Heteroaromatic molecules

Question 1

What are heteroaromatic molecules?

Answer 1

Aromatic molecules in which one or more carbon atom are replaced by a hertoatom

O, N, S

Question 2

Draw:

pyridine, pyrrole, furan, thiophene,

imidazole, oxazole, thiazole,

quinoline, isoquiniline and indole

Answer 2

Question 3

What is the structure of pyridine?

Answer 3

Obeys Hückel’s rule [4n+2] π electrons when n = 1

N is sp² hybridised so contribues 1 electron to the π system

6 π electrons over 6 orbitals.

N is electronegative so the ring is π deficient compared to benzene

Question 4

Describe the proton environments of pyridine

Answer 4

In the ortho position to the N: δ_H = 8.5 - string withdrawing effect from the nitrogen so very deshielded

In the meta position to the N: δ_H = 7.1 - alost the same as benzene environments - no mesomeric effect from the N

In the para position to the N = δ_H = 7.5 - less deshielded as further from N but still feels mesomeric effect due to resonance forms

Question 5

In pyridine is the N lone pair involved in the ring structure

Answer 5

NO

N donates 1 electron t the ring

The lone pair is in an orbital in the planne of the ring and orthogonal to the pi system so cannot interact with the other pi orbitals above and below the ring

Question 6

Draw the resonance forms of pyridine and use it to eplain the proton environements

Answer 6

There are 4 resonance forms

At no point s the +ve charge on the meta position so the H environment is similar to benzene

+ve charge can be placed on the oprtho p;ara position so the protons are more deshielded

Question 7

What is the reactivity of pyridine?

Answer 7

The lone pair allowes pyridine to act as a weak bae (pKa = 5.5). The pyridinium ion is acidic

The lone pair also makes pyridine nucleophilic at the N

Question 8

Draw N-alkylation of pyridine

Answer 8

Use a haloalkane

Question 9

Draw N-acylation of pyridine and show the further reaction that can occur

Answer 9

Use acyl halide

The N-C-O bond is not an amide because the lone pair is involved in bonding to the carbon rather than delocalised into the C=O bond

The further reaction can produce an ester and the pyridinium ion using an alcohol

Adding pyridine to the reaction between an acyl chloride and an alcohol speeds up ester formation

Question 10

Explain why electrophilic substitution does not often occur on pyridine

Answer 10

Electrophiles tend to attack at the nitrogen rather than the carbon forming pyridinium ions or complexes which are inert to other electrophiles

The elecron deficient ring is not very nucleophilic

Pyridines nitrogen atom destabalises the cationic intermediate

Question 11

How does N destabalise the cationic intermediate involved in electrophilic substitution of pyridine

Answer 11

Substituion at the C4 position (para) places a +ve charge on the C3 position. In resonance forms this moves to the N which is very unstable

Substitution of the C2 position place a +ve charge directly on the N which is very unfavourable

Substitution of the C3 position would be the most favourable as it has 3 resonance forms that do not place the +ve charge on the N - substitution only works in this position under very forcing conditions and produces ~5% yield

Question 12

How can make a pyridine undergo electrophilic aromatic substitution?

Answer 12

Activate the ring - one method is to convert to a pyridine N-oxide

Question 13

How can we convert a pyridine N-oxide back to pyridine?

Answer 13

Use PCl₃

Forms substituted pyridine and POCl₃

Reaction is driven by the strength if the P=O bond - similar to Wittig reaction

Question 14

Can pyridines undergo nucleophilic substitution and why?

Answer 14

The N atom makes pyridine more reactive to nucleophilic substitution particularly at the C2 and C4 positions as the -ve charge can be delocalised onto the N.

Question 15

What is the reactivity of enones?

Answer 15

substitution occurs at the C4 and C2 prosition but not at C3 similar to pyridines

Question 16

What is the mechanism of the Chichibabin reaction?

Answer 16

Nucleophilic substitution of pyridine with the unusual example of hydride (H^-) as a leaving group.

Requires high temperatures

Question 17

What is the mechanism of reaction of pyridines with grignards and organolithiums

Answer 17

There is the fomal loss of hydride but the mechanism is actually more complex.

Question 18

What is the mechanism of substitution of 2- and 4-Halopyridines

Answer 18

Question 19

What is the mechanism of substitution of Pyridine N-Oxides

Answer 19

Question 20

How do we know which reaction to use for nucleophilic substitution?

