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Chemistry 1B – CHEM1102
Professor Max Crossley, Room 547, [email protected]
Week 7– Polymers, Synthetic sequences and Summary
H3N CH
R
C N CH
R1
O
H
peptidelinkN-terminus
C N CH
R2
O
H
peptidelink
C N CH
R3
O
H
peptidelink
C N CH
R4
O
H
peptidelink
and so on
where the R groups are the side-chains of the various amino acids
Proteins are natural polymers with a repeating peptide linkage : actually an amide bond
CHEM1102 – Organic Chemistry
1. Representations of Molecular Structure
2. Alkanes, Alkenes, Alkynes
3. Aromatic Compounds
4. Structure Determination
5. Alcohols & Amines
6. Stereochemistry
7. Organic Halogen Compounds
8. Aldehydes & Ketones
9. Carboxylic Acids & Derivatives
10. Synthetic Strategies
OH
O
O
OH3C
Aspirin
Recap Ester & amide formation
R OH
O
SOCl2R'OHH+ (cat)
carboxylic acid
ester
acid chlorideR Cl
O
R OR'
O R'OH
R NHR'
O
amide
R'NH2 excess
R'NH2
H+ (cat)
heat
heat
most reactive
least reactive
Recap Ester & amide formation
Cl
O
OCH2CH3
O+ HClH OCH2CH3+
acid chloride + alcohol = ester + HCl
OCH3
O
NCH2CH3
O+ HOCH3
H NCH2CH3+
ester + amine = amide + alcoholH
H
Cl
O
NCH2CH3
O+ HClH NCH2CH3+
acid chloride + amine = amide + HCl
HH
need to add a base to scavenge HCl or it will react with starting amine
Di-Esters
+ H OCH2CH3
Cl
O
Cl
O2
OCH2CH3
O
H3CH2CO
O+ 2 HCl
diacid chloride + alcohol = diester + HCl
Cl
OH OCH2CH2O H
OCH2CH2O
O O
+2
+ 2 HClacid chloride + dialcohol = diester + HCl
Di-amides can be made similarly, using amines in place of the alcohols
Polymer formation - polyesters +
Cl
O
Cl
O
OCH2CH2O
O
Cl
O + HClH OCH2CH2O H
di(acid chloride) + dialcohol = polyester + n HCl
H
OCH2CH2O
O
Cl
O
OCH2CH2O
OO
H
+ HCl
OCH2CH2O
O
Cl
O
OCH2CH2O
OO
OCH2CH2O
OO
H
+ HCl
OCH2CH2O
O
OH2CH2CO
O
OCH2CH2O
OO
OCH2CH2O
OO
H
OCH2CH2O
OO
n
O
Cl
O+ HCl
Condensation Polymers
This type of polymerisation usually involves ejection of a small stable molecule, eg HCl, CH3OH, H2O
If polymerisation conducted above b.p. of ejected molecule, this is ‘lost’ as gas, so doesn’t interfere with polymer product
condensation reaction
O
O
NH
HN
Cl
OCl
O
NN
+ H Cl
H
HH
H
n
n
Structure of Nylon
Regular packing and hydrogen bonding gives strength while retaining flexibility
NH
O
O
N NHH
ONH
O
O
NH
NH
O
O
N NHH
ONH
O
O
NH
δ δ δ δ δδ δ δ δ δ
nylon 6,6 space filling model …
Strength & Structure
eg., Lycra Rigid groups give a fabric strength Hydrocarbon chains provide elasticity (remember conformers)
OH2C C
H2O C
O
N
H
CH2 N
H
O
N
H
N
H
O
N
H
N
H
O
nm
Elastic segment Rigid segment
Molecular structure links directly to macroscopic properties
Kevlar
Kevlar is used in bullet proof vests. What feature of the molecular structure makes it suitable for this application?
Rigid aromatic rings and hydrogen bonds between the polymer chains
Exercise
Nomex is used in flame-resistant fabrics. It has this structure:
Suggest two monomer units that could be combined in the manufacture of this polymer.
