organic molecules with functional groups containing …€¦ · · 2008-11-20organic molecules...
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Organic molecules with functional groups containing oxygen
alcohols
carboxylic acids
aldehydes
ketones
C,H
X
X =
X =
X = C
O
C
H
O
C
OH
O
OH
X =
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 C C
H
H
H
H
H
H
C CC C
To break a bond, the electron pair has to move
away from the space between the atoms
To make a bond, a pair of electrons has to
move into the space between the atoms
OH
• Drawing structures: we can represent a molecule in a variety of ways
Example: ethanol, C2H6O
Never!! -unless you mean
1,1,2,2-tetramethylpropanol!
A bit long winded – but good if you want to use
the structure in a mechanism
Correct –useful if
space is an issue
Compact –it is the
standard for large
molecules
CH3
CH2
The ability to “read” and draw structural formulae is an absolutely essential skill!
C C OH H C C OH
H
H
H
HH3CCH2OH
CH3 CH2 OH
OH
OH
OH
Problem
How many hydrogens are on each of the carbons indicated below?
A very, very, very, common mistake!
OH
≠
• 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)
• Most reactions involve intermediates, the nature of which determine the type of mechanism involved
• Reactions can involve a neutral intermediate with an unpaired electron (a radical) or a charged intermediate (a cation (+) or an anion (-))
productintermediatereactant
• 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.
• 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
H C C O
H
H
H
H
H2SO4
H
H
H H C C O
H
H
H
H
H
H
C C
H
H
H
H
+ H2O+ H
≡Example: a reaction mechanism involving charged intermediates
• 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
RO
Hδ+
δ−
Functional Group
HO
Hδ+
δ−
General Alcohols
Key Point: alcohols and water contain the same functional group (FG)
C,H
functionalgroup
R
Famous Alcohols1. Ethanol
H C C O
H
H
H
H
H OH
C C
H
H
H
H
+ H2O H3CCH2OH
H3PO4 oncharcoal
300°C
or
• World Production (2006): 51 gigalitres (5.1 x 1010litres) – 69% from the US/Brazil
• Structure
• Methods of Production
(a) Hydration of ethene: production of ethanol for use as an industrial feedstock
H3CCH2OH or
gas phase reaction
crude oil
ethanol produced in this way is a petrochemical: non-renewable/not
sustainable
(b) Fermentation
+ 2CO2C6H12O6yeastno O2
H3CCH2OH
fermentable sugars such as glucose, fructose or sucrose
(C12H22O11)
sugar cane
(Brazil)
corn (starch) (US):
production of ethanol a a fuel
barley:production of ethanol as a
beverage
malting -involves the
enzyme amylase
H2SO4
(c) Cellulosic ethanol
Cellulose is a glucose polymer which makes up 38% of all plant matter but which cannot be fermented directly
materials such as straw, sawdust, bagasse (residue after extraction
of sugars from sugar cane), switchgrass (an “energy crop”)
fermentable sugar
cellulose glucose
enzymic hydrolysis
cellulase
(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?
fertilizer (natural gas (CH4) is one of the raw materials used
in its manufacture), energy used (machinery/transport/
processing)
ethanol energy + CO2corn
sunlight and CO2
Key question: what is the “energy return on energy invested” - EROEI
The value of corn as an energy crop is marginal as
its EROEI = 1.34
• Corn
• Sugar cane Much better: EROEI ≈ 8
• Best solution for corn: use grain as food and the straw to produce cellulosic ethanol
2. Methanol
• Structure C O
H
H
HH H3COH
CH4 + H2O
10 - 20 atm850°C
Ni catalystCO + 3H2
or
• Method of Production
50 - 100 atm250°C
Cu, ZnO/Al2O3
CO + 3H2 H3COHStage 2
Stage 1
mixture is known as syngas
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
O C C O
H
H
H
H
HHHO
OH
HOCH2CH2OH
HOOHC C
H
H
H
H Ag/Al2O3
200-300°CO2, 1-2 atm
C C
H
H
H
H
H2SO4, H2OO
or
or
• Manufacture
crude oil
ethylene oxide – an epoxide or oxirane
once again this product is a
petrochemical
• Uses: ethylene glycol is used as antifreeze
OH
H3C CH3
CH3H
H3C CH3
CH3
OH
CH3CH3
CH3
OH
4. More complicated alcohols
geraniolrose oil
(R)-(+)-citronellollemon grass oil
(1R,2S,5R)-(-)-menthol peppermint oil
Something that is most certainly not an alcohol!!
phenol cyclohexanol
OH OH
≡ ≡
OHCheck the
number of Hs on each C!
