heterocyclic compounds furan

Heterocyclic Compounds

Furan

By

DR.RUPESH KUMAR

Department of Chemistry , Kirori Mal College

University of Delhi, Delhi -110007

1

2

Aromatic Heterocycles:

• Heterocyclic compounds contain elements other

than carbon in a ring, such as N,S,O

• Cyclic compounds that contain only carbon are

called carbocycles (not homocycles)

• Nomenclature is specialized

Pyrrole Imidazole Pyridine Pyrimidine TriazinePyrazole Triazole

Thiophene Furan 3

4

Pyrrole• Four sp2-hybridized carbons with 4 p orbitals perpendicular to the

ring and 4 electrons

• Nitrogen atom is sp2-hybridized, and lone pair of electrons occupies a p orbital (6 electrons)

• Since lone pair electrons are in the aromatic ring, protonation destroys aromaticity, making pyrrole a very weak base (conjugate acid pKa=-4)

Other heterocycle compounds

Thiophene Furan

S O

Lone pair in sp2 orbital

six π electrons

Lone pair in sp2 orbital

six π electrons

5

6

Why 4n +2?

• When electrons fill the various molecular orbitals, it takes two electrons (one pair) to fill the lowest-lying orbital and four electrons (two pairs) to fill each of n succeeding energy levels.

• This is a total of 4n + 2.

7

Why 4n +2?Cyclopetadienyl molecular orbitals

8

Why 4n +2?Cycloheptatrienyl cation molecular orbital

+

Cycloheptatrienyl cation

9

10

11

Furan has planar pentagonal structure in which four carbon atoms and oxygen atom are in

sp2-hybridized state. The sp2-hybridized orbitals overlap with each other and with s-orbitals

of hydrogen to form carbon-carbon,carbon-oxygen and carbon-hydrogen bonds. Two lone

pairs of electrons on oxygen are in different orbitals; one lone pair of electrons is in sp2-

hybridized orbital, while other is in n-orbital. Four n-orbitals of four carbon atoms (each

containing one electron) and n-orbital of oxygen atom (with lone pair) are parallel to each

other and are perpendicular to the plane of the ring. The lateral overlapping of n-orbitals

produces a n-molecular orbital containing six n-electrons (Fig.30).

Furan

M.F.-C4H4O

Colour -Colourless and flammable

State-liquid, chloroform like smell and highly volatile

B.P. 31.4 °C

M.P. -85.6 °C

Dipole moment-0.97

Solubility- soluble in most organic solvents except diethyl ether

Insoluble in water

Density 0.936 g/mL

five-membered aromatic Compound

Molar mass-68.07 g/mol

12

O

Furan is aromatic because one of the lone pairs of electrons on the oxygen atom is

delocalized into the ring, creating a 4n+2 aromatic system similar to benzene. Because of

the aromaticity, the molecule is flat and lacks discrete double bonds. The other lone pair of

electrons of the oxygen atom extends in the plane of the flat ring system. The sp2

hybridization is to allow one of the lone pairs of oxygen to reside in a p orbital and thus

allow it to interact within the pi-system. Furan has a R.E.16.98 - 22.98 kcal/mol

13

SN

O> >

Order of electronegativity

O>N>S

Order of Aromaticity

14

15

O

6.30

7.38

7.38

6.30

For a detailed protocol of the 1H NMR estimation

switch to Notepad currently opened in the background

ChemNMR Prediction Result:

0246PPM

16

O

109.9

143.0

143.0

109.9

For a detailed protocol of the 13C NMR estimation

switch to Notepad currently opened in the background

ChemNMR Prediction Result:

050100150PPM

Synthesis of Furans

Paal Knorr (1,4-dikacarbonyl)

OO

R4 R3

R5 R2

TsOHOR5

R4 R3

OH R2O

R4 R3

R5 R2

OHH

- H2O O

R4 R3

R2R5

Carbonyl condensations

17

Acid catalyzed intramolecular dehydrative cyclization of 1,4-diketones provides furans. The reaction is

known as Paal-Knorr synthesis and proceeds with the intramolecular addition of enolic -OH of one

carbonyl group to the other carbonyl group Although sulfuric acid is normally used, the other reagents

such as zinc chloride, acetic anhydride, phosphorus pentaoxide and phosphoric acid are also used to

cause cyclization and dehydration of 1 ,4-diketones. This reaction is limited only to the easily available 1

,4-diketones which are not sterically hindered.

