOXYLIC ACIDS

4.2.1 Oxidation of Primary Alcohol (or Aldehyde)
RCH2OH → [RCHO] → RCOOH
4.2.2 Grignard Addition to CO2 (from alkyl halide)

Mg
R X R MgX
O H3O+ O
R MgX + CO2 R C R C
OMgX OH
Br
Mg 1. CO2
CH3 Et2O CH3 2. H3O+ CH3
4.2.3 Nucleophilic Substitution of Alkyl Halides (via Nitrile)

H3O O
CN
RBr RC N RC
nitrile OH

Practice Question: How might you prepare 3-methylbenzoic acid (A) from compound B?
(Hint minimum 3 steps).
NH2 COOH
H 3C H3C
(B) (A)
4.3 DERIVATIVES OF CARBOXYLIC ACIDS

4.3.1 Reactivity
The major reactions of carboxylic acid derivatives are classified as ‘nucleophilic acyl
substitution’, which involves an addition followed by elimination (two steps).
Recalling that in aldehydes and ketones:
But in carboxylic acid derivatives the reactions take a different pathway.
O O O
C R C Y but then C +
R Y R Nu
Nu
Reactivity order:
O O O O
R C R C R C R C
Cl OCOR OR NR2
Reason?
Remember that the first step is the slow step, so the leaving group ability of Y in the second
step (fast) cannot affect the relative rates of nucleophilic acyl substitution. Rather, the rate of
nucleophilic attack at carbonyl carbon in the first step varies with Y.

If the group Y is electron-withdrawing (e.g. Y= Cl), the polarisation of the carbonyl group will
be affected, the carbon becoming “more positive”. Such a carbonyl group will therefore react
relatively rapidly with a nucleophile in the rate-determining first step.
On the other hand, electron donation from Y to the carbonyl carbon will make the carbonyl
carbon “less positive”. Such a carbonyl group (e.g. Y= OR or NR2) will therefore react relatively
slowly with a nucleophile in the rate-determining first step.
O
Esters
C
R OR
Anhydrides lie between acid chlorides and esters in reactivity. This is because whilst there is
the possibility of donation from the O this results in an unfavourable resonance hybrid.
O O O O O O
C C C C C C
R O R R O R R O R
Amides are the least reactive, donation from the lone pair on the nitrogen is dominant resulting
in a carbonyl group with much less δ+.
O
C
R NR
H

4.3.2 Acyl (Acid) Chlorides and Acid Anhydrides - Preparation
Acid (or acyl) chlorides are the most reactive carboxylic acid derivative. They react faster than
all the other derivatives. They are prepared by the reaction of a carboxylic acid and thionyl
chloride (SOCl2), the same reagent which can convert an alcohol into an alkyl chloride. The
overall equation is shown below. Hydrochloric acid (HCl) and the gas sulfur dioxide are formed
as by-products in the reaction. The reaction is non reversible as the SO2 gas bubbles out of the
reaction mixture.
O O
R C + SOCl2 R C + HCl + SO2
OH Cl
acid
chloride
We will look at some of the reactions of acid chlorides in the lecture today.
O O
Carboxylic acid anhydrides have the general structure (shown right) where
R and R1 can be the same (called symmetrical anhydrides) or different
R O R1
(unsymmetrical anhydrides).

Carboxylic acid anhydrides can be formed in two ways.

Using a carboxylic acid and reacting it with a dehydrating agent such as P2O5, this results in
only symmetrical anhydrides. The balanced equation is given below.
O O O
P2O5
6 x CH3COH 3 x CH3COCCH3 + 2 x H3PO4
Alternatively both symmetrical (if R and R1 are the same) and unsymmetrical (if R and R1 are
different) anhydrides can be formed from the reaction of an acid chloride and a carboxylic acid.
O O O O
+
RCOH R1C Cl R COCR1 + HCl
Practice Question: Give possible reagents for the preparation of:
O O
4.3.3 Acyl (Acid) Chlorides and Acid Anhydrides - Reactions

Appropriate nucleophiles convert acyl chlorides into all other acid derivatives.
O O
RC NHR 1 RC OR1
O
RC Cl
O O
1
RC OH RC OCOR
In Block 6, Unit 1 you also saw that reactions with Grignard reagents yield 3o alcohols:
1
O 1. 2R MgX
RC Cl R C
2. H3O
This reaction can be viewed as nucleophilic acyl substitution to give a ketone, followed by
nucleophilic addition to give a 3o alcohol. Note that this generates an alcohol in which two of
the R groups are the same.