O O
N
H
N
H n
• Amino acids contain both an acidic and a basic functionality • So an internal acid-base reaction takes place:
2. Similarly, they are extremely soluble in water
1. Because they are zwitterions, amino acids are extremely polar (like salts) and so are solids with high melting points
H2NO
OH
R
H3NO
O
R
zwitterion
• This forms a zwitterion: a dipolar ion with both positive and negative charges at different sites in the same molecule
Zwitterions
Peptides
Amino acids condense to form a peptide (amide) link Two amino acids condense to form a di-peptide and three
amino acids for a tri-peptide … etc
H3N CH
H
COO H3N CH
CH3
COO H3N CH
H
C N CH
CH3
COO
O
H
peptidelinkN-terminus C-terminus
glycine alanine
glycyl-alanine
Natural polymers - proteins
Amino acids condense to form long chains with repeating peptide linkages: actually amide bonds Proteins contain chains of >50 amino acids (up to >1000!)
H3N CH
R
C N CH
R1
O
H
peptidelinkN-terminus
C N CH
R2
O
H
peptidelink
C N CH
R3
O
H
peptidelink
C N CH
R4
O
H
peptidelink
and so on
where the R groups are the side-chains of the various amino acids
Protein Structure Primary structure
Is the sequence of amino acids that make up the chain N-terminus is written as the left hand end of the
sequence and the C-terminus the right hand end
Human insulin
CHEM1102 – Organic Chemistry
1. Representations of Molecular Structure
2. Alkanes, Alkenes, Alkynes
3. Aromatic Compounds
4. Structure Determination
5. Alcohols & Amines
6. Stereochemistry
7. Organic Halogen Compounds
8. Aldehydes & Ketones
9. Carboxylic Acids & Derivatives
10. Synthetic Strategies
OH
O
O
OH3C
Aspirin
Strategies of Synthesis
1. The Challenge of Synthesis
2. Synthesis and Retrosynthesis
3. Several Examples
Synthesis Rules?
“There is excitement, adventure, and challenge, and there can be great art in organic synthesis.”
R. B. Woodward
• There are a number of choices for any interconversion • Choices multiply like moves in a chess game
Retrosynthesis - Possible Routes
OHONaBH4
dil. H2SO4
OHBr i) Mg
ii)
H
O
OH
OH
?Means ‘could be made from’
Exercise
Suggest reagents for the following conversions …
OH
HO
O
O OCH3
H3CO
Ester - suggests made from carboxylic acid
Got to be oxidised at these positions
Answer to Exercise
O
O Cl
Cl
1. K2Cr2O7/ H+
Suggest reagents for the following conversions …
OH
HO
O
O OCH3
H3CO
2. SOCl2
3. CH3OH
O
O OH
HO
No direct route
The Challenge of Synthesis
The challenge of synthesis lies in combining more than one reaction
?H
O
NH
O
?
?Br O
Need to think backwards as well as forwards.
Synthesis & Retrosynthesis
We can think forwards from reagents: “What reactions do we know?”
BrOH
CN
N Br
conc. KOH in ethanolheat
dil. aq. NaOH
CN-
N(CH3)3
Synthesis & Retrosynthesis
More powerful (but also more difficult) is to think backwards as well
"Retrosynthetic" arrowHypothetical reverse of a
synthesis step
OH O
?
?
? Means ‘could be made from’
Synthesis & Retrosynthesis
Combine the two to solve our puzzle …
First stepNucleophilic SubstitutionUse H2O (and dilute OH-)
OH OBr
Second stepOxidation
Use K2Cr2O7 and H+
Synthesis & Retrosynthesis
Combine forwards and backwards for several solutions …
Br
H
Cl
H
OH
H
Exercise:
What Reagents would you use?
Challenge of Synthesis
And backwards from product…
NH
O
Cl
O
OCH3
O
OH
O
H
O
1. K2Cr2O7/ H+
2. SOCl23. CH3CH2NH2/ dil NaOH
OH
O
1. K2Cr2O7/ H+
2. MeOH/ H+
3. CH3CH2NH2/ dil NaOH
1.2.