Mechanism

18

HO OHK2Cr2O7, acid

HO OO OH

H+

O- H2O

Commercial Method (From Aldopentoses or Ketopentoses)Acid catalyzed consecutive dehydrations of aldoses or ketoses 240 result in the formation of a

ketoaldehydes 242 via 1,2-enediol 241. The resulting a-ketoaldehyde 242 undergoes acid catalyzed

cyclization involving carbonoxygen bond formation to provide furfural which on steam distillation at

400°C in the presence of oxide catalyst gives the corresponding furan (scheme-115).

Cl

OO

O R'

OR

Aldehyde

HO H

OR'

ClCO2R

B

O

HO CO2R

R' O

CO2R

R'

H2O

R''

ClO

O R'

OR

Ketone

O

H

OR'

''RCO2R

O

acid

"Paal Knorr" O

CO2R

R'''R

O

OH

R

EtO

PPh3

O

OR

OEt

PPh3"Wittig"

O

R

OEt - EtOHO

R

19

O

CHO

Ag2O at 400 oC

O

Furfural

20

Phosphorus Ylides Heterocyclic ChemistryPhosphorus ylides can also be conveniently used for the synthesis of furans. The reaction of sodium salt

of a-hydroxy ketone 252 with 13-ethoxyvinyltriphenylphosphonium salt 253 gives phosphorus ylide 254

which undergoes intramolecular Wittig reaction providing dihydrofuran 225 and subsequently furan 256

with the loss of ethanol (scheme-122).

21

From a-Halocarbonyl Compounds (Feist-Benary Synthesis)The reaction of a-halo aldehydes or ketones with P-keto esters in the presence of a base, sodium

hydroxide or pyridine, results in the corresponding furans 259 involving aldol-type condensation

(scheme-123).

O

OHH

COOH

OH

H

HO

HOOCOH

H

Distillation

COOH 2H2O

2CO2

+

+

O

Decarboxylation

Furoic acid

1.

2.

O O

OEt

i.C2H5O-Na

+ , -2C2H5OH

ii.I2

iii.Heating with H+

O

COOEt

EtOOC2

i.Hydrolysis

ii.strongly heating

O

3.O

O

Strongly Heating P2O5

or heating with HF

O

Mucic acid

Succinic dialdehyde

H OH

H

OH

More Methods of Preparation of Furan

22

Electrophilic Substitution Reactions in Furan

Furan is considered to the resonance hybrid of the following resonating structures In which the lone pair on the

oxygen atom is delocalized around the ring .The positivelyCharged trivalent oxygen makes the dipolar structure

less stable because of high electronegativity of oxygen and therefore contributing less to the resonance hybrid of

furan.

23

•Furan undergoes electrophilic substitution reaction at C-2 and C-5 position preferably than C-3 position.Explain.

Furan is pi-excessive heterocycles and exhibits greater reactivity towards electrophile substitution. Furan is less

reactive than pyrrole and more reactive than thiophene.Explain

24

Reactivity and Orientation Effects

Furan is n-excessive heterocycle and exhibits greater reactivity towards

electrophilic substitutions. As far as the comparison of reactivity is concerned,

furan lies between pyrrole and thiophene i.e. less reactive than pyrrole, but more

reactive than thiophene. The lower reactivity of furan than pyrrole is because the

oxygen atom accommodates positive charge less readily than the nitrogen atom,

while the higher reactivity of furan than thiophene can be attributed to the smaller

orientation effect (+M effect) of sulfur than that of oxygen.

Furan undergoes electrophilic substitution preferentially at the C-2 and C-5

positions (a-substitution) and these positions are comparatively 6x 10-11 times

more reactive than a benzene position. If these positions (C-2 and C-5) are

occupied, the substitution takes place at the C-3 and C-4 positions (~-substitution)

and these positions are also even more reactive than a position of benzene. The

preferential electrophilic substitution at the C-2 and C-5 positions (a-substitution)

is attributed to the resonance stabilization of the transition state resulting from

the attack of electrophile at the a-position and the powerful orientational effect of

the ring oxygen (Fig. 33).