Acid anhydrides react in the same manner as acyl halides (but less reactive). With the appropriate
nucleophile an anhydride can form an ester, an amide, or a carboxylic acid. As acid anhydrides
are less reactive than acyl halides, they cannot be converted directly into acyl halides.
You saw an example of acid anhydride synthesis when you prepared aspirin in lab assignment
2.
CO2H O O
OH CH3COCCH3
4.3.4 Esters
Preparation.
You have already seen that you can prepare an ester from the corresponding acyl halide (or
acid anhydride).
Acyl halide + Alcohol
O
CH3CH2OH + C
Cl
O O
OH + CH3CH2CCl OCCH2CH3
Esters can also be prepared directly from the corresponding carboxylic acid.
Carboxylic Acid + Alcohol
O +
H
CH3COH + CH3OH + H2O
Reactions.
Esters are less reactive towards nucleophiles (slower) than acyl chlorides or anhydrides. They
react principally via nucleophilic acyl substitution, as for all other carboxylic acid derivatives.
O
R2NH2 H2O / H3O
+
1
RCOR
(H2O / HO )
O 1. 2R2MgX OH
1. LiAlH4
+ RCOR1 RC
2. H3O+ 2. H3O+
Esters can also react with a strong reducing agent (LiAlH4) or two equivalents of a Grignard
reagent to give 1o or 3o alcohols respectively. As with acyl chlorides, mechanistically these
reactions are nucleophilic acyl substitution followed by nucleophilic addition.

Practice Question: Draw both (organic) products of the following reactions:
O 1. LiAlH4
O 2. H3O+
O
H2O / H3O+
O
O -
H2O / HO
O
Hydrolysis of Esters
Esters can be hydrolised back to the corresponding carboxylic acid under either basic or acidic
conditions. This reaction is another example of nucleophilic acyl substitution. Recall that
the first step of this reaction is nucleophilic addition to the carbonyl (C=O) carbon (the same
reaction we saw for aldehydes and ketones). As with aldehydes and ketones, there are two
possible mechanisms for this step, depending on the strength of the nucleophile used.
Base-promoted (saponification). e.g. Lab assignment 4: PhCOOMe + HO–.

If the strong nulceophile HO- is used (ie basic conditions) no catalyst is required.
O O
_
CH3 C C + OCH2CH3
CH3 OCH2CH3
_ OCH2CH3
HO
HO
O
CH3 C + HOCH2CH3
_
O
Note that the final carboxylic acid is produced in its conjugate base form (deprotonated), as the
reaction conditions are basic.

Acid-Catalysed
If the weak nucleophile H2O is used, acid catalysis is required (ie acidic) conditions.
Note that the final carboxylic acid is produced in its conjugate acid form (protonated), as the
reaction conditions are acidic.
You may wish to go back and compare these two mechanisms with the mechanisms for
nucleophilic substitution you saw in Block 6, Unit 2.
A useful example of ester hydrolysis involves synthetic surgical staples. A synthetic polymer
called Lactomer is used for closing wounds after surgery. Lactomer is a polyester made from
two compounds (lactic acid and glycolic acid) which occur naturally in our bodies.
HOCH(CH3)COOH + HOCH2COOH HOCH(CH3)COOCH2COOH

Under acid conditions present in biological fluids and tissues the polyester hydrolyses slowly,
releasing harmless lactic acid and glycolic acid.
4.3.5 Amides
Preparation.
From an acid chloride or an acid anhydride with ammonia (to give a 1° amide) or RNH2 (to give
a 2° amide) or R2NH (to give a 3° amide).
O
NH2 + CH3CCl
or
O O
CH3COCCH3
O
COCl + C NEt2

