Download Organic molecules with functional groups containing oxygen

Organic molecules with functional groups
containing oxygen
alcohols
X =
OH
O
X =
aldehydes
C
H
C,H
X
O
X =
carboxylic
acids
O
X =
C
OH
C
ketones
Key Skills
1. Dealing with structures (Bruice 1.4)
We need to understand the following concepts:
•
Valency: the number of bonds that an atom must have
eg carbon: 4; hydrogen: 1; oxygen: 2
• Bond Concept: a pair of electrons
H
H
H
C
C
H
C
C
To break a bond, the
electron pair has to move
away from the space
between the atoms
C
C
To make a bond, a pair
of electrons has to
move into the space
between the atoms
H
H
• Drawing structures: we can represent a molecule in a variety of ways
Example: ethanol, C2H6O
C
C
OH
Never!! unless you mean
1,1,2,2tetramethylpropanol!
H
CH3
H
H
C
C
H
H
CH2
OH
A bit long
winded – but
good if you
want to use
the structure in
a mechanism
CH3
CH2
OH
OH
H3CCH2OH
Correct –
useful if
space is an
issue
Compact –
it is the
standard
for large
molecules
The ability to “read” and draw structural formulae is an
absolutely essential skill!
Problem
How many hydrogens are on each of the carbons indicated below?
OH
OH
OH
OH
A very, very, very, common mistake!
≠
• What is the molecular formula of each of the above molecules?
• How many hydrogens are on each of the carbons?
• What is the name of each compound?
• Is there any other way of drawing the first structure?
2. Dealing with mechanisms (Bruice 1.18, 3.6)
• A mechanism is a description, in terms of the electrons involved, of how
the reactant molecule(s) changes into the product molecule(s). “Curly
arrows” are used to show how the electrons move during the change.
• Most reactions involve intermediates, the nature of which determine
the type of mechanism involved
reactant
intermediate
product
• Reactions can involve a neutral intermediate with an unpaired electron
(a radical) or a charged intermediate (a cation (+) or an anion (-))
Example: a reaction mechanism involving charged intermediates
H
H
H
C
C
H
H
H
O
H
H
≡
H2SO4
H
H
H
C
C
H
H
H
H
O
H
C
H
H
C
H
+ H2O
+ H
• The arrows are double headed in this case, indicating the movement
of a pair of electrons
• The arrows begin at a definite pair of electrons - a bond or a lone pair –
and move towards a positive charge
• If they move into the space between two atoms, a bond is formed
• If they move out of the space between two atoms, a bond is broken
• If a new bond is formed with a neutral atom, another bond involving
that atom has to be broken
• If an atom gains an electron, it acquires a negative charge; if an atom
loses an electron, it acquires a positive charge
The Chemistry of Alcohols
Functional Group
General
Alcohols
δ−
R
O
R
C,H
δ+
H
functional
group
Key Point: alcohols and water contain
the same functional group (FG)
δ−
O
H
δ+
H
Famous Alcohols
1. Ethanol
• Structure H
H
H
C
C
H
H
O
H
or
H3CCH2OH
or
OH
• World Production (2006): 51 gigalitres (5.1 x 1010litres) – 69% from
the US/Brazil
• Methods of Production
(a) Hydration of ethene: production of ethanol for use as an industrial
feedstock
crude
oil
H
H
C
H
C
+
H
H 2O
H3PO4 on
charcoal
300°C
H3CCH2OH
gas phase
reaction
ethanol produced in this way is a
petrochemical: non-renewable/not
sustainable
(b) Fermentation
C6H12O6
yeast
no O2
H3CCH2OH
+
2CO2
fermentable sugars such as
glucose, fructose or sucrose
(C12H22O11)
sugar
cane
(Brazil)
malting involves the
enzyme
amylase
barley:
production of
ethanol as a
beverage
H2SO4
corn (starch)
(US):
production of
ethanol a a fuel
(c) Cellulosic ethanol
Cellulose is a glucose polymer which makes up 38% of all plant matter but
which cannot be fermented directly
enzymic
hydrolysis
cellulose
glucose
cellulase
materials such as straw, sawdust,
bagasse (residue after extraction
of sugars from sugar cane),
switchgrass (an “energy crop”)
fermentable sugar
(d) Bioethanol production in Ireland
The fluid left when the solids are removed from the milk during the making of
cheese is called whey and contains fermentable sugars. This is currently
the source of all bioethanol produced in Ireland. However the amount of
bioethanol available from this source would not be sufficient to satisfy the
demand for it as a fuel.
The Food vs Fuel Debate: Is bioethanol a green fuel? ≡ Is bioethanol a
sustainable source of energy?
Key question: what is the “energy return on energy invested” - EROEI
sunlight and CO2
• Corn
corn
ethanol
fertilizer (natural gas (CH4) is
one of the raw materials used
in its manufacture), energy
used (machinery/transport/
processing)
• Sugar cane
energy + CO2
The value of corn as an
energy crop is marginal as
its EROEI = 1.34
Much better: EROEI ≈ 8
• Best solution for corn: use grain as food and the straw to produce
cellulosic ethanol
2. Methanol
• Structure
H
H
C
O
H
or
H3COH
H
mixture is known
as syngas
• Method of Production
Stage 1
Stage 2
CH4 + H2O
CO + 3H2
10 - 20 atm
850°C
Ni catalyst
50 - 100 atm
250°C
Cu, ZnO/Al 2O3
CO + 3H2
H3COH
steam-methane
reforming
methanol is thus a
petrochemical
• Uses
(a) Industrial feedstock
(b) Denaturing ethanol: Methanol is toxic - it is added to ethanol to make it
unfit for consumption; this mixture is called methylated spirits
3. Ethylene glycol (1,2-ethanediol)
•
Structure
H
O
H
•
crude
oil
H
C
C
H
H
or
O
H
HO
or
OH
HOCH2CH2OH
Manufacture
H
C
H
C
H O2, 1-2 atm H
200-300°C
H
Ag/Al2O3
H
O
C
H
C
H2SO4, H2O
HO
OH
H
ethylene oxide – an
epoxide or oxirane
• Uses: ethylene glycol is used as antifreeze
once again this
product is a
petrochemical
4. More complicated alcohols
CH3
CH3
CH3
H
OH
OH
OH
H3C
H 3C
CH3
(R)-(+)-citronellol
lemon grass oil
geraniol
rose oil
OH
Something that
is most certainly
not an alcohol!!