Not an alcohol
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
HO
1
25
HO
1
2
6
OH
1(6)6(1)
3(4)
pentan-2-ol or2-pentanol
4-methylhexan-2-ol or 4-methyl-2-
hexanol
hexan-3-ol or3-hexanol
Examples
Cyclic alcohols: uses the name of the cycloalkane on which they are based
OH
HO
1
OH3
Alcohols which have more than one OH group: named using the basic rules and the ending diol, triol, etc., as appropriate
HOCH2CH2OH
cycloheptanol
1,3-butanediol orbutane-1,3-diol
1,2-ethanediol orethane-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
Primary Alcohol (1°)- attached to one
carbon
Secondary Alcohol (2°)- attached to two carbons
Tertiary Alcohol (3°)- attached to three
carbons
methanol
H3C CH2 OH∗ ∗H3C
CH3C
OHH3CH3C
CHH3C
OH∗
H3C OH
Physical Properties (Bruice 2.9)
Key Point
1. Solubility of alcohols in water
alcoholsolubility
(g/100cm3)
R O Hδ− δ+
H O Hδ−
δ+ δ+very polar
∞
∞2.3
0.05
non-polarpolar Key
concept: like
dissolves like
H3C OH
H3CCH2 OH
H3CCH2CH2CH2CH2 OH
H3CCH2CH2CH2CH2CH2CH2CH2 OH
There is competition between the polar and non-polar parts of the molecule
13888
11874
9760
BP (°C)MMMolecule
CH3CH2CH2CH2 O Hδ+δ−
CH3CH2CH2 O Hδ+δ−
CH3CH2CH2CH2CH2 O Hδ+δ−
2. The effect of alcohol structure on boiling point (BP)
(a) Boiling point / molecular mass relationship
The BP increases as the MM increases
(b) Boiling point / FG relationship
11874Hydrogen
7672Dipolar
3672VdW
BP (°C)MWIntermolecular BondingMolecule
CH3CH2CH2CH2 O Hδ+δ−
CH3CH2CH2Cδ+
δ−O
H
CH3CH2CH2CH2CH3
The BP increases as the strength of the intermolecular bond increases
General Methods of Synthesising Alcohols1. Acid catalysed hydration of alkenes (see section on Alkenes; Bruice 4.5)
C C
H
H
H
HH2SO4
H2OH C C O
H
H
H
H
HBasic Reaction
Mechanism
H2SO4
H
C C
H
H
H
H≡ H2O
H C C
H
H
H
H
H C C O
H
H
H
H
H
H
H C C OH
H
H
H
H
H +
key intermediate: carbocation
Problem
The acid catalysed hydration of the following alkene could, in principle, lead to the formation of two products:
H2C CCH2CH2CH3
CH3
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 “
1. Draw the structures of the two products
2. Hydroboration of alkenes (see section on Alkenes; Bruice 4.10)
Basic Process
H2C CH2BH3 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(1) BH3, THF
(2) NaOH/H2O2CH3CH2CH2OH
hydrogen adds here
Problem: suggest a synthetic route to each of the following alcohols
The following problems relate to either acid catalysed hydration or hydroboration-oxidation
OH
??
?? H3CCHCH2CH2CH3
OH
??
OH
2 routes
Problem: draw the structure of the product formed in each of thefollowing reactions:
?H2SO4, H2O (1) BH3
(2) NaOH, H2O2
?
