chemistry 1b – chem1102 7-1102.pdfchemistry 1b – chem1102 professor max crossley, room 547,...

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


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

Answer to Exercise

O O

N

H

N

H n

Cl

O O

Cl

H3CO

O O

OCH3

H2N NH2andor

•  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

Sugars and DNA are natural polymers

Cellulose

DNA

CHEM1102 – Organic Chemistry











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


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’


Combine the two to solve our puzzle …

First stepNucleophilic SubstitutionUse H2O (and dilute OH-)

OH OBr

Second stepOxidation

Use K2Cr2O7 and H+

Challenge of Synthesis

Howabout this one? ?

Thinking forwards from reagents …

H

H

OH

H

Br

H


OH

H

Cl

H

Br

H

?

Thinking backwards from product …


Combine forwards and backwards for several solutions …

Br

H

Cl

H

OH

H

Exercise:

What Reagents would you use?


And this one?

Thinking forwards from reagents …

H

O

OH

OH

O

H

OH

R

?H

O

NH

O


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











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

Mass Spectrometry

CH3 OHMolecular Ion

•  Example: methanol

CH3

Daughter Ion

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

Isomers -revisited

Better described As Diastereomers

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)

ChemGlobe Periodic Table – http://www.vcs.ethz.ch/chemglobe/ptoe/

Electrons & Protons

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


eg. Amines

Organic Reactions


NCH3CH3C

NCH3CH3C

H3CHH

HH

+ H Cl

HH3CCl

OH+ H2ONCH3CH3C

NCH3CH3C

H3CHH

HH

+HH3C

Cl


eg. Phenols

Organic Reactions


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 Esters Note that the products formed depend on the conditions used

e.g., Aspirin

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.


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.

Summary

You should now be able to

1.  Appreciate the challenge of synthesis

2. Work forwards and backwards to devise a synthetic route

3.  Begin to understand mechanism and reactivity

4.  Begin to spot the links that tie organic chemistry together

chemistry 1b – chem1102 7-1102.pdfchemistry 1b – chem1102 professor max crossley, room 547,...

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