Not an
alcohol
CH3
CH3
(1R,2S,5R)-(-)-menthol
peppermint oil
OH
OH
≡
phenol
CH3
≡
cyclohexanol
Check the
number of Hs
on each C!
An
alcohol
Nomenclature of alcohols (Bruice 2.6)
The IUPAC name of an alcohol is based on the name of the alkane from
which it comes, using the name ending -ol
• Identify the longest continuous chain of carbon atoms in the molecule
→ parent name
• Change the name ending from –e to –ol
• Giving the –OH group the lowest number possible, number the position
of attachment of side chains
Examples
1
HO
2
pentan-2-ol or
2-pentanol
1
6
1(6)
6(1)
3(4)
5
HO
2
4-methylhexan-2-ol
or 4-methyl-2hexanol
OH
hexan-3-ol or
3-hexanol
Cyclic alcohols: uses the name of the cycloalkane on which they are
based
OH
cycloheptanol
Alcohols which have more than one OH group: named using the
basic rules and the ending diol, triol, etc., as appropriate
3
HO
1
OH
1,3-butanediol or
butane-1,3-diol
HOCH2CH2OH
1,2-ethanediol or
ethane-1,2-diol
(trivial name:
ethylene glycol)
Classes of alcohol
The division is based on the number of carbons which are attached to the
carbon (*) bonded to the functional group
∗
H3C CH2 OH
Primary Alcohol (1°)
- attached to one
carbon
H3C
∗
CH OH
H3C
OH
H3C
Secondary Alcohol (2°)
- attached to two carbons
H 3C
H3C
∗
H 3C C
OH
methanol
Tertiary Alcohol (3°)
- attached to three
carbons
Physical Properties (Bruice 2.9)
Key Point
1.
δ−
O δ+
R
H
very
polar
δ+
H
δ−
O δ+
H
Solubility of alcohols in water
solubility
(g/100cm3)
alcohol
non-polar
H3C OH
polar
H3CCH2 OH
H3CCH2CH2CH2CH2 OH
H3CCH2CH2CH2CH2CH2CH2CH2 OH
∞
∞
2.3
Key
concept:
like
dissolves
like
0.05
There is competition between the polar and non-polar parts of the molecule
2. The effect of alcohol structure on boiling point (BP)
(a) Boiling point / molecular mass relationship
Molecule
CH3CH2CH2
δ− δ+
O H
CH3CH2CH2CH2
δ− δ+
O H
CH3CH2CH2CH2CH2
δ− δ+
O H
MM
BP (°C)
60
97
74
118
88
138
The BP increases as the MM increases
(b) Boiling point / FG relationship
Molecule
Intermolecular
Bonding
MW
BP (°C)
CH3CH2CH2CH2CH3
VdW
72
36
Dipolar
72
76
Hydrogen
74
118
δ−
δ+ O
CH3CH2CH2C
H
CH3CH2CH2CH2
δ− δ+
O H
The BP increases as the strength of the intermolecular bond increases
General Methods of Synthesising Alcohols
1. Acid catalysed hydration of alkenes (see section on Alkenes;
Bruice 4.5)
H
Basic
Reaction
H
C
H
H2O
C
H
H2SO4
H
H
H
C
C
H
H
O
H
H
H
C
C
H
H
Mechanism
H
H
C
H
H
C
≡
H
H
H2SO4
H
H
C
C
H
H
H
H2O
key intermediate:
carbocation
H
+
H
H
H
C
C
H
H
H
O
H
OH
Problem
The acid catalysed hydration of the following alkene could, in
principle, lead to the formation of two products:
H2C
CCH2CH2CH3
CH3
1. Draw the structures of the two products
2. Using the mechanism on the previous page as a template,
draw a mechanism for the formation of the two products
3. Which of the two will be the major product? Explain your answer.
The reaction proceeds in accordance with the Markovnikov
Principle: the hydrogen adds to the carbon which already has the
most hydrogens. The product formed is said to be the “Markovnikov
product “
2. Hydroboration of alkenes (see section on Alkenes; Bruice 4.10)
Basic Process
H2C
CH2
BH3
H3C
CH2 3B
NaOH/H2O2
H3C
CH2
OH
We are interested in this reaction as a way of making alcohols and so
we need to know that the reaction gives an anti-Markovnikov product:
H3CHC
CH2
hydrogen
adds here
(1) BH3, THF
(2) NaOH/H2O2
CH3CH2CH2OH
The following problems relate to either acid catalysed hydration or
hydroboration-oxidation
Problem: suggest a synthetic route to each of the following alcohols
OH
?
?
H3CCHCH2CH2CH3
OH
?
?
OH
?
?
2 routes
Problem: draw the structure of the product formed in each of the
following reactions:
?
H2SO4, H2O
(1) BH3
(2) NaOH, H2O2
?