25

FURAN

O The least aromatic 5-membered ring

S O

H

H

H

H

7.1 ppm127 ppm

7.2 ppm126 ppm

6.3 ppm110 ppm

7.4 ppm144 ppmS O

1.71Å

1.37Å

1.42Å

1.37Å

1.35Å

1.44Å

Reaction with electrophiles - Protonation

O O

HH

Ring opening

O

H

Much less basic than ordinary ethers

O

H

H

Major protonated form

Conc. H2SO4

Lewis acids (i.e. AlCl3)Decomp.

O

HH H2O

O OH

Hemiacetal

OO

26

•Suggest a reason why pyrrole is an extremely weak base compared with aliphatic amines.

27

Furan is readily hydrolyzed under very mild acidic conditions. The reaction is

considered to proceed via protonated intermediate involving protonation at the

C-2 position rather than at the oxygen atom and results in the formation of a

ring-opened product, succindialdehyde (scheme-132).

28

Protonation of furan generates reactive electrophilic intermediate which

participates in polymerization and the ring opening reactions. Furans substituted

with electron-withdrawing substituents are stable towards acid, but furans

substituted with electron-releasing substituents usually undergo polymerization

with mineral acids due to facile protonation at the position-2 (scheme-131).

29

Nitration

Furan is nitrated with mild nitrating agent, acetyl nitrate, at low temperature. The reaction

proceeds by an addition-elimination mechanism involving an intermediate, 2,5-addition

product 282 ( scheme-136). In certain cases, the intermediate 2,5- addition product

282 may be isolated, if a base (pyridine) is not used to eliminate acetic acid (

scheme-137).

30

31

32

33

34

Reaction with electrophiles - Acylation

O

DMF, POCl3

OO"Vilsmeyer"

Furfural Also very readily available by other routes

O

R'COCl or

(R'CO)2O

BF3 . Et2OR

R: H, Me

O

R

O

R'

Alkylation Generally not practical (polyalkylation, polymerisation)

Condensation with Aldehydes and Ketones

O

RCHO, H+

OOH

R

Further react.

OOH

CCl3

stable From chloral

C.f.

N H

H+, RCHO

N HR=H, alkyl

H

OHR

H±H+

N H R H

OH2

- H2O N H R

H Polymer

35

36

Reactions with Aldehydes and Ketones

The acid catalyzed reaction of furan with aldehydes produces a mixture of

oligomers involving reactive electrophile 313 (scheme-155), but the reaction of 2-

methylfuran affords 317 (scheme-156). The reaction of furan with protonated

ketones results in the formation of a cyclic tetramer 318 analogous to that

obtained from pyrrole. The yield of the cyclic tetramer is improved with the

change in pH by adding lithium perchlorate (scheme-156).

37

Reaction with electrophiles - Condensation with imines / iminium ions

CH2O, R2NH, H+

N

R

RO

Unsubst furan: iminium ion must be preformed

O

HNR

RH-

ON

R

R

Reaction with oxidating agents

O

Br2, MeOH

OH H

OMeMeO

Pb(OAc)4

O OAcAcO

38

Metallation and further react.

O

n-BuLi

Et2O, O Li

O

n-BuLi

THF, -78oC

Br

O

Li

> -40 oC

n-BuLi TMEDA

hexane, O LiLi

O

Li

OLi

O

BrLDA

O

Br

Li

(ODG)n-BuLi

O CO2HLDA

O CO2LiLiO CO2Li

Li

O Li

B(OR)3Hydrolysis

O B(OH)3

BR3

O B

R

RR

Li

I-I O

R

BR2

H

I

I

O R

39

Additional Reactions

Cycloadditions

X+

O OO

XO

O

O

HH

X=O: r.t.; 80% X=S: 100 oC, 15kbar; 42%

Furanes as diene - one of the first DA examples

Furan reacts with many dienophiles (alkenes, alkynes, allenes)

exo isolated (termodyn favoured)

endo (kinetic prod.)