3.
1.2.
3.
Exercise: What Reagents would you use?
Some synthetic successes
N
NO
OCH2CH3Cl
Claritin
SNH
NO2
NHH3C O N
CH3
CH3
Zantac
H
HO
OHHN CH3
CH3CH3HO
R-salbutamol
N
O
CH3HS OH
O
Captopril CH3CH2O
O2S N
NN
O CH3
CH2CH2CH3
CH3N
N
HN
COOHOHCOOH
HOOC
Sildenafil citrate
HN
NO
S
CO2H
O
NH2
HO
Amoxicillin
Formidable achievements!
Brevotoxin B
Taxol O
O
OH
HN
PhO
AcO O OBz
OHO H
OAcOO
…
Both of these have been synthesised by organic chemists
Chemistry 1B – CHEM1102
Summary of the key reactions and concepts
1. Representations of Molecular Structure
2. Alkanes, Alkenes, Alkynes
3. Aromatic Compounds
4. Structure Determination
5. Alcohols & Amines
6. Stereochemistry
7. Organic Halogen Compounds
8. Aldehydes & Ketones
9. Carboxylic Acids & Derivatives
10. Synthetic Strategies
OH
O
O
OH3C
Aspirin
1. Mass spectrometry and IR, UV & vis,
and NMR spectroscopy give structures
2. Electrons, Protons and Electronegativity
3. Functional Groups
4. Reactions & Mechanism
Summary - bringing it all together
Effect of isotopes •Each fragment recorded in the mass spectrum registers the specific isotopes of the various elements present
• Some elements have more than one isotope of high natural abundance (e.g. 79Br 49% and 81Br 51%; 35Cl 75% and 37Cl
25%) • Eg., bromomethane: since a sample will contain almost equal amounts of CH3Br79
and CH3Br81, see two molecular ion peaks
m/z
freq
uenc
y
90 92 94 96 98 100 102 104
CH3Br79 CH3Br81
Bromobenzene
Fragment ion does not show same isotope distribution, contains C & H only
Br
Two molecular ions, almost equal intensity, two mass units apart: indicates bromine
M (C6H579Br) = 156
M (C6H581Br) = 158
High resolution mass spectrometry
If we have no empirical formula it is difficult to assign a molecular formula to a molecular ion
Eg., a molecular ion at m/z = 72 could be C4H8O, C3H4O2 or C3H8N2
The mass of the major isotopes of each element is known to high accuracy
isotope12C1H
14N16O
atomic mass12.00001.007814.003115.9949
High resolution mass spectrometry
The different possibilities may be distinguished using high resolution mass spectrometry
Molecular formula
C4H8OC3H4O2C3H8N2
M (low resolution)
727272
M (high resolution)
72.057372.021072.0686
Infrared Spectroscopy
• Absorption of IR light excites bond vibrations ⇒ indicates functional group(s) present ⇒ ‘fingerprint’ a molecule
Bonds
N-H
O-H (broad)
C-H
C≡C
C≡N
C=O
C=C
IR absorption (cm-1)
~3300
~3000
~2200
~1700
~1600
Amines, amides, alcohols, phenols, carboxylic acids
Ketones, aldehydes, esters, amides, carboxylic acids
Compounds with conjugated multiple bonds absorbs in the UV-visible region
Which of the compounds will show an absorption in the UV-visible part of the spectrum?