Reactions
Amides are much less reactive (much slower) than acyl chlorides or anhydrides or esters
towards nucleophilic acyl substitution. Therefore, hydrolysis requires strong aqueous acid or
strong aqueous base.
70% aq. H2SO4
NHCOCH3 +
heat
_
HO
Amides are neutral. The absence of basicity and the low reactivity towards nucleophiles are
due to resonance interaction effectively decreasing the availability of the lone pair of electrons
on nitrogen:
O O O
1 1 1
R C R C R C
NR2 NR2 NR2
Amides are very stable an example is nylon which is a synthetic polyamide:
O O O O
at interface
ClC(CH2)8CCl + H2N(CH2)6NH2 _ ClC(CH2)8CNH(CH2)6NH2
HCl
in hexane in H2O

UNIT 5 - AMINES, AMINO ACIDS, PEPTIDES AND PROTEINS

Nitrogen is an important component of many organic compounds. The most common functional
groups in which it is found is amides and amines. Many biomolecules contain nitrogen, including
DNA and proteins.
5.1 AMINES
5.1.1Classification and Nomenclature N
Recall: N is tetrahedral (sp -hybridised) and has the generic structure
3
Amines are classified as: 1° 2° 3° (primary, secondary, tertiary) for

1 2 3 groups (alkyl or aryl) directly bonded to the nitrogen
Compounds with four groups attached to N are also known. The N in such compounds has a
positive charge. Such compounds are called quaternary ammonium salts.
Aliphatic amines: The nitrogen is directly bonded to an sp3 carbon.

Examples: CH2NH2
CH3CH2NH2 (CH3)2NH (CH3)2NCH2CH3
1° 2° 3° 1°
ethylamine dimethylamine N,N-dimethylethylamine benzylamine
Aromatic amines: The nitrogen is directly bonded to an sp2 carbon of an aromatic ring.

1° 3° 1°
phenylamine N,N-dimethylphenylamine 2-aminobenzoic acid
(aniline)
Where the amine is the principle functional group, the suffix amine is used (see Block 1, Unit
2). Where the amine functional group is considered a substituent, the prefix amino is used.
You will only be examined on examples where the amine is the principle functional group,
however an example of how the amino prefix is used can be seen in the examples above.
For secondary and tertiary amines, the second (and third) groups bonded to the nitrogen are
treated as substituents (branches). The prefix N- is used to indicated that the group is directly
bonded to the nitrogen and NOT a branch on the carbon backbone.
Example:
CH3NHCH2CH3 vs NH2CH(CH3)2
N-methylethylamine methylethylamine

5.2 AMINO ACIDS

Amino acids are bifunctional compounds containing both amine O
an amine and a carboxylic acid functional group. Any organic H2N
molecule which has an amine and a carboxylic acid can be called OH
R H carboxylic
an amino acid. In this course the amino acids we consider are acid
variable
α-amino acids because the amine group is found on the adjacent group
carbon (which is called the α-carbon) to the carboxylic acid.
The ‘R’ group varies with particular amino acids; there being 20 common α-amino acids. In this
course you do not need to know and remember all 20 common α-amino acids (we will give you
the structures if needed).
Examples:
R Amino Acid R Amino Acid
–H Glycine (Gly, G) –CH3 Alanine (Ala, A)
–CH2OH Serine (Ser, S) –CH2CO2H Aspartic acid (Asp, D)
–(CH2)4NH2 Lysine (Lys, K) –CH2SH Cysteine (Cys, C)
–CH2Ph Phenylalanine (Phe, F) –CH(CH3)2 Valine (Val,V)
5.2.1 Chirality in Amino Acids

With the exception of glycine (R=H), the α-carbon of an amino acid is a stereogenic centre (it
has four different groups) and hence two enantiomeric forms are possible.
O O
CO2H CHO
H2N H2N
OH OH H2N H HO H
H CH3 H3C H CH3 CH2OH

