Heterocyclic and Aromatic Chemistry

Question 1

Draw a mechanism with Imines that show how delocalisation can explain reactivity with an electrophile

Answer 1

should be an imine in a resonance form with the alpha carbon attacking electrophile for electrophilic addition

Question 2

Explain inductive effects

Answer 2

describes bond polarisation due to electronegativity differences like when an electronegative polarises a bond, withdrawing electrons from electropositive atom

Question 3

Explain mesomeric effects

Answer 3

describes how functional groups extends resonance/ delocalisation of electrons in a molecule

Question 4

Why is benzene so stable

Answer 4

conjugated molecule, lots of resonance forms, all carbons are sp2 hybridised, follows aromaticity rule. all electrons occupy the lower energy bonding MOs

Question 5

what is the aromaticity rule

Answer 5

4n+2+number of pi electrons, where n has to be an integer. if this rule is followed, molecule said to be a planar, fully conjugated, cyclic system and are exceptionally stable

Question 6

what is pKa

Answer 6

measure of acidity and basicity, describes how much of the acid has deprotonated and exists in its conjugate base form

Question 7

what is an acid

Answer 7

species with tendency to loose proton

Question 8

what is a base

Answer 8

species with tendency to accept proton

Question 9

what does a lower pKa mean

Answer 9

lower pKa = stronger the acid

Question 10

what are 3 main factors that effect strength of an acid

Answer 10

stability of its conjugate base (A-)
the H-A bond strength
the solvent

Question 11

how do we measure strength of bases?

Answer 11

base strength measured by considering pKa of conjugate acid = pKaH
the lower pKaH = weaker the base

Question 12

What factor effects base strength

Answer 12

availability of it s lone pair of electrons, if B is electronegative it will likely be a good base, but if B has electron withdrawing groups attached, lone pair is less available so weaker base

Question 13

What is an aniline? is it a good base?

Answer 13

an NH2 group, often a good base but when attached to an EWG like benzene, becomes a weaker base but aniline sp3 hybridised so only partial delocalisation into benzene ring

Question 14

Why does phenol have such high acidity

Answer 14

because its conjugate base is very stable as it has many resonance forms

Question 15

describe properties of pyridine

Answer 15

is isoelectric with benzene, similar just 1 carbon atom replaced with nitrogen atom. al atoms are still sp2 hybridised, but nitrogen has a a lone pair orthogonal to the ring is not involved in delocalisation (is available for reactions)

Question 16

how does pyridine fulfil the rules of aromaticity

Answer 16

its cyclic, planar, fully conjugated and fits the 4n+2 rule as nitrogen only donates 1 electron

Question 17

how does the nitrogen effect the structure and reactivity of pyridine?

Answer 17

nitrogen is electronegative so pulls electron density towards it so the carbon-4 has a lower electron density. this makes the resonance stability weaker than benzenes. also causes pyridine has lower HOMO/LUMO energies than benzene.

Question 18

how does pyridine react?
acid/base?
nucleophile/electrophile?

Answer 18

its a weak base and a reasonable nucleophile, it can easily undergo nucleophilic aromatic substitution

Question 19

how do EWG/ EDGs effect basicity

Answer 19

electron withdrawing groups decrease basicity, electron donating groups increase basicity

Question 20

Why is hydroxypyrimidine a special case of pyrimidines

Answer 20

hydroxy pyrimidine can act as a weak base or weak acid. can also exist as tautomeric forms

Question 21

how can pyridine act as a nucleophilic catalyst? when is it useful?

Answer 21

often used with ester synthesis, the nitrogen lone pair is available for nucleophilic attack on electrophiles

Question 22

what is pyrrole

Answer 22

isoelectric with cylcopentadiene anion, 5 membered aromatic ring with a carbon replaced with a nitrogen. nitrogen is sp2 hybridised, the lone pair is delocalised into the aromatic ring

Question 23

is pyrrole basic/acidic?
how does it react?

Answer 23

pyrrole doesn’t have a lone pair available for reactivity, making the pyrrole nitrogen non-basic and non-nucleophilic.
making pyrrole electron rich so acts nucleophilic, making electrophilic aromatic substitution very easy

Question 24

what is the differences between furan and thiophene

Answer 24

stem from their differences in electronegativity, N and O are more electronegative which makes the resonance stabilisation weaker but S has a similar electronegativity to C so there is good orbital overlap and the lone pair is donated into the pi system making strong resonance stabilisation

Question 25

describe electrophilic aromatic substitution. Draw mechanism.

Answer 25

includes bromination, nitration or sulfonation. benzene attacks reactive electrophile formed from Lewis acid includes a Wheland intermediate formation as the RDS Check notes for correct mechanism

Question 26

What is Friedel-Crafts alkylation used for? Draw mechanism

Answer 26

used for adding r(alkyl) groups onto benzene from R-Cl. Lewis acid used to form reactive electrophile (carbocation) Check notes for mechanism

Question 27

What are some disadvantages with Friedel-Crafts alkylation

Answer 27

the product formed from alkylation is more reactive than the starting materials as alkyl groups are electron donating so over-alkylation may occur. Its only useful with tertiary alkyl halide electrophiles as rearrangement occurs from carbocation formation

Question 28

What the best way to convert benzene to propylbenzene

Answer 28

not Friedel crafts alkylation as it'll be the minor product so low yield due to the carbocation forming on the wrong carbon. best way is to make a ketone via Friedel-Crafts acylation then reduce it to form alkane

Question 29

Draw the mechanism of Friedel-Crafts acylation

Answer 29

check notes for mechanism generation of acylium ion electrophile electrophilic aromatic substitution

Question 30

how do substituents effect electrophilic aromatic substitution

Answer 30

substituents will have an effect on rate and selectivity of reaction electron rich aromatics are more nucleophilic and so will react faster electron poor aromatics are less nucleophilic so will react slower

Question 31

Why is toluene nitrated faster than benzene

Answer 31

because toluene has an alkyl group which is electron donating, making aromatic ring more electron rich so is more nucleophilic so will react faster with the nitrate electrophile

Question 32

How do substituents effect regioselectivity?