Answer 20

Striong nucleophiles can be substitued directly with the Chichibabin reaction

Medium nucleophiles can be substituted if a suitable leaving group is present on pyridine (halogen)

If a weak nucleophile must be substituted pyridine N-Oxide can be substitued with a halogen and then further substituted

Question 21

Describe the reactivity of 2- and 4- methyl puridines

Answer 21

2- and 4-Methyl pyridines can be deprotonated with a base as the resulting anion is resonance stabalised (-ve charge can be delocalised on N and aromatic ring)

Protons alpha to the ring are basic

Addition can then occur

Question 22

What is the RSA of pyridine?

Answer 22

Pyridines have enamine like and an imine like features

This allows disconnection back to a 1,5-dicarbonyl compound and an amine equivalent

Question 23

What is the mechanism of the synthesis of pyridines?

Answer 23

Uses an enone, ketone and an amine

Ketone tautomerises to enol, addition to enone, tautomerisation to ketone, addition of amine, enamine formation, imine formation, loss of water (in situ when NH₂OH is used)

Question 24

What is the mechanism of the Hantzch synthesis for pyridines?

Answer 24

Uses 3 carbonyls (2 ketones, 1 aldehyde) and ammonia

Enone is made in situ

Addition of ammonia to one ketone to form enamine, tautomerisation of other ketone, aldol reaction between enol and aldehyde, dehydration to form enone, addition of enamine, tautomerisation to ketone, imine formation, dehydration, tautomerisation to enamine, oxidation

Usually a drying agent used to push the reaction in forward direction, Imine, enamine formation is reversible

Question 25

What is the structure of pyrrole?

Answer 25

Pyrroles obey the Huckel's rule where n=1 There are 4 sp² hybridised carbons contributing 1 electrons each and 1 sp² hybridised nitrogen which contributes 2 electrons to the pi ring. The pi ring is pi excessive as the nitrogen lone pair is delocalised into the ring. The N-H bond is orthogonal to the ring. The proton environments reflect the pi excessive

Question 26

What are the resonance forms of pyrrole

Answer 26

Question 27

What is the reactivity of pyrrole?

Answer 27

A consenquence of nitrgens lone pair being delocalised into the ring is that pyrrole is not basic at nitrogen. If when prrole does act as a base it protonates on C2 carbon and has a pKa of -4 The N-H is acidic with the pKa of 16.5

Question 28

Does pyrrole undergo electrophilic substitution?

Answer 28

Pyrrole readily undergoes electrophilic substitution at the C2 position Sunstitution occurs at C2 as there are 3 canonical forms compared with 2 canonical structures associated with C3

Question 29

Examples of electrophilic aromatic subsitution

Answer 29

Question 30

What is the Vilsmeier Formylation?

Answer 30

Electrophilic aromatic substituion of pyrole using DMF and POCl₃

Question 31

What is the Mannich reaction?

Answer 31

2 step reaction Step 1: use methanal and Me₂NH to form an iminium and then add this to the pyrrole with a loss of H⁺ Step 2: Use MeI and NaOH to subsitute the NMe with an OH group

Question 32

How can susbstitution on the N take place in pyrrole?

Answer 32

Deprotonation with a strong base and then trapping eith an electrophile

Question 33

Explain lithiation of N-Methylated Pyrrole

Answer 33

N-Methylated pyrroles can be deprotonated at the C2 position by a strong base Deprotonation occurs at C2 because of the electron withdsrawing nature of the heteroatom The 2-lithopyrroles are mucleophilic and can react with a variety of electrophiles to get substitution in the 2 position

Question 34

What is the RSA of a pyrrole?

Answer 34

Pyrroles have enamine like features which allows a disconnection to a 1,4-dicarbonyl and an amine equivalent

Question 35

What is the Hantzch sythesis for pyrroles?

Answer 35

Use of a bromoketone, ketone and ammonia enamine formation, alkylation, tautomerisation, imine formation, loss of water, tautomerisation

Question 36

What is the Paal-Knorr synthesis

Answer 36

Use of diketone and BnNH₂ enamine formation, imine formation, loss of water, tautomerisation

Question 37

What is the Knorr synthesis of pyrroles?

Answer 37

3 step process Step 1: form oxime from ketoester and HNO₃ Step 2: Zn reduction of NOH on oxime to NH₂ Step 3: USe ketone with AcOH to make pyrrole

Question 38

What are furans and thiophenes?

Answer 38

Oxygen and sulfur analogues of pyrrole THey obey Huckel's rule when n=1 They have 4 s_p² hybridised carbons whch contributre 1 electron each and 1 s_p² hybridised heteroatom which contributes 2 electrons Has 6 electrons over 5 atoms and is therefore electron rich

Question 39

What is the reactivity of furans and thiophenes?