3. Substitution reactions of alkyl halides (haloalkanes) (Bruice 8.5)
leaving
group
electrophilic
carbon
nucleophile
δ+
Na
≡
δ− Br
OH
OH
NaOH
+
H 2O
Na
Br
An example of
nucleophilic
substitution
Problem: write a simple curly arrow mechanism for the above reaction
H3CH2C Cl
Experimentally:
haloalkane:
a liquid
NaOH solution
heat
4. Redox reactions (Bruice 10.5, 19.3, 19.1)
Alcohols, ketones/aldehydes and carboxylic acids can be interconverted
using redox reactions
common reducing agent: lithium aluminium hydride
O
H 3C
O
LiAlH4
C
H3C
red
OH
LiAlH4
C
red
H
carboxylic acid
aldehyde
OH
Na2Cr 2O7
ox
ox
O
H3C
CH2
1° alcohol
Na2Cr 2O7
common
oxidising agent:
sodium
dichromate
CH3
C
CH3
LiAlH4
red
ketone
H3C
C
H3C
OH
H
2° alcohol
Na2Cr 2O7
ox
These
reactions allow
some of the
most important
functional
groups to be
interconverted
Overall: using redox reactions to synthesise/prepare alcohols
aldehyde
1° alcohol
ketone
2° alcohol
Discussed in more detail in the “Aldehydes and Ketones” section below
5. Grignard Reaction
Victor Grignard was born in Cherbourg in 1871,
the son of a sail maker. He did his PhD in Lyons,
working with Philippe Barbier who suggested that
he study organomagnesium compounds. He
published his thesis in 1900 and over the
succeeding 10 years he studied the applications of
organomagnesium reagents in synthesis. He
was so successful that he was awarded the Nobel
Prize for Chemistry in 1912. Today, the terms
organomagnesium reagent and Grignard Reagent
are used interchangeably.
Grignard Reactions are important because they are a very good way of
making the C-C bonds which provide the framework for all organic (carbonbased) molecules
haloalkane
What led to
Barbier’s
suggestion?
H3C–Br
solvent such as dry
diethyl ether
H3CCH2-O-CH2CH3
magnesium
dissolves
reaction
magnesium
metal
H3C–Br + Mg
→
δ- δ+
H3C–MgBr
organometallic
compound
What’s in the solution
and what properties
does it have?
methylmagnesium bromide
organomagnesium compound
≡ Grignard Reagent
How are Grignard Reagents formed and why use diethyl ether (Et-O-Et) ?
H3C
Br
haloalkane adsorbs
onto the Mg surface
Grignard Reagent (GR)
forms on the surface
H3C
Mg
Br
surface of piece of Mg
Et
the surface is now free to
react with more haloalkane
H3C
Et
O
Mg
O
Et
Br
Et
The magnesium only has 4 electrons. This is made up to 8 by the
formation of coordinate bonds by two solvent molecules. The solvated
GR is now soluble and moves away from the surface
Problem Tetrahydrofuran (THF) is also a frequently used solvent for
GRs. Why?
Why is the use of a “dry” solvent essential?
H3C
MgI + H2O
CH4 +
MgI(OH)
We have made the GR to react it with something.
Water in the solvent (or indeed in any the
reactants) will react instead with the GR,
converting it rapidly to the corresponding alkane.
Problem The GR/H2O reaction belongs to what class of reaction?
(Hint: what is being transferred in the course of the reaction?)
Reactivity of Grignard Reagents
What sort of reactions would we expect for GRs?
Key bond in the GR – always draw the GR in this way so as to
emphasise the importance of the Mg-C bond
δ−
H 3C
δ+
MgI
The introduction of a Mg atom inverts
the polarity present in the haloalkane
we started with:
δ+ δ−
H3C
The carbon has a partial
negative charge because of the
electronegativity difference
between carbon and
magnesium. It has carbanion
character and acts as a
nucleophile.
I
The GR will thus react with
molecules containing an
electrophilic atom – an
atom with a positive or
partial positive charge, eg a
carbon with a δ+ charge
What sort of molecules do GRs react with?
O
δ+
H
C
O
C
δ−
δ−
O
δ+
C
δ−
aldehydes
ketones
N
O
δ−
C-N multiple
bonds
O
esters
δ−
δ+
δ+
δ+
epoxides
(oxiranes)
δ−
δ+
δ−
O
C
O
carbon
dioxide
The molecules in red all react with Grignrd Reagents to give alcohols
Using the Grignard Reaction to make alcohols
• Tertiary alcohols: the reaction of a GR with a ketone
H3C
CH3
δ+C
O δ−
δ−
H3C
δ+
MgBr
Stage 1
Mg + H3CBr
Stage 2
H3C
O
C
H3C
CH3
MgBr
H2SO4
H3C
OH
+
C
H3C
CH3
Although some
simple GRs (such
as this one) are
available
commercially, we
usually have to
make them
magnesium
salts
3° alcohol
Acid (H+) is added at the end of
the reaction to convert the
alcohol salt to the alcohol
The reaction is an
example of a
nucleophilic addition
• Tertiary alcohols: the reaction of Grignard Reagents with esters
O
δ−
+ 2
H3CCH2 δ+C
OCH3
δ− δ+
Mg Br
H3CH2C
C
HO
This reaction involves 2 moles of GR and the introduction of two”R” groups
from the GR
This reaction can be used to make any 3° alcohol in which two of the R
groups are the same
Mechanism of the reaction of a Grignard reagent with an ester
H3CCH2
δ+
C
δ−
O
OCH3
δ−
Ph
MgBr
δ+
O
H3CCH2
C
MgBr
H3CO MgBr
O
+
Ph
H3CCH2
C
OCH3
Ph
Ph
MgBr
OH
H3CCH2
C
Ph
Ph
Problem: write a simple mechanism for the second stage of the reaction
Problem: the 3° alcohol shown can be prepared by
the reaction of H3C-MgBr with (a) a ketone and (b) an
ester. Provide structures for both starting materials