Answer 32

electron donating groups form ortho and para products and electron withdrawing groups form meta products. this is due to the type of intermediate formed and the resonance structures it can form.

Question 33

How do halogens effect selectivity?

Answer 33

halogens are inductively electron withdrawing which deactivate the benzene ring causing a much slower reaction but they do have a mesomeric electron donating effect due to overlap of sigma and pi orbitals but very weak and so gives little influence

Question 34

why doesnt pyridine readily undergo electrophilic aromatic substitution

Answer 34

due to 3 factors nitrogen in ring lowers the HOMO compared to benzene making the ring electron deficient so less nucleophilic pyridine acts similar to a deactivated benzene kinetic product is attack at N forming an inert transition state. overall a low reactivity with electrophiles

Question 35

how can we make pyridine undergo electrophilic aromatic substitution?

Answer 35

if we activate pyridines with electron donating group substituents or with N-oxides where the O acts as a protecting group and activating group. pyridine becomes nucleophilic on ortho and para carbon

Question 36

Draw the mechanism of electrophilic aromatic substitution of pyridine with N-oxides and NO2 group

Answer 36

check notes for mechanism 1st step protection with oxidation of N 2nd step is electrophilic substitution 3rd step is deprotection/reduction with PPh3

Question 37

When pyrrole undergoes electrophilic aromatic substitution, where is attack generally preferred

Answer 37

attack on 2-position favoured due to it having the most resonance forms so most stable intermediate carbocation formed. Very fast EAS

Question 38

What is the Vilsmeier-Haak reaction used for?

Answer 38

used for over reactive heteroaromatics, to selectively react. Lewis acid free alternative to Friedel-Crafts reaction

Question 39

Explain and draw Vilsmeier-Haak reaction (3steps)

Answer 39

step1-formation of carbon electrophile using DMF and POCl3 step2-electrophilic aromatic substitution step3-hydrolysis of imine

Question 40

Explain the selectivity of indoles with electrophilic aromatic substitution

Answer 40

reactive pyrrole ring and an unreactive benzene ring joined together. electrophilic aromatic substitution occurs on the pyrrole ring, favouring the 3-position so the aromaticity of benzene is not disturbed.

Question 41

What is quinoline and where is it most reactive for EAS

Answer 41

benzene ring attached to pyridine ring. EAS occurs on more electron rich benzene ring on carbon 5 from N

Question 42

Why is nucleophilic aromatic substitution less common? What are ways it actually can occur?

Answer 42

mechanistically it doesnt occur via normal substitution processes. Sn2 is impossible with aromatics and Sn1 is very unfavourable as benzene cation isnt stable. NAS can happen with a strong nucleophile, a halide leaving group, and EWGs para/ortho to LG

Question 43

how does leaving group ability effect nucleophilic aromatic substitution

Answer 43

a good leaving group like a halogen can speed up the RDS due to their inductive effects

Question 44

Draw the mechanism of NAS addition-elimination reaction of 1-flouro,4-nitrobenzene with HNMe2

Answer 44

check lec 6 sides for ans

Question 45

How do diazonium salts do Sn1 nucleophilic substitution

Answer 45

they work well as they have a very good leaving group- N2, which make the benzene cation.

Question 46

Draw mechanism of NAS via Sn1 mechanism with diazonium salt

Answer 46

lec 6 for ans, check summary

Question 47

What is an aryne mechanism? how does it work

Answer 47

substitution via a benzyne intermediate. starting material is halo benzene, X substituted for NH2 or OH works because benzyne is electron deficient so highly electrophilic so reacts readily with nucleophiles

Question 48

How is benzyne formed? Draw simple mechanism

Answer 48

using a very strong base and benzene with a good leaving group

Question 49

Why does nucleophilic attack occur easily in pyridines but not benzene?

Answer 49

because in pyridine the pi system is electron deficient so acts as an electrophile. due to its imine-like properties

Question 50

briefly describe the reactivity of imines

Answer 50

imines are susceptible to nucleophilic attack, halogen derivates are reactive and the halide is readily displaced. the alpha hydrogen is acidic (keto-enol tautomerism)

Question 51

What is the chichibabin reaction? draw mechanism of formation of 2-aminopyridine

Answer 51

example of nucleophilic aromatic substitution on pyridine. addition of NH2 group by leaving group H- ans in notes (L7)

Question 52

Draw mechanism of 2-Chloropyridine NAS with OMe

Answer 52

2-chloropyridine very reactive towards nucleophilic attack. check notes for ans

Question 53

Draw mechanism of pyridine-N-oxide NAS to form chloropryidine. What reagents needed?

Answer 53

POCl3 needed, strong O=P bond used as driving force check notes for ans

Question 54

Why is nucleophilic attack difficult for 5-membered aromatics?

Answer 54

because they are Pi-excessive due to lone pair being in the pi system so they are very electron dense so theyre more nucleophilic but can be more favourable when electron withdrawing groups are present.

Question 55

Draw mechanism of 5-membered NAS replacing Br with CO2R

Question 56

What is lithiation of aromatics useful for?

Answer 56

can use lithiation to extend reactivity and help direct reactivity

Question 57

Explain ortho-lithiation

Answer 57

n-Butyllithium can deprotonate aromatic compounds and form nucleophilic organolithium reagents that react with electrophiles aromatic compounds can be selectively lithiated ortho to certain substituents by DGs