3. Substitution reactions of alkyl halides (haloalkanes) (Bruice 8.5)
leaving group
An example ofnucleophilic substitution
Br
NaOH
H2O
OH
Na Br+δ+δ−
Na OH≡
nucleophile
Problem: write a simple curly arrow mechanism for the above reaction
H3CH2C ClExperimentally:
heat
haloalkane: a liquid NaOH solution
electrophilic carbon
4. Redox reactions (Bruice 10.5, 19.3, 19.1)
Alcohols, ketones/aldehydes and carboxylic acids can be interconverted using redox reactions
C
O
OH
H3C C
O
H
H3C CH3LiAlH4 LiAlH4 CH2 OH
C
O
CH3
H3CLiAlH4
C OH
H3C
H3C H
carboxylic acid aldehyde 1° alcohol
red red
ox ox
2° alcoholketone
ox
red
common reducing agent: lithium aluminium hydride
commonoxidising agent:
sodium dichromate
These reactions allow
some of the most important
functional groups to be
interconverted
Na2Cr2O7 Na2Cr2O7
Na2Cr2O7
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 (carbon-based) molecules
What led to Barbier’ssuggestion?
magnesiummetal
magnesiumdissolves
reaction
What’s in the solution and what properties
does it have?
H3C–Br
H3C–Br + Mg → H3C–MgBr
organometalliccompound
organomagnesium compound ≡ Grignard Reagent
δ+δ-
haloalkane
solvent such as dry diethyl ether
H3CCH2-O-CH2CH3
methylmagnesium bromide
How are Grignard Reagents formed and why use diethyl ether (Et-O-Et) ?
H3C Br
H3C Mg Br
EtO
Et
EtO
Et
H3C Mg Br
surface of piece of Mg
Grignard Reagent (GR) forms on the surface
The magnesium only has 4 electrons. This is made up to 8 by theformation of coordinate bonds by two solvent molecules. The solvated GR is now soluble and moves away from the surface
the surface is now free to react with more haloalkane
haloalkane adsorbs onto the Mg 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
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.
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
The introduction of a Mg atom inverts the polarity present in the haloalkane we started with:
H3C MgIδ+δ−
H3C Iδ+ δ−
What sort of molecules do GRs react with?
CH
O
C
O
O C OO
C
O
O
N
δ+ δ+δ+
δ+
δ+
δ+
δ−δ−
δ−
δ− δ−δ−
δ−
aldehydes ketones
epoxides(oxiranes)
C-N multiple bonds
carbon dioxide
esters
The molecules in red all react with Grignrd Reagents to give alcohols
H3CC
CH3
OH3C MgBr
δ+δ−δ+
δ−
H3CC
O
H3C CH3
MgBr H3CC
OH
H3C CH3
magnesiumsalts+
H2SO4
Mg + H3CBrStage 1
Stage 2
Using the Grignard Reaction to make alcohols
• Tertiary alcohols: the reaction of a GR with a ketone
Acid (H+) is added at the end of the reaction to convert the alcohol salt to the alcohol
Although some simple GRs (such as this one) are
available commercially, we usually have to
make them
The reaction is an example of a
nucleophilic addition
3° alcohol
• Tertiary alcohols: the reaction of Grignard Reagents with esters
δ+δ−+ C
HO
H3CH2CH3CCH2 C
O
OCH3
δ−
δ+ Mg Br2
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
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
Ph C
OH
CH3
CH3
H3CCH2 C
O
OCH3
Ph
MgBrδ+
δ+
δ−δ−
H3CCH2 C
O
OCH3
MgBr
Ph H3CCH2 C
O
Ph
Ph MgBr
H3CCH2 C
OH
Ph
Ph
H3CO MgBr+
• Secondary alcohols: the reaction of a GR with an aldehyde
HC
CH3
O
MgBrδ+δ−δ+
δ−H3CH2C+
CH2CH3
CHO
CH3H2°
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)
HC
H
OMgBrδ+δ−δ+
δ−H3CH2C+
CH2CH3
CHO
HH1°
alcohol
aldehyde
methanal
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+
δ−
H3CH2C MgBr
O
H2C CH2
δ− δ+
H2C CH2
O
H3CH2C
MgBrH2C CH2
OH
H3CH2C
H
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
Ph MgBrO
HC CH2
δ− δ+CH CH2
OH
PhH3C
δ+ δ+H2C CH
OH
H3C Ph
H3C
+
not formed
formed
Reactions of alcohols
weakly acidic hydrogen
HO
H + Na 1/2 H2↑ + Na OH
H3CO
H + Na 1/2 H2↑ + Na OCH3
CO
HH3CCH3 CH2 OH
Na2Cr2O7
2. Redox reactions (see “General Methods of Synthesising Alcohols; Reaction 4” above)
CO
CH3
H3CC OHH3C
H3C H
Na2Cr2O7
1° alcohol
2° alcohol
aldehyde
ketone
1. Water like reactions
Problem Assign an oxidation to the indicated C-atom and confirm that this changes during the reaction.