OH
Ph
C
CH3
CH3
• Secondary alcohols: the reaction of a GR with an aldehyde
aldehyde
H
CH3
δ+ C
+
O δ−
δ−
H3CH2C
δ+
MgBr
H
CH3
C
HO
CH2CH3
2°
alcohol
Problem: using the mechanism on the previous page as a template, write
a simple mechanism for this reaction
• Primary alcohols: the reaction of a GR with the simplest aldehyde,
methanal (formaldehyde)
methanal
H
H
δ+C
O δ−
δ−
+ H3CH2C
δ+
MgBr
H
H
C
HO
CH2CH3
1°
alcohol
Problem: using the mechanism on the previous slide as a template, write
a simple mechanism for this reaction
• Primary alcohols: the reaction of Grignard Reagents with epoxides
(oxiranes)
δ+
H2C
δ−
O
O
CH2
H3CH2C
δ−
H2C
CH2
OH
MgBr
H
H2C
H3CH2C
MgBr H3CH2C
δ+
CH2
1° alcohol
This reaction is regiospecific because the following epoxide gives a
product resulting from attack of the nucleophilic GR at the less
sterically hindered carbon of the three-membered ring
δ+
HC
H3C
O
δ+
CH2
Ph
δ−
MgBr
δ+
H3C
OH
CH CH2
Ph
OH
+
H2C
CH
H3C
not
formed
formed
Ph
Reactions of Alcohols: overview
nucleophilic
oxygen
R
δ−
O δ+
H
acidic hydrogen
Reactions of alcohols
1. Water like
reactions
H
O
H
1/2 H2↑ + Na
+ Na
OH
weakly acidic hydrogen
H 3C
O
H
1/2 H2↑ + Na OCH3
+ Na
2. Redox reactions (see “General Methods of Synthesising Alcohols;
Reaction 4” above)
O
Na2Cr 2O7
1° alcohol
CH3 CH2 OH
H3C
H3C
C
OH
H
ox
aldehyde
H
O
Na2Cr 2O7
C
2° alcohol
ox
H3C
H3C
ketone
C
CH3
Problem Assign an oxidation to the indicated C-atom and confirm that
this changes during the reaction.
3. Acid catalysed elimination reactions (dehydration) (see “Alkenes”
above)
H
H
H
C
C
H
H
H ≡
O
H
H
H2SO4
H
H
H
C
C
H
H
H
H
O
H
C
H
H
C
H
+ H2O
+ H
• This is an elimination reaction: a small molecular unit (H2O) is lost and a
multiple (double) bond is formed
• This elimination can also be heterogeneously catalysed by alumina
(Al2O3)
• The acid catalyst converts a poor leaving group (OH) into a good leaving
group (H2O)
• This mechanism is known as an E2 mechanism as the alkene π bond
forms and the bond to the leaving group beaks, at the same time. It is
the counterpart of an SN2 reaction
R
Relative ease of
dehydration
R
C
H
OH > R
R
C
H
OH
> R
R
3°
C
OH
H
2°
1°
3° and 2° alcohols are easier to dehydrate because they can do so via a
different route, the E1 mechanism. Paralleling the SN1 mechanism this
involves the formation of a carbocation intermediate:
CH3
H3C
2°
C
H
H2SO4
OH
H
H3C
H3C
C
H
H3C
H
O
H2C
H
The intermediate formed is a 2° carbocation. A 3°
alcohol would form an even more stable 3°
carbocation and so is more reactive. A 1° alcohol
will not react by this E1mechnism as the 1°
carbocation it would give is too unstable to form; a
1° alcohol will react via the E2 mechanism.
C
H
+ H2O
H
H
CH3
C
H
C
+ H
H
4. Conversion to haloalkanes
• These are substitution reactions. 2° and 3° alcohols react via an
SN2 mechanism, whereas 1° alcohols follow an SN2 route
CH3
CH3
H3C
C
H
OH
HBr
H3C
OH
C
H
Br
+ H2O
I
HI
+ H2O
• Phosphorous trihalides are efficient alternatives to the hydrogen halide
H3CCH2CH2CH2OH
PBr 3
H3CCH2CH2CH2Br
Problem Write a simple SN1 mechanism for the reaction of 2-propanol
and HBr shown above.
5. Reaction of alcohols with carboxylic acids: ester formation
δ+
H3C C
O
δ−
+
OH
H3CCH2OH
H2SO4
O
H3C
C
+
H2O
OCH2CH3
More information on this very important reaction is given in the section
on Carboxylic Acids below
Ketones and Aldehydes: the chemistry of the carbonyl group
Functional Group
R
Ketones
R
δ+ δ−
C O
R
C,H
R
functional
group
δ+ δ−
C O
Aldehydes
H
Key Points
• the chemistry of ketones and aldehydes is the chemistry of the
carbonyl group and so they are considered together
• the only real difference between the two is in terms of oxidation – the
aldehyde group is the most easily oxidised FG of all. Oxidation involves
the H-atom attached to the carbonyl group and so we can include this
atom in the FG of the aldehyde
Famous aldehydes
O
C
HO
O
H
C
H
O
H
H3C
methanal
(formaldehyde)
vanillin
OCH3
C
H
ethanal
(acetaldehyde)
air pollutants: photochemical smog
Famous ketones
H3C
O
H3C
C
CH3
CH3
CH3
O
O
CH3
H3C
O
propanone
(acetone)
solvent
camphor
H3C
CH2
(R)-(-)-carvone
spearmint oil
H 3C
CH2
(S)-(+)-carvone
caraway seed oil
Nomenclature of ketones and aldehydes
All the usual rules apply
• Name ending for aldehydes: al
• The carbon of the aldehyde FG is always given the number 1
• Name ending for ketones: one
• The carbon of the ketone group is given the lowest number possible
Examples of aldehyde nomenclature
O
H
C
H3C
H
C
H2
C
CH3
O
hexanal
C
H
H
C
C
H
O
O
3-methylbutanal
butanedial
Examples of ketone nomenclature
C
O
2-hexanone
H3C
C
H2
H2
C
C
H2
C
CH3
C
H2
O
7-methyl-4-octanone
not 2-methyl-5-octanone
CH
O
C
CH3
H3C
3-methylcyclobutanone
Physical Properties of aldehydes and ketones
Boiling Point (BP)
Intermolecular bonding (----) is of
the dipolar type => BPs are higher
than for alkanes (VdW) but not as
high as for alcohols (H-bond) (see
table in “Alcohols” section )