OH
O
H
O
1H NMR Spectroscopy
Information Observation
Number of H environments Number of signals
Type of H environment Position of signal
Number of H of each type Size of signal
Number of adjacent H that interfere with signal
Multiplicity of signal
Equivalent hydrogens have the same resonance
10 9 8 7 6 5 4 3 2 1 0Chemical shift δ (ppm)
Downfield
TMS
δ 3.6 δ 2.1
CC
O
O
These 2 sets of H atoms have different local environments
H
H
HC
HH
H
These H atoms reside on aC attached by a σ bond to another
C
These H atoms reside on aC attached by a σ bond to O
Two singlets each dueto 3 H atoms
Ratio 1:1
1H NMR
There are two sources of extra information in a 1H spectrum:
1. The integral – tells you how many H’s in a given environment
2. The multiplicity (splitting) – tells you how many neighbours an H has
Integral: How many hydrogensSignal is split:
How many neighbours
1H NMR Spectroscopy
• Number of signals corresponds to number of types of 1H atom • If non-equivalent 1H atoms are separated by only 3 bonds they
interfere with each others signal - splitting them
CC
Cl
These 2 sets of H atoms are different and
separated by 3 intervening bonds
H H
H
HH
Isomers same molecular formula
Constitutional Isomers Different nature/sequence of bonds
Stereoisomers Different arrangement of groups in space
Configurational Isomers
Interconversion requires breaking bonds
Conformational Isomers
Differ by rotation about a single bond
Enantiomers Non-superposable mirror images
Diastereoisomers Not mirror images
Flashback
Isomerism
Conformational Isomers
Use ethane as an example (CH3CH3)
H
H H
H H
H
H
H
H
H H
H
H
H
H
HH
HH
H
H HH
H
Sawhorse representation
Newman projection
eclipsed staggered
rotate back carbon 60°
Stereoisomerism
Two sorts of configurational isomers 1. Some alkenes exist as diastereoisomers: (Z) or (E)
3. Molecules with C atom with four different groups attached • exist as two enantiomers • rotate plane polarised light in opposite directions • absolute configuration of stereogenic C is (R) or (S)
H
H3C
CH2CH3
H H
H3C CH2CH3
H
CO2H
H3C NH2H
HO2C
CH3H2NH (R) (S)
(Z) (E)
Carbon 1s2 2s2 2p2
• has 6 electrons ⇒ 4 in valence shell ⇒ needs 4 more for full shell (8) ⇒ forms 4 covalent bonds
• has 6 protons ⇒ not particularly electronegative (2.5)
Carbon Forms Four Bonds
Nitrogen 1s2 2s2 2p3
• has 7 electrons ⇒ 5 in valence shell ⇒ needs 3 more for full shell (8) ⇒ forms 3 covalent bonds AND has 1 lone pair
• has 7 protons ⇒ more electronegative (3.0) ⇒ forms polar bonds to carbon
BUT lone pair is available for reaction
Nitrogen Forms Three Bonds
Oxygen 1s2 2s2 2p4
• has 8 electrons ⇒ 6 in valence shell ⇒ needs 2 more for full shell (8) ⇒ forms 2 covalent bonds AND has 2 lone pairs
• has 8 protons ⇒ even more electronegative (3.5) ⇒ forms more polar bonds to carbon
AND lone pairs are less available for reaction
Oxygen Forms Two Bonds
Hydrogen 1s1
• has 1 electron ⇒ needs 1 more for full shell (2) ⇒ forms 1 covalent bond
• has 1 proton ⇒ not very electronegative (2.1)
Hydrogen Forms One Bond
Ether
Amine
Alkyl chloride*
Acid chloride*
NH2
O
Cl
Cl
O
-ether
Amino- or –amine
Chloro- or –chloride
-anoyl chloride
Diethyl ether
Ethyl amine
2-Chlorobutane
Propanoyl chloride
* Similarly for F, Br & I: alkyl / acid fluorides, bromides & iodides
FLASHBACK
Functional Groups
O
HO
OH
OHO
OO
NH2O
Alcohol
Ketone
Aldehyde
Carboxylic Acid
Ester
Amide
-ol
-one
-al
-oic acid
-oate
-amide
