heterocyclic compounds furan
TRANSCRIPT
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.