Solubility in water
R
(H)R
R
δ
C
Cδ
δ
O
Oδ
(H)R
non-polar
• As with alcohols there is
competition between the polar and
non-polar part of these molecules
R
δ
C
δ
O
(H)R
polar
• If R is small (few C/H): very soluble in water
• As the number of C/H increases, the solubility decreases
Preparation of aldehydes and ketones
Redox Reactions
Oxidation of alcohols (see “Preparation of Alcohols” above)
Ketones
K2Cr2O7
2° alcohol
→
ketone
O
OH
Na2Cr 2O7
H3CCO2H
Aldehydes
1° alcohol
K2Cr2O7
→
K2Cr2O7
[aldehyde]
→
carboxylic acid
The problem here is that as aldehydes are so easily oxidised, it is difficult to
stop the reaction at the aldehyde stage. Special reagents/conditions have to
be used to prevent the aldehyde being converted to the carboxylic acid
One approach is to make use of the fact that the BP of an aldehyde is lower
than that of the alcohol from which it comes. A simple aldehyde such as
ethanal can be distilled out of the reaction mixture as it is formed and before
it can be oxidised further
distilled out
O K2Cr2O7
K2Cr2O7
CH3
CH2
OH
CH3
C
O
CH3
H
C
H
Reactions of ketones and aldehydes
General Expectations
δ−
Electrophilic carbon
which can be attacked
by nucleophiles
resulting in
nucleophilic addition
O
δ+C
α
H
The hydrogen atoms
on the α-carbon are
weakly acidic. They
can be removed by a
strong base to give a
carbanion (C-)
Chemistry of the carbonyl
group: (1) nucleophilic
addition to carbonyl group
and (2) carbanion based
reactions at α-carbon
Problem: (a) what sort of alcohol is formed from the reaction of a
ketone with a GR
(b) provide an example of this reaction
Problem: (a) what sort of alcohol is formed from the reaction of
methanal with a GR
(b) provide an example of this reaction
(c) write out the mechanism of the reaction you provided
Relative reactivity of aldehydes and ketones in terms of nucleophilic
addition
• The process involves a nucleophile attacking the electrophilic carbon
of the carbonyl group
• The larger the δ+ charge on this carbon, the more attractive it is to the
nucleophile and the more reactive the ketone/aldehyde.
Nu
<
R
O
δ−
Nu
δ+
H
R
O
<
R groups such as CH3
are electron donating
groups (induction).
This reduces the size
of the δ+ charge on
the C-atom of the
carbonyl group
δ−
<δ+
R
Aldehydes are thus
more reactive than
aldehydes for
electronic reasons
• Large groups attached to the carbonyl carbon block the approach of
the nucleophile and so reduce reactivity for steric reasons: aldehydes
are more reactive than ketones for steric reasons
2. Nucleophilic addition with primary amines and derivatives of primary
amines
H
H
R
R
amines
H
N
R
H
N
R
H
R
N
H
Primary
(1°)
Ammonia
N
R
Secondary
(2°)
Tertiary
(3°)
The reaction of ketones/aldehydes with 1° amines: imine formation
H3C δ+
C
H3C
H
δ−
O + HN
R
electrophile
H+
nucleophile
nucleophilic addition
H3C
O
H
H3C
C
H3C
C
N
H
R
Imine (Schiff
base)
H3C
N
+ H2O
R
elimination
Overall: nucleophilic
addition-elimination
Nucleophilic Addition
1. Grignard Reaction (see “Preparation of Alcohols” above)
aldehyde
H
Ph
δ+ C
+
O δ−
δ−
H3CH2C
Key step in the nucleophilic
addition mechanism
H
δ+
MgBr
Ph
C
HO
CH2CH3
2°
alcohol
H
Ph
δ− CH2CH3
δ+ C
O δ−
electrophile
Problem: Write out the
mechanism in full for this
aldehyde /GR combination:
δ+ MgBr
nucleophile
H3C
H
HCH2C
H3C
MgCl
C
H3CH2C
O
Mechanism for imine formation
H3C
H
H3C
C
C
O
H3C
OH
H
HN
R
H3C
H3C
OH
C
H3C
NH H
R
+ H
H
H3C
H3C
C
N
H3C
C
R
H3C
+ H
H+: acid catalyst
H
H3C
R
H3C
N
+ H2O
O
H
H3C
O
H
N
H
C
C
N
H
H3C
R
Overall this is a nucleophilic
addition-elimination reaction
R
Evidence for the proposed mechanism: effect of pH on the reaction of
acetone with methylamine
second
order rate
constant, k
Reaction slow: too
much H+, resulting in
protonation of the
amine, removing its
nucleophilic properties:
+
RNH2 H
RNH3+
1
2
3
4
pH
5
6
7
Reaction slow: not
enough H+ to
protonate the
neutral tetrahedral
intermediate. This
is required so that
a good leaving
group (H2O) is
available
Related reactions of 1° amines
R δ+
C
(H)R
R
δ−
O +
NH2 NH2
N
C
(H)R
hydrazine
+
NH2
a hydrazone
O2N
R δ+
C
(H)R
δ−
O +
H2O
O2N
R
H
NH2 N
C
NO2
N
H
N
NO2
(H)R
2,4-dinitrophenylhydrazine
R δ+
C
(H)R
δ−
O +
a 2,4-dinitrophenylhydrazone
R
NH2 OH
C
(H)R
hydroxylamine
+
N
OH
an oxime
H2O
Problem: using H2O as B
write out a detailed
mechanism for the reaction
of the following:
Problem: Write out the
structure of the product
formed by the following:
Problem: Draw the structures
of the ketone, or aldehyde, and
amine derivative that would be
required to form the following:
C
O
C
O
NH2CH3
H
H3C
H2N
H2CH3C
H3C
C
H
N
HO
CH3CH2
N
C
Ph
4. The reaction of aldehydes and ketones with hydride ion: reduction
(see “Preparation of Alcohols” above)
The reduction of the carbonyl group in an aldehyde or ketone using metal
hydride reagents, such as sodium borohydride or lithium aluminium hydride,
is effectively a nucleophilic addition process in which the nucleophile is the
hydride ion, H-.