FLASHBACK
Functional Groups
1. Extra-specially stable from aromaticity (6π electrons in ring)
2. Undergoes electrophilic aromatic substitution reactions
Benzene - aromatic compound
Functional Groups – C
Alkenes CCH3C
CH3
HBr
H
HCCH3C
H3CBrH+
H
H
Alkenes have lots of electrons … ⇒ react with ‘electron-lovers’ (electrophiles) ⇒ electrophilic addition
Benzene is not an alkene … but it does have lots of electrons
1. Alcohols are not very acidic or basic 2. Alcohols can be nucleophilic 3. Alcohols can be oxidised 4. Alcohols undergo elimination reactions
OHRAlcohols
OR2R1
Ethers1. Ethers are generally unreactive 2. Ethers are often used as solvents
Functional Groups – O
1. Amines are basic 2. Amines are nucleophilic H
NH
Amino Acids
R
OHO
NH2RAmines
O
CNH
R1R2
Amides
1. Amides are neutral 2. Amides are not nucleophilic 3. Amides are quite unreactive
1. Amino acids have >1 F.G. 2. Amino acids are zwitterions 3. Amino acids make proteins
Functional Groups – N
Functional Groups – C=O
O
CHR1
Aldehyde
O
CR2R1
Ketone O
COHR1
Carboxylic acidO
CClR1
Acid chlorideO
CORR1
Ester
O
C δ+
δ-
The Carbonyl Group
Nu
O
CNH
R1R2
Amide
O
COR1
O
R2
Anhydride
Reactions
chemical reactions are all about electrons – which compound has them and which
compound wants them –
a reaction is an ‘electron transfer’
Organic Reactions
Four general types of organic reaction 1. Acid–base reactions: ± H+
2. Substitution reactions: one group replaces another
3. a. Addition reactions: new group(s) added
b. Elimination: group(s) taken away
4. Reduction-oxidation reactions: loss and gain of electrons
Two key types of reactant
Nucleophiles (are electron-rich) electron donors
Electrophiles (are electron poor) electron acceptors
1. Acid-Base – exchange of H+
eg. Carboxylic acids
Organic Reactions
OC
H3CO OH+
OC
H3CO H2O+
H
OC
H3CO
OC
H3CO +
H+ H Cl Cl
Protonation/deprotonation
1. Acid-Base – exchange of H+
eg. Amines
Organic Reactions
Protonation/deprotonation
NCH3CH3C
NCH3CH3C
H3CHH
HH
+ H Cl
HH3CCl
OH+ H2ONCH3CH3C
NCH3CH3C
H3CHH
HH
+HH3C
Cl
1. Acid-Base – exchange of H+
eg. Phenols
Organic Reactions
Protonation/deprotonation
OH+ H2O+
OH
O
+ +H Cl Cl
O OH
2. Substitution – one group takes the place of another
eg. Nucleophilic substitution
Organic Reactions
H
HCl OH+
H
H
HOH Cl+
H
+ +H OCH2CH3H3C Cl
O
H3C OCH2CH3
O
HCl
Reaction Scope
H3C I
HO
RO
N C
R C C
H2N
R3N
H3C I
H3C I
H3C I
H3C I
H3C I
H3C I
H3C C C R
H3C OH
H3C OR
H3C NH2
H3C NR3
H3C C N
I
I
I
I
I
I
I
Nucleophile + Product + Product class
+
+
+
+
+
+
alcohol
ether
nitrile
alkyne
amine
tetraalkylammoniumsalt
+
+
+
+
+
+
Wide range of nucleophiles can be used
3a. Addition add H2, H2O, HX etc
Organic Reactions
H3CC C
HH
CH3 H3CC C
BrH
CH3+ H Br H H
b. Hydrohalogenation (addition of a hydrogen halide)
H3CC C
HH
CH3 H3CC C
OHH
CH3+ H OH H H
c. Hydration (addition of water)H2SO4 catalyst
H3CC C
HH
CH3 H3CC C
HH
CH3+ H H H H
a. Hydrogenation (addition of a hydrogen)
Pd-C
catalyst
3b. Elimination • Reverse of addition: remove H2O, HX etc
Organic Reactions
RC
R
CR R
R C
R
CRR Br
H+ H2O + KBr
hot KOH in ethanol
RC
R
CR R
R C
R
CRR OH
H
+ H2Oconc. H2SO4, heat
H3O+ + HSO4-
H2SO4dehydration
dehydration
dehydrohalogenation
Zaitsev’s Rule
HC CH2H2CH3C + H2O + Br
major product
Where there’s a choice, the most substituted alkene forms
c. OH heat
+ H2O + Br
H3C CHH
HCBr
CH2H
HC CH CH3H3C
Note difference in conditions
Elimination Reaction or Substitution?