With 1O2

O

O OO

O

O

H

H

OOH

OO O

HO

H

O O

1O2 (singlet)h

O O

3O2 (triplet)

Diradical 3 lines ESR

No unpaired el. 1 line ESR

Photochemical cycloaddition

O O

R1R [2+2]

OO

RR'

acid

acetal

O

'R R

O

40

Pd-cat couplings

O

Li

O

Met Ar-X (or related) cat Pd

O

Ar

O

Br

O

Br

Br

Ar-Met cat Pd

O

Br

Ar

O

EWGcat. Pd

O EWG

O

cat. Pd

Ar-X

O Ar

like an alkene in Heck

Heteroaryl-Heck

O ArAr-Pd-X

O O

H

ArH

PdXH-Pd-X

41

42

•How will you carry out the following conversions:

•Furan to furoic acid.

•Furan into i) Furyl acrylic acid; ii) 1-naphthol;

•Furan to 2-ethyl furan

O

Br2,dioxane, 0 oC

?

Conc.HNO3+( CH3CO)2O, 10 oC

?

SO3 ,Pyridine-100 oC

?

BF3 +( CH3CO)2O

?2H2-Ni

?

O

C6H5N2+Cl

-

NaOH

Furan undergoes phenylation rather than diazo coupling on reaction why ?

Complete the following reactions.

O

O

O

O

O

O

O

NO2

SO3H

COCH3

Br

CHO

O

CH3COONO2

Py/SO3/H2SO4

CH3COCl/BF3

1.HgCl22.Br2

ArN2Cl-

1.HCN+ HCl/ AlCl3

2.H3O+

OH

H+

CHOCHO

O

H3O+

H2-NiO

2H2

Raney Ni

NaOHGomberg reaction

Gattermann aldehyde synthesis

Chemical Properties of Furan

43

Furan is readily polymerised by conc.acids and

probably the oxonium salt is involved.Thus nitration

and sulphonation in resinified products.In case,

alkylation reactions with furan lead to polymers.

O

O

O

O

N3COOEt

Heat , -N2

CH2N2 ,hv

O

RCHO

ONH

O

O

HN

O

O

25oC

OO

O

O

HN

O

O

30 o

C

O

O

CHO CHO

O2 Ni-H2

N

COOEt

N

O

COOEt

-N2

N

N

O

O2N

NO2

+

CH3COOH-H2O

O

N2Cl-

NaOH

H+

OHO

Oligomers44

Furan undergoes cycloaddition reactions(i:e Diel-Alder reaction) and behaves as diene.Furan undergoes faster

cycloaddition reaction in comparsion than pyrrole.Explain.

45

Cycloaddition Reactions

Furan, inspite of being n-excessive heterocycle, behaves as a diene and undergoes (4 + 2)

cycloaddition reactions with dienophiles with the formation of thermodynamically more

stable exo-products than the kinetically favoured endoproducts. The reaction of furan with

maleic anhydride in acetonitrile at 40°C provides initially endo-adduct 352 , which is

coverted to exo-adduct 353 by retroaddition followed by readdition in an alternative

orientation. The exo-adduct is 8.0 kJ/ mol more stable than the endo-adduct (scheme-173)

100

46

Similarly, the reaction of furan with male imide at room temperature results in the

formation of endo-adduct 354 which on heating at 90°C rearranges to exo-adduct

355 (scheme-174).

47

The ethylenic dienophiles substituted with only one electron-withdrawing

substituent (acrylonitrile and methylacrylate) react very slowly with furan at room

temperature providing moderate yields of both endo- 356 and exo- 357 adducts

(scheme-175). The reaction is greatly accelerated either by the addition of Lewis

acid (zinc iodide) which increases the electrophilicity of the dienophile or by using

high pressure and the adducts are obtained in improved yields

48

O

.HgCl2 / AcONa

OMe

MeO

OMe OMe

HCl-MeOH

aq.H2SO4

COOHCOOH

O

COOH

1.C4H9Li

2.CO2

3.H+

O

HgCl

O

COR

RCOCl

O

1.Br2

2.Heat -CO2

Br

•5-methyl furan-2-carboxylic acid on nitration gives 2-nitro-5-methyl furan. Give the mechanism.

49

O

CHO

O

COONa

O

CH2OH

+

2 molecules2 molecules

O

CHOH CO

O

KCN

Benzoin condensation

Cannizzaro reaction

O

COOH

OO

CH2OH

Ag2O

ZnCl2

NMe2

NMe2

NMe22

Copper chromite

H2

Furural is chemically similar to benzaldehyde.Furfural undergoes cannizzaro , benzoin , perkin, claisen reactions.