O
H3CH2CH2C
C
(a) NaBH4
H
(b) H
+
O
H3CCH2CH2CH2
HO
(a) LiAlH4
(b) H+
H
OH
Mechanism of hydride reduction of ketones/aldehydes
Key Point: sodium borohydride
and lithoum aluminium hydride are
synthetically equivalent to a
hydride ion
NaBH4
≡
LiAlH4
≡
H
nucleophile
Mechanism
δ−
O
R
δ+ C
H
R
O
R
H
C
R
+
H
HO
R
H
C
R
The reduction reaction fits in with the nucleophilic addition group of
reactions
5. The reaction of ketones and aldehydes with alcohols
This is a reaction with considerable biological importance
δ−
O
δ+
H
C
+
H3COH
H+
OH
H
R
C
OCH3
H+
δ+
R
O
C
+
R
H
H3COH
H+
OH
R
C
C
OCH3
R
R
a hemiacetal
δ−
OH
OCH3
R
a hemiketal
an acetal
H+
OH
R
C
R
a ketal
OCH3
So how does this reaction happen?
δ−
δ+
R
H+
O
C
O
H
R
C
H3C
R
H
O
R
C
H
H3CO
+
acetal
R
H+
H 3C
C
H3CO
H
C
O
OH
H
H
R
C
H
H3CO
hemiacetal
H
H
OCH3
H+
OH
H
H
OCH3
+
O
R
CH3
C
H3CO
H
H
R
OH
C
H
H3CO
hemi => half
Problem: write out the mechanism for the reaction of ethanol with ethanal
Problem: write out the mechanism for the reaction of methanol with acetone
(propanone)
So why are these reactions important?
Carbohydrates are extremely important molecules with a very wide range of
biological activity. Their behaviour depends on the fact that they can exist
in both an open chain and a ring form.
The difference between intermolecular and intramolecular reactions
Intermolecular reaction: the reactions on the previous slide are
intermolecular as the interacting functional groups are in separate,
independent molecules
Intramolecular reaction: the reaction involves functional groups which
are in the same molecule
chain of atoms
connecting the
two functional
groups
Y
X
Y
reaction
X
new bond
formed
In most cases intramolecular reaction lead to the formation of a ring
Problem: in terms of thermodynamics, intramolecular reactions enjoy a
certain advantage. What is it?
Ring and open chain forms of D-glucose
RO
R
H
OH
H OH
H O
HO
HO
H
H
OH
OH
H
H
C
O
intramolecular
hemiacetal
formation
RO
R
H
H OH
H
C
OH
HO
C
H
H
C
OH
H
C
OH
H O
HO
HO
H
H
OH
H
CH2OH
α-D-glucose
open chain
form
OH
β-D-glucose
The formation of the ring form of a carbohydrate is an example of
hemiacetal formation
OH
Reactions at the α-carbon: carbanion/enolate chemistry
Key point: α-hydrogen atoms are acidic
B
most important resonance form:
negative charge on
electronegative oxygen
H
H2C
base
C
O
CH3
H2C
C
H2C
CH3
C
CH3
O
O
H2C
enolate
≡
carbanion
C
O
CH3
resonance
hybrid
The α-hydrogens are acidic because the anion formed is resonance
stabilised
Where does the term enolate come from?
Ketones (and aldehydes) exist as an equilibrium mixture of two isomeric
forms which differ only in the position of a hydrogen atom. These isomers
are known as tautomers and the equilibrium as a tautomeric equilibrium
en
H3C
C
CH3
O
keto form
H2C
C
CH3
OH
ol
enol form
• Most simple ketones/aldehydes contain only a tiny amount of the
enol form (~1%)
• An enolate is the negative ion obtained by removing a proton from
an enol
α-Carbon Reactions of Ketones and Aldehydes
1. α-Alkylation of ketones and aldehydes
Ketones and aldehydes are not strong acids and in most cases
NaOH and related bases are not basic enough to remove an α-H.
A commonly used strong base is lithium diisopropylamide (LDA)
N
Li
≡
R2N Li
O
Basic α-alkylation reaction
R
O
R
H
LDA
R
R
R'Hal
R'
Mechanism of α-alkylation
C-C bond formed
O
I
CH3
O
O
H3C
H
+
I
Li
R2N
Li
+ R2NH
substitution
reaction
The carbanions/enolates formed by abstraction of an α-H atom can also get
involved in addition reactions
3. The aldol addition reaction
In this reaction the carbonyl group of an aldehyde or ketone provides
both the electrophile and the nucleophile component
R
O δ−
O
O
H
H
H
H
nucleophile
δ+
R
R
H
electrophile
The Aldol Reaction illustrates how versatility of the carbonyl group in
terms of reactivity and explains why it is the most synthetically
important of all the functional groups
Typical Aldol Reaction
unit 1
O
2 H3C
C
OH
NaOH
H
H3C
unit 2
O
HC
ol
Things to note:
conjugated system
C
CH3
H
H3C
+ H2O
H
O
C
C
H
CH3
ald
• It’s a dimerization
• It’s a C-C bond forming reaction
• The name of the reaction comes from the nature of the product – an aldol
• Ketones react more slowly because the reaction involves a nucleophilic
addition to the C=O of one of the reacting units (see above)
• The product is easily dehydrated as this results in the formation of a very
stable conjugated system – a double-single-double bond arrangement.