(S)-alanine (R)-alanine L-alanine L-glyceraldehyde
While (S)/(R) descriptors are systematic nomenclature for most molecules, the nomenclature
for amino acids uses the older L/D descriptors. The reason for this is that amino acids were
some of the first chiral compounds discovered and studied. Their extremely common nature
has meant that we continue to use the classical L/D notation when we talk about their
stereochemistry. Note that these descriptors do NOT relate to dextro or laevo-rotatory light
rotation. Rather they relate to carbohydrate stereochemistry whereby L-amino acids ‘look’ like
the structure of one of the first chiral compounds ever studied L-glyceraldehyde when drawn
in a Fischer projection format (an alternate method of depicting stereochemistry before the
‘dash-wedge’ notation became more prevalent). The two right-most structures above show
alanine (an amino acid) and glyceraldehyde as Fischer projections– notice carbonyl containing
group is at the top and the polar group (amine for alanine or alcohol for glyceraldehde) is on
the left. Please note, you do not need to draw or interpret Fischer projections in this course.
Fortunately for us Nature predominantly uses L-amino acids to build proteins (e.g. in our
bodies). D-amino acids are mainly found in bacteria, which can be good as this uniqueness
allows us to kill bacteria by targeting their D-amino acid pathways without harming ourselves.

Practice Question: Classify and give the systematic name for the following amine:

- Block 6 – Amines Structure
5.1.2 Basicity of Amines

The lone pair of electrons on N can act as a base (to attack a proton) or as a nucleophile (to
attack some other electron deficient nucleus).
N + H A
The higher the pKa for the conjugate acid (ammonium salt), the more basic the amine. For
simple alkylamines, pKa ≈ 10–11 (in aqueous solution).
Amine pKa of Conjugate Acid
NH3 9.26
CH3NH2 10.64
(CH3)2NH 10.73
(CH3)3N 9.79
In aqueous solution, simple arylamines (aromatic amines) are much weaker ( ~ 105 times)
bases than simple alkylamines. This is due to delocalisation of the lone pair of electrons on the
nitrogen into the aromatic ring, making them less available to act as a base.
Within a set of aromatic amines, electron-withdrawing substituents on the aromatic ring
decrease basicity, while electron-donating substituents increase basicity.
NH2 NH2 NH2
< < < aliphatic

amines
NO2 OMe

5.1.3 Preparation of Amines
Substitution reaction (SN) of an alkyl halide with NH3 , RNH2 , or R2NH
_
_ + HO
CH3CH2Br + NH3 Br + CH3CH2NH3 CH3CH2NH2
but then...
CH3CH2NH2 + CH3CH2Br CH3CH2NHCH2CH3 (CH3CH2)3N
and then... _
+
(CH3CH2)3N (CH3CH2)4N Br
So this type of reaction usually results in mixtures.
Note: Aryl halides do not undergo nucleophilic substitution to form an amine:
Br + NH3 Br + CH3NH2
Therefore, the best way to make ArNH2 is to reduce ArNO2 (Block 2)

+
1. Fe / H3O CH3Br
NO2 NH2 NHCH3
-
2. HO
Reduction of a nitrile, amide, imine or oxime with LiAlH4

RC N
O
RCNH2 1. LiAlH4
RCH NH 2. H3O+
RCH NOH
N-Substituted imines and amides give secondary amines and N,N-disubstituted amides give
tertiary amines.
O O
1
RCNHR 1. LiAlH4 1 2 1. LiAlH4
RCNR R
1 +
RCH NR 2. H3O 2. H3O+
Practice Question: How would you prepare propylamine (CH3CH2CH2NH2) from the
following? (More than one step may be required).
O
Br
Br

5.1.4 Reactions of Amines
As a nucleophile with alkyl and acyl halides
For reactions with an alkyl halide (alkylation) see 4.1.3 above.
With an acyl chloride (acylation):
RNH2 + R1COCl
1
R2NH + R COCl
1
R3N + R COCl
Formation and reactions of diazonium ions (Block 4)

(- from primary aromatic amines only). The diazonium ion is not isolated.
O R O OH
carboxylic acid
R derivatives H 3O +
CN
RX
RCOX AlX3 N
AlX3 NO2 NH2 N
CuCN
HNO3 Fe/H+
H2SO4
H3O+
X2
OH
FeX3
X O
nucleophile for NaH
addition/substitution (strong base)
reactions