RC
R
CR R
R C
R
CRR Br
H+ H2O + KBr
hot conc. KOH
in ethanol (solvent)
substitution
elimination
R C
R
CRR Br
H
dilute aq. NaOH
R C
R
CRR OH
H+ NaBr
Organic Reactions
4. Oxidation/reduction
eg.
H3CCO
CH3
Cr2O72
H3CCO
CH3
H
H
/ H
RC
H
O Et2O
EtOH RC
H
OH
H3O+
RC
H
O H
H+ NaBH4
Halogenation Reactions of Alkenes, Alkynes and Aromatics
HC C
HH
H HC C
BrBr
H+ Br Br H H
C CH HH
C CBrBr
H+ Br Br Br Br
2 equiv.
+ Br Br
Br
FeBr3catalyst
Alkyl Halides
Structure and properties
• Dense liquids and solids, insoluble in water • C-X bond is polar: δ+ on the carbon end, δ- on the halogen • C-X bond is long, weak and polarised - easy to break
C Xδδ
X = F, Cl, Br or I
dipole moment
the carbon can be readily attacked by a Nucleophile, Nu-
Nucleophilic Substitution
Nu H3C X+ Nu CH3 + Xδδ
Nu H3C X+ Nu CH3 + Xδδ
nucleophile
Electrophile (electron-loving): seeks an electron pair
Nucleophile (nucleus loving): supplies an electron pair
Nucleophilic: it's a nucleophile that substitutes
• Amines are classified as primary, secondary or tertiary
• Different from 1°, 2°, 3° alcohols or cabocations- depends how many ‘R’ groups are attached directly to the N
RN RR
Quaternary ammonium salt
RI
1°, 2°, 3° Amines
RN HH
Primary amine
RN HR
Secondary amine
RN RR
Tertiary amine
Amines
H3CC C
NH2H
HH
H
HCl
H3CC C
NH3 ClH
HH
HNaOH
amines are bases
and nucleophiles
H3CN
H3C
H3C
trimethylamine
H3C ClH3C
N
H3C
H3C CH3 Cl
tetramethylammoniumchloride
1°, 2° and 3° Alcohols
C OH C OH
R R
HH
H R'
C OHR
R''
R'
1° alcohol 2° alcohol 3° alcohol
1°, 2° and 3° indicate the number of groups other than Hattached directly to the carbon bearing the OH group
Reactions of alcohols
H3CC C
ClH
HH
HH3C
C COH
H
HH
H
H3CC C
H
H
HH3C
C CBr
H
HH
H
H3CC C
O
HH
H
H3CC C
H
H
O
OH
oxidation
Conc. H2SO4heat
Conc. HBr
SOCl2
substitution
or Conc. HCl
elimination
Cr2O72- / H+
Cr2O72- / H+
Conversion of Alcohols into Alkyl Halides
The reverse reaction is easy - see later in reactions of alkyl halides - must first convert the OH into a better leaving group
H3CC C
ClH
HH
H
H3CC C
OHH
HH
H
H3CC C
BrH
HH
H
Conc. HBr
SOCl2
substitution
Conc. HCl
H3CC C
OH
HH
HH
H
via
H3CC C
OHH
HH
HH3C
C CCl
H
HH
H
H3CC C
OH
HH
HSOCl
SO2 HCl
O
H
O
OH
O
H
O
OH
O
OH
OH
OH
OH
Cr2O72-
Cr2O72-
Cr2O72-
Cr2O72-
Cr2O72-
Cr2O72-
Cr2O72- Cr3+
1.
2.
3.
4.
Cr2O72-
Oxidation - aldehydes react further!