This dehydration often occurs under the reaction conditions used for the
Aldol Addition Reaction – so we never see the aldol.
Mechanism of the base promoted Aldol addition reaction
H
H2C
O
O
O
O
C
C
CH
C
H2C
H
O δ−
H
OH
H3C
C
δ+ H
H
H3C
C
H2
aldol
OH
H
H3C
+
new C-C bond
OH
O
CH
C
C
H2
HO
H
The overall process is known as the Aldol Condensation if dehydration
occurs at the same time
OH
H3C
HC
trans isomer
major product
O
H
C
C
H
H3C
conjugated system
H
O
C
C
C
H
+
OH
+
H 2O
O
C
C
C
H
H
H
H
H
CH3
+
HO
cis isomer
minor product
Condensation Reaction: two functional groups combine, eliminating a
small molecule – often water
Problem: write down the structure of the aldol addition product that
would be formed by the following
O
H
O
CH3CH2
CH2CH3
Problem: what aldehyde or ketone would be required to make the
following:
H3C
H
2-ethyl-3-hydroxyhexanal
Ph
Ph
O
The Mixed (Crossed) Aldol Reaction
All of the Aldol Reactions considered so far have been dimerizations – they
have involved a molecule reacting with another molecule identical molecule
A
+
A
→
2A
So wouldn’t the range of molecules we could make with this reaction be
greatly increased if we reacted a ketone/aldehyde with a ketone/aldehyde
with a different structure?
H
H3C
H3C
H
+
O
O
H
H3C
- H2O
HO
CH3 O
H
H3C
CH3
In principle yes – but there is a problem with such mixed (crossed aldol
reactions
O
The problem with Mixed Aldol Reaction
Most Mixed Aldol Reactions result in a complex mixture of products and so
are of no synthetic value. Why?
There are really 4 reactants involved in the reaction outlined above. Why?
Possible combinations
a
H
Products formed:
H
O
O
H
H3C
OH
b
c
H
O
d
H
b
H
H2C
CH2
CH2
O
CH3
CH3
H
O
OH
H
CH3 H
CH3
H
c
O
H
CH3
H
H
a
OH
d
O
H
CH2
H
H
CH3
H
OH
O
CH2
CH2
Problem: write out a simple mechanism for the formation of (a), (b), (c)
and (d)
Problem: write out the structures of the products that would be obtained
if dehydration of (a), (b), (c) and (d) occurred. You should get more than 4
products. Why?
Synthetically useful Mixed Aldol Reactions
• Mixtures are formed in Mixed Aldol Reactions because both carbonyl
compounds have α-hydrogens.
• Mixed Aldol Reactions can be controlled in a variety of ways. They are
for example synthetically useful if only one of the two reactants has an αhydrogen – this is the situation if one of the reactants is an aromatic
aldehyde:
O
H3C
CH3
+
H
NaOH
HO
H
CH3
H
NaOH
CH3
O
O
H
Problem: one other product could be formed in the Aldol Condensation
Reaction involving these two molecules. What is it?
Problem: draw the structure of the Aldol Addition product that would be
obtained from benzaldehyde and ethanal, and of the major product
resulting from the corresponding Aldol Condensation Reaction.
O
Carboxylic Acids
H
C
Famous carboxylic acids
O
O
H3C
H
C
Hexanoic Acid
(Caproic Acid)
C
C
O
C
C
Methanoic Acid
(Formic Acid)
C
OH
C
H
H
Benzoic Acid
CH3
O
H 3C
H
C
OH
OH
Ethanoic Acid
(Acetic Acid)
H
OH
HO
H
CO2H
(S)-(+)- Lactic Acid
HO2C
CO2H
HO
CO2H
Citric Acid
General Formula
O
R
C
Functional
Group
OH
Nomenclature of carboxylic acids
•
Name ending: oic acid
•
The carbon of the acid FG is always given the number 1
•
All the usual rules apply
Problem:
(a) Name the following acid:
(b) Draw the structure of the following
acid: 2,3-dimethylpentanoic acid
O
H3C
H3C
OH
Physical Properties
δ
O
R δC
C,H
non-polar
O
δ
H
δ
very polarpossibility of
hydrogen bonding
• BP is high because of strong intermolecular forces
• Water solubility
R small or medium: complete water solubility (like dissolves like)
R large: lower water solubility
• In non-polar solvents: carboxylic acids form dimers (two unit systems)
δ
O
H3C
δ
H
O
C
C
O
H
δ
O
δ
CH3
Preparation of carboxylic acids
Special case: acetic acid (ethanoic acid)
H
H
C
H
C
H
O2
H3C
catalyst
O2
H3CCH2CH2CH3
H3C
catalyst
H3COH + CO
catalyst
O
O2
H 3C
catalyst
C
H
C
OH
O
C
OH
O
H3C
O
C
All reactions occur in the
gas phase (high T and P)
and involve heterogeneous
catalysts
OH
World demand is 6.5 million tonnes / year: 1.5 million tonnes come from
recycling and most of the rest from petrochemical feedstocks (as above).
Used in producing polymers, pharmaceuticals, dyes, agrichemicals, etc.