5.2.1 Acid-Base Properties of Amino Acids
Amphoteric property - Amino acids can act as either acids or bases. In acid solution the overall
charge is 1+, in neutral solution the molecule exists as a zwitterion (neutral charge) and in
basic solution the overall charge is 1–.
O O O
H R H R H R
acidic solution neutral solution basic solution
5.2.2 Reactions of Amino Acids

Amino acids can link together into long chains by forming bonds between the
group of one amino acid and the group of another.
Two amino acids combine to form a dipeptide

e.g. alanine + glycine = Alanylglycine (Ala-Gly)
H2N
O H H
H CH3 - H2O
H2N OH
N
H H H CH3 H O
OH
Naming convention has N-terminal amino acid (free NH2) to the left, C-terminal amino acid
(free CO2H) to the right.
What is the structure of the dipeptide Gly-Ala ?
In practice, the chemistry of amide bond formation is considerably more complex. If you mixed
the two amino acids shown above, you would get a mixture of Gly-Ala and Ala-Gly (and also
Gly-Gly and Ala-Ala). If the side chain contains a reactive functional group (-NH2, -OH etc) then
even more combinations are possible. The controlled formation of peptide bonds has been a
very active area of research over the past few decades.

5.3 PEPTIDES AND PROTEINS

Long chains of amide bond connected α-amino acids are known as peptides or proteins. Chains
less than 50 amino acids are PEPTIDES while > 50 amino acids are PROTEINS. You saw an
example of a dipeptide in the previous lecture.
5.3.1 Protein Function

Proteins have a wide range of biological functions, from structural supports to acting as
hormones and biological messengers where they can be important in regulating normal body
functions.
One example of protein function is when they act as enzymes – here they act as catalysts for
biological reactions. As catalysts they do not alter the equilibrium constant of a reaction nor
do they bring about unfavourable reactions – rather they speed up reactions by lowering the
activation energy barrier: 1010 – 1012 usual acceleration, 1017 very fast. Enzymes play crucial
roles in cell metabolism, reproduction and function. Sometimes however the control of enzyme
function is not what it should be leading to imbalances and disease.
Recent advances in medicinal chemistry have seen the ability to solve the 3-dimensional
structure of enzymes, then model the structure on computers and design inhibitors – small
molecules that bind to enzyme active sites and inhibit the function of the enzyme. Many of
the new pharmaceuticals active against viral infections, influenza and inflammation have been
developed this way.
5.3.2 Protein Structure

As discussed earlier under amide chemistry, the amide (peptide) bond has low reactivity due to
the lone pair of electrons on nitrogen donating in to the carbonyl group, resulting in a certain
amount of double-bond character to the C–N bond. The amide bond is therefore planar with the
N–H oriented 180o to the C=O.
O R H O R H
N N
H
H R H R H
Due to this structural feature of amide bonds and other interactions between the side-chains
(the R groups in the amino acids) proteins exhibit three-dimensional structural organisation
that is termed primary, secondary, tertiary and quaternary structure.
• primary: amino acid sequence in the peptide chain

• secondary: hydrogen bonding alters the local peptide geometry producing coils.
• tertiary: disulfide bonds alter entire protein shape
R SH HS R' S R'
R S
• quaternary: different proteins aggregate to form new structures.
UNIT 6 - RADICALS AND ANTIOXIDANTS
6.1 INTRODUCTION
A radical (also called a free radical) is an atom, molecule or ion that has one or more unpaired
valence electrons. These unpaired electrons make free radicals highly reactive towards other
substances. In Block 1 we saw that radicals can be generated by homolytic bond cleavage.
Recall that in homolytic bond cleavage, one electron from the bond ends up on each of the
atoms which were formerly bonded.
The movement of each single electron is symbolised by a single-headed curly arrow (a “fish
hook”). Please note: this unit is the ONLY place we will use fish hook arrows in the course. In
all the other reactions you have seen, electrons are moving in pairs and we use the normal
‘double-headed’ arrow.
6.2 RADICAL REACTIONS