ox
ox
3. Acid catalysed elimination reactions (dehydration) (see “Alkenes”above)
H C C O
H
H
H
H
H2SO4
H
H
H H C C O
H
H
H
H
H
H
C C
H
H
H
H
+ H2O+ H
≡
• 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
• This is an elimination reaction: a small molecular unit (H2O) is lost and a multiple (double) bond is formed
Relative ease of dehydration R C
R
R
OH R C
H
R
OH R C
H
H
OH> >
2°3° 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:
H3C CH
OH
CH3H2SO4
H
H3C C O
H3C
H
H
H
C C
CH3
H
H
H
+ H2O
+ H
H2C CH
H3C
H2°
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.
4. Conversion to haloalkanes
OH
HI
I
+ H2O
H3C CH
OH
CH3HBr
H3C CH
Br
CH3
+ H2O
H3CCH2CH2CH2OHPBr3 H3CCH2CH2CH2Br
• These are substitution reactions. 2° and 3° alcohols react via an SN2 mechanism, whereas 1° alcohols follow an SN2 route
• Phosphorous trihalides are efficient alternatives to the hydrogen halide
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
H2SO4+ H2OH3C C
O
OH
+ H3CCH2OH H3C C
O
OCH2CH3
δ+
δ−
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 GroupKetones
Key Points
• the chemistry of ketones and aldehydes is the chemistry of thecarbonyl group and so they are considered together
C,H
functionalgroup
RR
C
R
Oδ−δ+
AldehydesH
C
R
Oδ−δ+
• 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
C
O
H
OCH3
HO
O
CH H
O
CH3C H
Famous ketones
vanillin methanal (formaldehyde)
ethanal(acetaldehyde)
air pollutants: photochemical smog
propanone(acetone) solvent
camphor
O
CH3C CH3
O
CH3H3C
H3C
O
CH3
CH2H3C
O
CH3
CH2H3C
(R)-(-)-carvonespearmint oil
(S)-(+)-carvonecaraway seed oil
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
Nomenclature of ketones and aldehydes
CH
O
H3C HC
H2C
CH
OCH3
HC
CH
O
O
2-hexanone
3-methylbutanal butanedial
7-methyl-4-octanone
not 2-methyl-5-octanone3-methylcyclobutanone
hexanal
Examples of aldehyde nomenclature
Examples of ketone nomenclature
C
O
H3CCH2
H2C
C
H2C
O
CH2
CHCH3
CO
H3C
CH3
Physical Properties of aldehydes and ketones
Solubility in water
• As with alcohols there is competition between the polar and non-polar part of these molecules
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 )
R
C
(H)R
Oδδ
polar
non-polar
• If R is small (few C/H): very soluble in water
• As the number of C/H increases, the solubility decreases
R
C
(H)R
Oδ δ
R
C
(H)R
O
δ
δ
Preparation of aldehydes and ketones
Redox Reactions
Oxidation of alcohols (see “Preparation of Alcohols” above)
2° alcohol → ketone K2Cr2O7
OOH
Na2Cr2O7
H3CCO2H
Ketones
Aldehydes
1° alcohol → [aldehyde] → carboxylic acid K2Cr2O7 K2Cr2O7
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
K2Cr2O7
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
CH3 CH2 OH CH3 C
O
H
CH3 C
O
H
K2Cr2O7
distilled out
Reactions of ketones and aldehydes
General Expectations
C
O
H
δ+
δ−
α
The hydrogen atoms on the α-carbon are weakly acidic. They can be removed by a strong base to give a
carbanion (C-)
Electrophilic carbon which can be attacked
by nucleophiles resulting in
nucleophilic addition
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.
• 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
R
O
H
< δ+
δ−Nu
R
O
R
< <δ+
δ−Nu Aldehydes are thus more reactive than
aldehydes for electronic reasons
R groups such as CH3are electron donating groups (induction).