Answer 39

Both have aromatic character Undergo very similar reactions to pyrrole Furan and thiophene are less nucleophilic than pyrrole (thiophene is the least reactive to electrophiles) This is due to the 3p orbital conjugating with the ring rather than the 2p used by N and O pyrrole \> furan \> thiophene \> benzene

Question 40

Do furans and thiophenes undergo electrophilic subsitution?

Answer 40

Bith can undergo electrophilic subsitution at C2 same as pyrrole Slightly more forcing conditions must be used as furan and thiophene are less reactive than pyrrole e.g use of lewis acid activator (ZnCl₂/Ac₂O)

Question 41

What are ghe differences in electrophilic substitution of furan and pyrrole

Answer 41

Furan can undergo either electrohphilic aromatic substitution or addition depending on conditions Furan is boarder line aromatic - low stabalisation energy, can act like a diene

Question 42

How can furans act like dienes?

Answer 42

Furan can undergo Diels-Alder reactions due to its low stabalisation energy

Question 43

How can furan or thiophenes act as organometallics?

Answer 43

The protons at the c2 position are acidic due to the electron withdrawing effect of the heteroatom It can therefore be removed by a strong base (BuLi) The resulting lithiated form can act as an organolithium

Question 44

What are the RSAs for furan and thiophene?

Answer 44

Furans and thiophenes have enol like features that allow their disconnection to 1,4-dicarbonyls

Question 45

What is the mechanism to form a furan using a 1,4-diketone and acid?

Answer 45

Addition of proton, tautomerisation, attack on carbonyl, H⁺ transfer, loss of water, tautomerisation

Question 46

How can you convert a 1,4-dicarbonyl to a 1,4-diC=S?

Answer 46

Use P₂S₅ Mechanism to form thiophene then the same as furan

Question 47

What are imidazoles, thiazoles and oxazoles?

Answer 47

Structures with the replacement of the C3 carbon in a pyrrole, thiophene or furan with a nitrogen atom Aromaticity is retained General term is 1,3-azoles Aromaticity comes from delocalisation of lone pair of the second heteroatom

Question 48

What is the reactivity of imidazoles, thiazoles and oxazoles?

Answer 48

All can be deprotonated at the 3-N Imidazole (pKa = 7), Thiazole (pKa = 2.5), Oxazole (pKa = 0.8) Imidazole is a stronger base than pyridine Oxazole is such a weak base that when protonated it acts as strong acid

Question 49

Can 1,3-azoles undergo electrophilic aromatic substitution?

Answer 49

The presence of the pyridine like 3N deactiviates the ring to electrophilic attack However if the ring has an electron donating group on it electrophilic aromatic substitution can take place.

Question 50

Can 1,3-azoles act as organolithiums?

Answer 50

The protons at the 2 position are acidic due to the withdrawing nature of both heteroatoms It can be removed by a strong base (BuLi)

Question 51

What is the reactivity of C2 alkyl groups?

Answer 51

Alkyl groups at the C2 position of a 1,3-azole can be deprotonated by a strong base and quenched by a range f eletrophiles. This leads to functionalisation

Question 52

What is the RSA of an 1,3-azoles?

Answer 52

Disconnection at the heteroatoms reveals an a-substituted ketone and a carboxylic acid derivative

Question 53

What is the mechanism for synthesis of an imidazole?

Answer 53

Use α-bromoketone and an amidine Attack of =NH onto α-carbon, attack of =NH₂ onto carbonyl, tautomerisation, loss of water

Question 54

What is the mechanism of a synthesis of a thiazole?

Answer 54

Use α-bromoketone and a thioamide Attack of =S onto α-carbon, attack of =NH₂ onto carbonyl, tautomerisation, loss of water

Question 55

What is the mechanism of synthesis of an oxazole?

Answer 55

Do not use a bromoketone and an amide - amides are not nucleophilic enough to react so the nucleophilic and electrophilic partners are swapped Use α-aminoketone and acyl chloride and SOCL₂ Attack of amine onto carbonyl, electrons from N-H bond form N=C and the carbonyl attacks SOCl_2, chloride attacks carbon of N=C-O and SO₂Cl is lost, carbonyl attacks carbon of N=C-Cl

Question 56

What are quinolines and isoquinolines?