There are three basic steps in radical reactions: initiation, propagation and termination.
1. Initiation:
Homolytic bond cleavage of a weak bond to generate two radicals. This is usually facilitated by
light (hv) or heat.
eg.
Cl Cl
2. Propagation:
A free radical reacts with a molecule with no unpaired electrons to generate a new radical (and
a new covalent bond).
eg.
H3C H
Note that there is no net change in the number of radical species present.
As each propagation step generates a new radical species, propagation is a repeating cycle and
will keep going until all the starting material is consumed OR until
3. Termination:
Eventually, a radical may combine with a second radical, generating a species with no unpaired
electrons.
eg.
CH3 + CH3
CH3 + Cl
Cl + Cl
In most radical reactions, the concentrations of radical species are low. This means a radical is
more likely to interact with a non-radical (propagation) than with a second radical (termination).
6.3 RADICAL STABILITY
Radicals are, as a general rule, highly reactive. However, some radicals are more stable than
others. The more stable a radical is, the more likely it will survive long enough to encounter
a second radical. Hence, stable radicals are more likely to react via termination compared to
unstable radicals.
Delocalisation (ability to form resonance hybrids) is one factor that increases radical stability.
For example:
O O O O
Delocalisation of the phenol radical – analogous to delocalisation of the phenolate anion (Block
6, Unit 1).
Practice Question: Draw the second resonance structure of the carboxyl radical.
6.4 RADICALS AND ANTIOXIDANTS

Free radicals play an important role in biological systems. Two of the most important free
radicals in biology are the hydroxl radical and superoxide. These are produced in the body as
part of natural, physiological processes, for example as part of the immune response or during
the production of ATP.
H O O2-
As free radicals are highly reactive, build up of free radicals causes damage to biological
molecules. They can cause DNA damage, denature proteins or disrupt lipid membranes. Free
radicals have been implicated in a number of diseases, including cancer, Parkinson’s disease
and Alzheimer’s.

The hydrogen adjacent to an alkene in an unsaturated fatty acid is particularly susceptible to
attack as the resulting radical is resonance stabilised.
O H O
OH
HO HO
O
O O O
O2
HO HO
OH
O O
decomposition
HO
The body protects itself from this damage, often termed ‘oxidative stress’ through the action of
enzymes and antioxidants. For example, vitamin E acts as an antioxidant, reacting with hydroxyl
radicals to form a more stable (more delocalised) radical.
This more stable radical does not do further cellular damage. Vitamin E is fat-soluble and hence
particularly important in protecting lipid membranes from oxidative damage.
O O
H
O O
vitamin E
Free radicals also play important roles in combustion, atmospheric chemistry, polymerisation
and materials chemistry.

REVISION EXERCISES FOR BLOCK 6 Units 4-6
1. Arrange the following in order of decreasing acid strength:

CH2ClCO2H CHCl2CO2H CH2ClCH2CO2H CH3CH2CO2H CC13CO2H
2. Suggest a possible route for the preparation of (CH3)2CHCH2CO2H starting from:

(a) (CH3)2CHCH2OH (b) (CH3)2CHCH2CH2OH
3. Write down the products from the reactions of the following compounds
(a) ethanoyl chloride + sodium ethanoate (sodium acetate)
(b) 2,3-diethylpentanoyl chloride + sodium ethoxide
(c) benzoyl chloride (C6H5COCl) and ethanol
(d) butanoyl chloride and water
(e) ethanoyl chloride + methylmagnesium chloride (2 mol. equiv.) followed by
addition of H3O+
(f) 2-propyl ethanoate + hydroxide
4. Arrange the following in order of increasing reactivity towards nucleophilic substitution:

amide acid chloride acid anhydride ester carboxylic acid
5. Draw all the amines that have the formula C4H11N, and classify them as primary,
secondary or tertiary.
6. Give a specific example of each of the following:

(a) a secondary aromatic amine.
(b) a tertiary aliphatic amine.
(c) a stable diazonium salt.
7. Arrange the following compounds in order of increasing base strength:
NH2 O2N NH2 (CH3)2NH CH3NH2
8. Outline a synthesis for each of the following compounds from the indicated starting
material:
(a) butylamine from 1-bromobutane.
(b) butylamine from 1-butanol.
(c) pentylamine from 1-bromobutane.
(d) propylamine from propanamide
(e) from
NHCH3 NO2
9. Give the products from the reaction of:

(a) propylamine with ethanoyl chloride.
(b) propylamine with excess bromomethane.
(c) p-chloroaniline with HNO2, 0oC

10. Three amino acids are shown below:
O O O
H2N H2N
OH OH HO OH
CH3 NH2
glycine (Gly) D-alanine (D-Ala) L-serine (L-Ser)
a. Identify any chiral centres and classify each one as either (R) or (S).
b. Draw the structure of alanine at pH 3, pH 7 and pH 10.
c. i) Draw the structure of the dipeptide L-ser-D-ala
ii) Draw the structure of the tripeptide D-ala-gly-L-ser
11. Draw the amino acids that make up the tripeptide below (you don’t have to name them):

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CHEM110/Block 6/Functional Groups II/2020 1

BLOCK 6: FUNCTIONAL GROUPS II

Dr Kaitlin Beare (KDB) Prof David Barker (DB)

This handout should be brought to all lectures.

Laboratory Day and Time: Bench Number:

© School of Chemical Sciences The University of Auckland

At the end of block 4, you should be able to:

© School of Chemical Sciences The University of Auckland

Pre-Lecture Reading Lecture 1

1.2 PROPERTIES of ALCOHOLS

1.3 PREPARATION of ALCOHOLS

1.3.1 Alkyl Halide Hydrolysis

1.3.2 (a) Acid Catalysed Addition of H2O to Alkenes

© School of Chemical Sciences The University of Auckland

Want more practice with these concepts? Try BestChoice modules:

1.3.2 (b) Hydroboration-Oxidation of Alkenes

Design of a synthetic route – appropriate choice of reagents.

© School of Chemical Sciences The University of Auckland

Nu- = H- (hydride anion, from NaBH4 or LiAlH4)

1.3.3 Reduction of Aldehyde, Ketone or Ester

(a) Aldehyde or Ketone - Mechanism covered in Block 6, Unit 2

© School of Chemical Sciences The University of Auckland

2 Equivalents of Grignard reagent + Ester or Acid Chloride → 3° alcohol.

© School of Chemical Sciences The University of Auckland

Pre-Lecture Reading Lecture 2

Phenols are named using the root ‘phenol’ adding OH

Want more practice with these concepts? Try BestChoice modules:

1.4 REACTIONS of ALCOHOLS

In these examples, the alcohol is acting as the electrophile.

© School of Chemical Sciences The University of Auckland

1.4.2 Elimination (Recall elimination of alkyl halides, Block 4)

Primary alcohols proceed via E2 mechanism.

Secondary alcohols proceed via either E1 or E2 mechanisms.

© School of Chemical Sciences The University of Auckland

(a) Primary alcohol to an aldehyde (or carboxylic acid)

(b) Secondary alcohol to a ketone

Ketones do not undergo further oxidation.

© School of Chemical Sciences The University of Auckland

2.2 PREPARATION OF ALDEHYDES and KETONES

2.2.2 Friedel-Crafts Acylation of an Aromatic Ring

© School of Chemical Sciences The University of Auckland

2.3.1 Nucleophilic Addition - General Mechanisms

Mechanistically these are either:

© School of Chemical Sciences The University of Auckland

2.3.2 Reduction to an Alcohol with NaBH4 or LiAlH4

2.3.3 Addition of a Grignard Reagent (RMgX)

2.3.5 Addition of Oxygen Nucleophiles

© School of Chemical Sciences The University of Auckland

G Reagent Compound Formed

-OH NH2OH oxime

-NH2 NH2NH2 hydrazone

© School of Chemical Sciences The University of Auckland

An Aside: Changing the Carbon Skeleton

Addition of the cyanide anion or alkylidine anion to a carbonyl

Can you think of any C-C single bond forming reactions?

© School of Chemical Sciences The University of Auckland

Pre-Lecture Reading - Lecture 4

Carbohydrates are a class of compounds of tremendous biological and commercial importance.

Carbohydrates are made by green plants during photosynthesis:

3.1 CLASSIFICATION OF CARBOHYDRATES