Hydride Reduction
Use “H¯” (LiAlH4 or NaBH4) followed by H+ Aldehydes → primary alcohols, ketones → secondary alcohols
RC O
H
RC O
H
HH R
C O
H
HH
primary alcohol
δ δB
H
H
H
H
RC O
R
RC O
R
HH R
C O
R
HH
secondary alcohol
δ δB
H
H
H
H
Formation of Grignard Reagents
Uses an alkyl halide or aryl halide and magnesium metal
R X + Mg R Mg X X = Cl, Br, IR = alkyl, aromatic
δ δδδ
methylmagnesium bromide
butylmagnesium iodide
phenylmagnesium chloride
I
Cl
Mg I
MgCl
CH3Br + Mg CH3MgBr
+ Mg
+ Mg
Grignard Reaction
H3C
RC O
H
RC O
H
H3CH
MgBr MgBr
RC O
H
H3CH
secondary alcohol
δ δ
With other aldehydes: makes a secondary alcohol …
H3C
RC O
R
RC O
R
H3CH
MgBrMgBr
RC O
R
H3CHδ δ
tertiary alcohol
With ketones: makes a tertiary alcohol …
Grignard Reaction
CO
H3CH
CO
H3CH
carboxylic acidMgBr
H3C δ
δ
MgBr
O
C
O δ
O O
And with CO2 can make a carboxylic acid!
Reactions of carboxylic acids
H
O
OH
OH
O
Cl
O
O
O
NaCr2O72- / H+ aq. NaOH
aq. HCl
1. LiAlH42. H+
1. LiAlH42. H+
SOCl2
OCH3
O
CH3OHH+ (cat)
aldehyde carboxylic acid sodium carboxylate
alcohol ester acid chloride
Reactions: Ester formation
OH
O
OCH3
O
CH3OH
H+ (cat)
carboxylic acid ester
R OH
O
R OR'
OH+ (cat)+ R'OH
alcohol
heat
water+ +
Reactions: Reduction
Reduction to a primary alcohol Two step reaction - lithium aluminium hydride then
aqueous acid
RC
OH
HRC
O
OH
alcohol
2) H
reduction H
1) LiAlH4
carboxylic acids
Example:
OH
O
2) H
reduction
1) LiAlH4
OH3-propylhexanoic acid 3-propylhexanol
Carboxylic Acid Derivatives Structure
• Carboxylic acid derivatives all have an acyl group, attached to a heteroatom (O, N, halogen) that is an element of the periodic table groups 15,16, or 17
• Four classes to consider here:
RC
Cl
O
acid chloride
RC
O
O
R'
ester
RC
N
O
R'
R"
amide
RC
O
O
CR
O
acid anhydride
O
CR Y
acyl
-OH of carboxylic acid replaced by new group
Hydrolysis All carboxylic acid derivatives can be hydrolysed to the parent acid and another product with water (and a catalyst H+ or OH-)
RC
Cl
Oacid chloride
RC
O
Oester
RC
N
O
R'
R"
amide
+ H2O + H2O + H2O
RC
OH
O
+
H Cl
R'
RC
OH
O
OR'H
RC
OH
O
N
R'
R"H+ +
hydrochloric acid alcohol amine
acid acid acid
RC
O
Oacid anhydride
+ H2O
C
RC
OH
O
H
+
acid
acid
R
O
OC
R
O
Hydrolysis of Amides Note that the products formed depend on the conditions used
e.g.
H2NNH
O
cold 1M HCl
no reaction
boiling 4 M HCl
12 hours
cold 1M NaOH
boiling 6 M NaOH
12 hours +H2N
ON
H H
O Na
NNH
O
H
HH
Cl
NOH
O
H
HH
Cl
+
NH H
H
Cl
Interconversion of derivatives - summary
R OH
O
SOCl2R'OHH+ (cat)
carboxylic acid
ester
acid chloride
R Cl
O
R OR'
O R'OH
R NHR'
O
amide
R'NH2 excess
R'NH2
H+ (cat)
heat
heat
most reactive
least reactive
Interconversion - examples Acid chloride to ester
H3CC
Cl
O
RC
N
O
H
CH3+ N
H
CH3H+ H Cl
2 equivalentsneeded
reacts with amine!