Answer 56

Contain a pyridine ringfused to a benzene ring Two possible isomers: N fused in 1 position (quinoline) or in 2 position (isoquinoline) Both are aromatic: obey huckels rule when n=2 N is sp2 hybridised so contributes 1 electron

Question 57

What is the recativity of quinoline and isoquiniline?

Answer 57

The N containing ring has reactivity similar to pyridine The carbocyclic ring has reactivity similar to benzene

Question 58

Can quinolines/isoquinilines undergo electrophilic aromatic substitution?

Answer 58

N deactivates the rig making it less reactive to lectrophilic aromatic subsitution Electrophilic substituion takes place on the benzene ring at positions 5 and 8 (2 canonical forms without distrupting the aromaticity ofthe heteroaromatic ring) Position 6 and 7 only has 1

Question 59

Can quinolines/isoquinolines undergo nuceophilic substitution?

Answer 59

Nucleophilic substitution does not occur take place on the carbocyclic ring. Nucleophilic substitution can occur on the pyridine ring In quinoline substitution happens on the 2 and 4 position On isoquinoline it happens on the 1 position

Question 60

What is the reactivity of methyl quinolines/isoquinolines

Answer 60

2- and 4- methyl quinolines and 1-methyl isoquinolines can be deprotonated by a base - the resulting the anion is resonance stabalised and the negative charge can be delocalised onto the N

Question 61

What is the RSA of a quinoline?

Answer 61

Disconnection at the imine like functional group reveals an aromatic amine and a 1,3-*bis*-electrophile either 1,3-ketone or enone

Question 62

What is the mechanism of a quinoline synthesis?

Answer 62

Use aromatic amine and1,3- diketone enamine formation, Friedel Crafts, tautomerisation, loss of water

Question 63

What is the Skraup synthesis of quinolines?

Answer 63

Uses aromatic amine and unsaturated ketone Michael addition of amine, tautomerisation, benzene ring attacks carbonyl, tautomerisation, lossof water, air oxidation

Question 64

What si the RSA of an isoquinioine?

Answer 64

Disconnection a imine like functional group reveals an aromatic aldehyde or ketone and an aminoketone To stop the aminoketone reacting with itself the ketone needs to be protected as a ketal

Question 65

What is the mechanism to synthesise an isoquinoline?

Answer 65

Use an aromtic aldehydeand an aminoketal Amine attacks carbonyl (imine formation), deprotection, Friedel Crafts, tautomerisation, loss of methanol

Question 66

What is the alternative RSA for isoquinolines?

Answer 66

Disconnect between N and C3 and between C1 and bridge to form an amine and an acyl chloride

Question 67

What is the Bischler-Napieralski synthesis of isoquinolines?

Answer 67

Uses amine, acyl chloride and POCl₃ Amide formation, carbonyl attacks POCl₃, Vilsmeier, tautomerisation, oxidation

Question 68

What are indoles?

Answer 68

Pyrrole ring fused to a benzene Obeys Huckels rule when n=2 The indole N is sp2 hybridised and contributes 2 electrons so indole is not basic

Question 69

What is the reactivity of indole?

Answer 69

The indole ring is electron rich and can therefore undergo electrophilic aromatic substitution Electrophilic aromatic substitution occurs at C3 position as substitution at C2 distrupts the aromaticity of the benzene ring

Question 70

What effect does a strong base have on indoles?

Answer 70

The N-H can be deprotonated with a string base. The resukting anion can react with electrophiles at the N or the C3 With lithium, sodium and potassium counter ions reaction tends to occur and the N whereas with Mg (due to more covalent nature) reaction tends to occur and C3 When the nitrogen is blocked deprotonation can occur at C3

Question 71

What is the RSA of an indole?

Answer 71

Disconnection at the enamine like function reveals an aminal Further disconnection at the aminal reveals an amide which can be formed from a substituted analine and an acyl chloride

Question 72

What is the Madelung synthesis of indoles?

Answer 72

Uses substitutes aniline, acyl chloride and ^tBuOK Amide formation, deprotonation of α carbon, -ve charge attacks carbonyl, loss of water

Question 73

Alternative RSA of indoles?

Answer 73

Disconnection at the enamine like feature reveals a ketone Further disconnection betweent the aromatic ring and a position of the ketone reveals an amine precursor and a ketone The precursor can be a hydrazine

Question 74

What is the Fischer indole synthesis?

Answer 74

Uses hydrazine, and ketone and acid Enamine formation, sigmatropic rearrangement, addition of NH₂ to C=N, loss of ammonia, tautomerisation Loss of ammonia is the driving force