This reduces the size of the δ+ charge on the C-atom of the carbonyl group
2. Nucleophilic addition with primary amines and derivatives of primary amines
The reaction of ketones/aldehydes with 1° amines: imine formation
N
H
H
N
R
H
N
H
H
N
R
R
H R R Ramines
Secondary (2°)
H3CC
H3CO
δ+ δ−HN
R
H+
H3CC
O
H3C N H
R
H H3CC
H3CN
RH2O
H++
nucleophileelectrophile
nucleophilic addition
eliminationImine (Schiff
base)
Primary (1°)
Tertiary (3°)
Ammonia
Overall: nucleophilic addition-elimination
Nucleophilic Addition1. Grignard Reaction (see “Preparation of Alcohols” above)
2°alcoholaldehyde
HC
H3CH2CO
HC
Ph
O
MgBrδ+δ−δ+
δ−H3CH2C+
CH2CH3
CHO
PhH
HC
Ph
O MgBrδ+
δ−δ+
δ−
CH2CH3Key step in the nucleophilic addition mechanism
electrophile nucleophile
Problem: Write out the mechanism in full for this aldehyde /GR combination:
MgClHCH2CH3C
H3C
H3CC
H3CN
R
H
+ H2O
H3CC
H3CN
R
+ H
Mechanism for imine formation
H+: acid catalystOverall this is a nucleophilic addition-elimination reaction
H3CC
O
H3C N H
R
H
H
H3CC
OH
H3C NH
R
H
H3CC
O
H3C N H
R
H
+ H
H3CC
H3CO
H
H3CC
H3COH
HNR
H
1 2 3 4 5 6 7
Evidence for the proposed mechanism: effect of pH on the reaction of acetone with methylamine
pH
second order rate constant, k
Reaction slow: not enough H+ to protonate the
neutral tetrahedral intermediate. This is required so that
a good leaving group (H2O) is
availableReaction slow: too
much H+, resulting in protonation of the
amine, removing its nucleophilic properties:
RNH2 H+ RNH3+
Related reactions of 1° amines
(H)RC
RO
δ+ δ−NH2+ H2O+NH2
(H)RC
RN
NH2
(H)RC
RO
δ+ δ−NH2+
HN
O2N
NO2 NHN
O2N
NO2C
R
(H)R
(H)RC
RO
δ+ δ−NH2+ + H2OOH
(H)RC
RN
OH
hydrazine a hydrazone
2,4-dinitrophenylhydrazine a 2,4-dinitrophenylhydrazone
hydroxylamine an oxime
Problem: using H2O as B write out a detailed mechanism for the reaction of the following:
HC O NH2CH3
H2CH3CC
H3CO H2N
CH3CH2
CPh
NHO
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:
H3CC
HN
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-.
H3CH2CH2CC
O
H H3CCH2CH2CH2 OH(a) NaBH4
(b) H+
O HHO
(a) LiAlH4
(b) H+
Mechanism of hydride reduction of ketones/aldehydes
RC
O
R
Hδ+
δ−
H+
RC
R
O H
RC
R
HO H
LiAlH4 ≡ HNaBH4 ≡Key Point: sodium borohydrideand lithoum aluminium hydride are synthetically equivalent to a hydride ion
Mechanism
nucleophile
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
HC
R
O
+ H3COHδ+
δ− OH
C OCH3H
R
H+ H+OH
C OCH3H
R
a hemiketal
an acetal
RC
R
O
+ H3COHδ+
δ− OH
C OCH3R
R
H+ H+OH
C OCH3R
R
a hemiacetal
a ketal
So how does this reaction happen?
hemiacetal
acetal
RC
O
H
H+
δ+
δ−
RC
O
H
H
OH3C
R C
OH
H
OH3C H
R C
OH
H
H3CO
+ H+
R C
OH
H
H3CO
H
HC
H3CO
R
H
OCH3H
R C
OCH3
H
H3CO
H
R C
OCH3
H
H3CO + H+
hemi => half
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.
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)
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
reaction
new bond formed
In most cases intramolecular reaction lead to the formation of a ring
XY
XY
Problem: in terms of thermodynamics, intramolecular reactions enjoy a certain advantage. What is it?