N
H
CH3H
N
H
CH3H
H Cl
H3CC
Cl
O
RC
O
O
CH3+ OCH3H + H Cl
Acid chloride to amide
Interconversion - examples
Acid anhydride to ester
OH
O
O
OH3C
OH
O
OH+
H3C O CH3
O O heat+ H
O CH3
O
acetic anhydride acetic acid
ester
Aspirin synthesis involves this reaction. The reagent acetic anhydride is an illegal compound in Thailand because it can be used in heroin production.
Recap Ester & amide formation
Cl
O
OCH2CH3
O+ HClH OCH2CH3+
acid chloride + alcohol = ester + HCl
OCH3
O
NCH2CH3
O+ HOCH3
H NCH2CH3+
ester + amine = amide + alcoholH
H
Cl
O
NCH2CH3
O+ HClH NCH2CH3+
acid chloride + amine = amide + HCl
HH
need to add a base to scavenge HCl or it will react with starting amine
Curly Arrows
A mechanism shows the exact sequence of steps that takes place in a reaction
• A ‘time-lapse photograph’ or ‘blow-by-blow account’ • Movement of a pair of electrons represented using curly
arrows
The mechanism of a reaction shows exact sequence of steps that takes place – a ‘time-lapse photograph’ or ‘blow-by-blow account’
eg.
Mechanism
OCR'
R
B OC
R'
R
HH
H
H
H
OC
R'
R
H H OC
R'
R
H H
H3CC
CH3
O Et2OEtOH H3C
CCH3
OH
H+
H3CC
CH3
O HH+ NaBH4
Hydration
Addition of water: H+ catalyst required (eg., dilute H2SO4) Again two main steps … but also a third mini-step Step 1: H+ adds to give a carbocation
Step 2: H2O intercepts (using spare electrons on O)
Step 3: H+ is removed (by conjugate base of H2SO4)
HCC
H3C H
H3C+ H
HCC
H
H3CH
H3Ccarbocation
step 1
HCCH
H3CH
H3C+
carbocation
HOH
step 2 HCC
H3C H
OHH3C
HH
water molecule
HCC
H3C H
OHH3C
Hstep 3
HSO4-
+ H2SO4
Hydrohalogenation
Two steps Step 1: H+ adds
An unstable intermediate carbocation is formed
Step 2: Br- adds The carbocation is intercepted by bromide anion
HCC
H3C H
H3C+ H Br
step 1 HCC
H
H3CH
H3C+
a carbocation
Brδ δ
HCC
H3C H
BrHH3C
HCC
H
H3CH
H3C+
step 2
a carbocation
Br
Three stages 1. Protonation
2. Loss of water
3. Deprotonation to form alkene
C C
OH
HH CH3
H
HH
OH
HC CH
HH CH3
H
carbocation
+
Flashback
Mechanism of Dehydration
C COH
HH CH3
H
HH HSO4
C C
OH
HH CH3
H
HH oxonium ion
( )
C C
H
HH CH3
H
HSO4
C CH
H CH3
HH2SO4+
Hydrolysis
RC
Cl
O
acid chloride(electrophile)
+O
H Hδ
δ
water(nucleophile)
step 1
RC
Cl
O
O
H
Hδδ
δ
nucleophilicadditionδ
Mechanism: Nucleophilic acyl substitution
step 1: nucleophilic addition to electrophilic carbon of acid chloride ... gives a tetrahedral intermediate
step 2: acid/base reaction (deprotonation of the tetrahedral intermediate)
step 3: collapse of the tetrahedral intermediate to regenerate the C=O π-bond with elimination of chloride anion as leaving group
step 2acid-base reaction
RC
Cl
O
OH
+ H
Base
RC
O
O
+
H
hydrochloric acidcarboxylic acid
Cl
step 3H
elimination
The Challenge of Synthesis
The challenge of synthesis lies in combining more than one reaction
?H
O
NH
O
?
?Br O
Need to think backwards as well as forwards.