General methods: redox reactions (see Preparation of Alcohols above)
Chemical Reactions
1. Carboxylic acids are acidic!
(a) In water they ionize to give H+ ions (protons), the active ingredients of
acids
O
O
They are weak acids as
dissociation / proton
H3C C
H3C C
+ H+
donation is partial
OH
O
Why are they acid at all? The carboxylate anion is stabilized by
resonance and so is happy to form.
resonance
forms
O
H3C
C
O
H3C
O
C
O
≡
O
H3C
C
O
Resonance hybrid: actual structure of the
anion - very stable as the charge is not
carried by a single atom
(b) Any other factor which reduces the electron density in the carboxylate
anion, makes it easier for it to form and so increases the acidity of the acid
eg the presence of an electronegative (EN) atom such as F
OH
H2C < C
C
F
O
<
H2C
O
O
F
The inductive effect of the F
atom draws some of the
electron density away from
the carboxylate ion stabilizing
it further and thus increasing
the acidity of the acid
Increasing the number of EN atoms further increases the acidity:
OH
H3C
C
O
< XH2C
OH
< X2HC
C
O
OH
< X3C
C
O
OH
C
O
Carboxylic acids undergo the standard reactions of acids
(a) Reaction with metals
O
H3C
C
+
O
Na
H 3C
OH
Compare with
+ 1/2 H2 ↑
C
O Na
HCl
+
Na
Na Cl
+
1/2 H2
(b) Reactions with bases
H3C
H3C
O
+
CH C
H3C
Compare with
CH C
KOH
H3C
OH
HCl
O
+
KOH
K Cl
O K
+
+ H2O
1/2 H2O
2. Redox reactions
Carboxylic acids can be reduced to aldehydes (see Preparation of
Alcohols above) .
3. Conversion to carboxylic acid derivatives
O
O
O
anhydride
R
R
P2O5
(-H2O)
H2O
O
R
C
OH
1
R OH, H
O
R
R
OR1
H+, H2O
NaOH
H2O
SOCl2
H2O
O
+
R1NH2
Cl
acyl chloride or
acid chloride
ester
A carboxylic acid
derivative can be
made from the parent
acid and converted to
it by reaction with
water (hydrolysis)
Reactivity: acyl chloride >
anhydride > ester > amide
O
O
R
NH2
amide
R
acyl group
The formation of a carboxylic acid derivative– a detailed look:
esterification of a carboxylic acid
H3C
δ+
O
δ−
+
OH
H3CCH2OH
H2SO4
O
H3C
+
H2O
OCH2CH3
• One of the problems with using this type of reaction to make esters is
that its equilibrium constant is close to 1 and so at equilibrium only
about 50% of the starting materials have been converted to product
• If we are trying to make an ester with a simple alcohol (eg methanol,
ethanol, etc.), we can make use of the Principle of Le Chatelier to force
the reaction to go to completion. If use a large excess of alcohol the
reaction will move to the right-hand side to try to remove it and in so
doing will convert almost all of the carboxylic acid to the ester. The
excess alcohol is easily removed afterwards as its boiling point will be
lower than that of the product
• This won’t work if the alcohol is expensive or if it is difficult to remove
after the reaction.
Ester formation: the mechanism
tetrahedral intermediate
H
H3C
δ+
O
δ−
H3C
O
H3C
H
OH
OH
OH
CH2CH3
OH
H
H
O
O
+
H3C
O
HO
The catalyst converts the δ+ into a whole +,
making the carbon more electrophilic and
more attractive to the nucleophilic alcohol
H2O
+
H
OCH2CH3
H3C
CH2CH3
O
HO
The catalyst is
regenerated
CH2CH3
H
A second example of the conversion of a carboxylic acid into a
carboxylic acid derivative: acyl chloride formation
δ−
O
O
Cl
H 3C
tetrahedral intermediate
O
H
O
S
δ+ Cl
H 3C
O
O
Cl
acyl
chloride
+ SO2 +
Cl
S
O
Cl
Cl
O
H3C
O
H
thionyl
chloride
O
H3C
O
H 3C
Cl
Cl
+
Cl
+
H
H
δ−
O
O
O
S
S
O
δ+
Cl
H3C
O
S
Cl
Cl
a gas: leaves the
reaction mxture as
it is formed
tetrahedral
intermediate
good leaving
group
acyl group
Nucleophilic Acyl Substitution
This term describes the reactions of carboxylic acids and
their derivatives that we have been considering above:
δ−
O
O
δ+
R
Y
R
O
X
+
X
R
Y
O
R
X
Y
tetrahedral
intermediate
Examples
Acid → ester : OH substituted by OR
Acyl chloride → amide: Cl substituted by NH2
Acid → acyl chloride: OH substituted by Cl
All these reactions
involve the substitution
of the group X
attached to the acyl
group by a nucleophilic
group Y
Key points in relation to nucleophilic acyl substitution
• If X- is not a good leaving group then Y- leaves again and we are right
back where we started.
• HO- is not a good leaving group and so carboxylic acids are relatively
unreactive in terms of nucleophilic acyl substitution
• In the conversion of the acid to the acyl halide using SOCl2, the success
of the reaction is based on replacing the OH with OS(O)Cl which is a much
better leaving group. The acid is said to be activated towards nucleophilic
acyl substitution by this replacement.
• The fact that Cl- is a good leaving group accounts for the reactivity of
acyl chlorides in terms of nucleophilic acyl substitution
Activation of carboxylic acids for nucleophilic acyl substitution in
biosynthesis
• Biosynthesis is the process of making molecules in biological systems
– for example, in a cell
• The carboxylic acid group is a common component in biological
molecules which thus can use nucleophilic acyl substitution as a building
tool
• The problem is that activated carboxylic acids – such as acyl chlorides
would not survive in the aqueous environment in which biosynthesis takes
place
• Nature activates carboxylic acids in a different way - by converting them
into acyl phosphates or acyl pyrophosphates
Use of acyl phosphates and acyl pyrophosphates in biosynthesis
good leaving groups
O
R
O
O
P
O
O
O
R
acyl phosphates
O
O
O
P
P
O
O
O
O
acyl pyrophosphates
Using these activated carboxylic acids in nucleophilic acyl substitution
δ−
O
δ+
R
O
O
O
P
O
O
R
Y
O
O
P
O
O
O
O
+
R
Y
O
P
O
≡
O
Y
phosphate
ion
PO43-
Recommended Text
Organic Chemistry (5th Ed.),
Paula Y. Bruice
Pearson Education/Prentice Hall
Library: 547 BRU