Ring and open chain forms of D-glucose
C
C
OH
OHH
C HHO
C OHH
C OHH
CH2OH
O
H
HO
H
HO
H
OHOHH
H
OH
O
H
HO
H
HO
H
HOHH
OH
OH
open chain form
α-D-glucose β-D-glucose
intramolecularhemiacetalformation
RO
H
OHR
RO
OH
HR
The formation of the ring form of a carbohydrate is an example of hemiacetal formation
Reactions at the α-carbon: carbanion/enolate chemistry
Key point: α-hydrogen atoms are acidic
enolatecarbanion
resonance hybrid
most important resonance form: negative charge on
electronegative oxygen
The α-hydrogens are acidic because the anion formed is resonance stabilised
H2C C
O
CH3
HB
H2C C
O
CH3 H2C C
O
CH3
H2C C
O
CH3
≡base
H3C C
O
CH3 H2C C
OH
CH3
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
keto form enol form
en
ol
• 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
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)
LiN ≡ R2N Li
Basic α-alkylation reaction R
O
R
H
LDA
R'HalR
O
R
R'
α-Carbon Reactions of Ketones and Aldehydes
Mechanism of α-alkylation
LiR2N
O
H
OCH3I O
H3C
+ R2NH
+ ILi
substitution reaction
C-C bond formed
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
H
O
R
H
H
O
R
H
δ+
δ−
H
O
R
nucleophile 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
CH
O
H3C CH
O
HC
CH3
OH
H3CNaOH
CH
O
C
CH3
H3C
+ H2O
2
H
Things to note:
• 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.
ald
ol
unit 1 unit 2 conjugated system
Mechanism of the base promoted Aldol addition reaction
H2CC
H
O
OH
H
H2CC
H
O
H3CC
H
O
δ+
δ−
CH2
CH
O
CH
O
H3C CH2
CH
O
CH
OH
H3C
H OH
+ HOnew C-C bond
aldol
OH
HC
CH
O
HC
OH
H3C
H
CC
H
O
CH3C
H
H
+ H2O + HO
CC
H
O
CH
H
CH3
+
The overall process is known as the Aldol Condensation if dehydration occurs at the same time
Condensation Reaction: two functional groups combine, eliminating a small molecule – often water
conjugated systemtrans isomer major product
cis isomer minor product
Problem: write down the structure of the aldol addition product that would be formed by the following
O
H
CH3CH2
O
CH2CH3
Problem: what aldehyde or ketone would be required to make the following:
2-ethyl-3-hydroxyhexanal
H3C
Ph
H
O
Ph
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?
H3C
O
H H3C
O
HH3C
O
H
HO CH3+
- H2O H3C
O
H
CH3
In principle yes – but there is a problem with such mixed (crossed aldol reactions
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?
CH3
O
H
CH2
O
H
CH3
O
H
H2C
O
H
H
H
a
b
d
c
Products formed:Possible combinations
a
b d
c
CH3
CH3
H
OH3C
OH
H
CH2
O
H
H
CH3
HOH
CH3
O
H
CH2H
OHH
CH2
O
H
CH2H
OHH
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 α-hydrogen – this is the situation if one of the reactants is an aromatic aldehyde:
O
H
+
H3C CH3
O
NaOHHO
CH3
O
H CH3
O
H
H
NaOH
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.
Carboxylic Acids
Famous carboxylic acids
Ethanoic Acid(Acetic Acid)
Methanoic Acid (Formic Acid)
Benzoic Acid
H3C CO
OHH C
O
OH
C C
C
CC
C
H H
C
HH
HOH
O
O
OHH3C
CH3
HO CO2HH
Hexanoic Acid (Caproic Acid)
(S)-(+)- Lactic Acid
HO2C CO2HHO CO2H
Citric Acid
R CO
OH
General Formula Functional Group
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
H3COH
H3C
O
Problem:
(a) Name the following acid: (b) Draw the structure of the following acid: 2,3-dimethylpentanoic acid
Physical Properties
very polar-possibility of
hydrogen bondingC,H non-polar
• BP is high because of strong intermolecular forces
• Water solubilityR 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)
R CO
O H
δ
δ δ
δ
H3C CO
OCH3C
O
O
H
Hδ δ
δδ
Preparation of carboxylic acids
Special case: acetic acid (ethanoic acid)
CO
OHH3CC
O
HH3C
O2C CH
H
H
Hcatalyst
O2
catalyst
CO
OHH3C
O2
catalystH3CCH2CH2CH3
CO
OHH3C
catalystH3COH + CO
All reactions occur in the gas phase (high T and P)
and involve heterogeneous catalysts
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
CO
OHH3C C
O
OH3C + H+
They are weak acids as dissociation / proton donation is partial
Why are they acid at all? The carboxylate anion is stabilized by resonance and so is happy to form.
Resonance hybrid: actual structure of the anion - very stable as the charge is not
carried by a single atom
resonance forms C
O
OH3C C
O
OH3C C
O
OH3C≡
(b) Any other factor which reduces the electron density in the carboxylateanion, 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
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:
COH
OH2C C
O
OH2C
F F
<
<
COH
OH3C C
OH
OXH2C C
OH
OX2HC C
OH
OX3C< < <
Carboxylic acids undergo the standard reactions of acids
(a) Reaction with metals
CO
OH3CC
O
OHH3C + Na
Na+ 1/2 H2 ↑
(b) Reactions with bases
Compare with
Compare with
HCl + Na Na Cl + 1/2 H2
CO
OCH+ KOH
K+ H2O
H3C
H3CC
O
OHCH
H3C
H3C
HCl + KOH K Cl + 1/2 H2O
2. Redox reactionsCarboxylic acids can be reduced to aldehydes (see Preparation of Alcohols above) .
3. Conversion to carboxylic acid derivatives
R C
O
OH
R
O
OR1
R
O
Cl
R
O
NH2
R
O O O
R
P2O5(-H2O)
R1OH, H+
SOCl2
R1NH2
NaOHH2O
H+, H2O
H2O
H2O
anhydride
ester
acyl chloride or acid chloride
amide
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
R C
O
OH
R
O
OR1
R
O
Cl
R
O
NH2
R
O O O
R
P2O5(-H2O)
R1OH, H+
SOCl2
R1NH2
R C
O
OH
R
O
OR1
R
O
Cl
R
O
NH2
R
O O O
R
P2O5(-H2O)
R1OH, H+
SOCl2
R1NH2
R C
O
OH
R
O
OR1
R
O
Cl
R
O
NH2
R
O O O
R
P2O5(-H2O)
R1OH, H+
SOCl2
R1NH2
R
O acyl group
The formation of a carboxylic acid derivative– a detailed look: esterification of a carboxylic acid
H2SO4+ H2OH3C
O
OH
+ H3CCH2OH H3C
O
OCH2CH3
δ+
δ−
• 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.
H3C
O
OH
δ+
δ−H
CH2CH3
O
H
H3C
OH
OH
H3C
OH
HO
OCH2CH3
H
H3C
O
HO
OCH2CH3
H
+ H2OH3C
O
OCH2CH3
+ H
H
Ester formation: the mechanism
The catalyst converts the δ+ into a whole +, making the carbon more electrophilic and more attractive to the nucleophilic alcohol
The catalyst is regenerated
tetrahedral intermediate
A second example of the conversion of a carboxylic acid into a carboxylic acid derivative: acyl chloride formation
H3C
O
O
H
ClS
O
Cl
H3C
O
O
H
S
O
ClCl
H3C
O
OS
O
Cl
H
H3C
O
OS
O
Cl
+ Cl
Cl
δ+
δ+
δ−
δ−
H3C
O
OS
O
ClCl
+ HH3C
O
Cl + SO2 + Cl
acyl chloride
thionylchloride
good leaving group
a gas: leaves the reaction mxture as
it is formed
tetrahedral intermediate
tetrahedral intermediate
Nucleophilic Acyl Substitution
This term describes the reactions of carboxylic acids and their derivatives that we have been considering above:
R
O
X
Y
δ+
δ−
R Y
O X
R
O
Y+ X
tetrahedral intermediate
R
Oacyl group
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
R OP
O
O O
O
P
O
OO
R OP
O
O O
O
acyl phosphates acyl pyrophosphates
R OP
O
O O
OY
δ+
δ−
+R O
PO
O O
OYR
O
Y OP
O
O
O
≡ PO43-
Using these activated carboxylic acids in nucleophilic acyl substitution
phosphate ion
R OP
O
O O
OR O
PO
O O
O
good leaving groups
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