HETEROCYCLIC CHEMISTRY Nomenclature systems I. Hantzsch-Widman system This is the most widely used systematic method and is used for naming 3 to 10 membered monocyclic heterocycles of various degree of unsaturation containing one or more more heteroatoms. This nomenclature system specifies the ring size and the nature, type and position(s) of the heteroatom(s). 1. Combination of prefix(es) with stem The heteromonocyclic system is named by combining one or more ‘a’ prefixes for the heteroatom(s) with a stem indicating the size of the ring. Prefixes for heteroatoms O-Oxa, S-Thia, Se-Selena, Te-Tellura, N-Aza, P-Phospha, Sn-Stanna, Mercury-Mercura. Stems for 3 to 10 membered heterocycles Ring size Unsaturation 3 -irene 4 -ete 5 -ole 6 -ine -ine -inine 7 -epine 8 -ocine 9 -onine 10 -ecine
Saturation -irane -etane -olane -ane -inane -inane -epane -ocane -onane -ecane
The stem ‘irine’ is used for 3 membered N-containing unsaturated heteromonocycles. The stems ‘iridine’, ‘etidine’ and ‘olidine’ is used for N-containing saturated 3, 4 and 5-membered heteromonocycles respectively. The stems for six membered rings depend on the least preferred heteroatom in the ring, i.e. the heteroatom immediately preceding the stem. To determine the proper stem for a six membered ring, the following set containing least preferred heteroatom is selected: 6A: O, S, Se, Te, Bi, Hg 6B: N, Si, Ge, Sn, Pb. 6C: B, P, As, Sb. Oxine must not be used for pyran p yran because it has been used as a trivial name for quinolin-8-ol. qu inolin-8-ol. Azine must not be used for pyridine because of its use as a class name of the compounds containing =N-N= group. Examples H H O N N S O HN N
NH Oxirane, Aziridine, Azirine, Oxazairidine, Azetidine, Azete, Thietane,
H P
S
O
Phosphole
Oxolane
H N
S
Thiolane
Thiepane
N
O
Azepine
Oxepine
Azocine
2) Presence of two or more heteroatoms H N
O
N
N N
O
N N
N
1,3-dioxolane 1,2,4-triazole
1,3-diazine
H N
S N
N
1,3, 5-triazine
H N
O 1,4-oxazine
1,3-thiazole
S 1,4-thia zine
3) Numbering H N
O
H3C
N
S
O
O S
N
CH3
CH3
N
N
N
N
N
O
S N N
N
N
4) Presence of saturated atom
When a heterocyclic ring with maximum number of noncumulative double bonds caontains a saturated atom, its position is given the lowest possible locant and is numerically indicated by an italic capital H before the name of the heterocyclic ring system. H N
N
N
N
S O S 4 H -1,4-thiazine -1,4-thiazine 2 H -1,4-thiazine -1,4-thiazine 6 H -1,3-oxazine -1,3-oxazine 2 H -pyrrole -pyrrole
N S 2 H -1,3-thiazine -1,3-thiazine
N 3 H -azepine -azepine
H P
S
O
Phosphole
Oxolane
H N
S
Thiolane
Thiepane
N
O
Azepine
Oxepine
Azocine
2) Presence of two or more heteroatoms H N
O
N
N N
O
N N
N
1,3-dioxolane 1,2,4-triazole
1,3-diazine
H N
S N
N
1,3, 5-triazine
H N
O 1,4-oxazine
1,3-thiazole
S 1,4-thia zine
3) Numbering H N
O
H3C
N
S
O
O S
N
CH3
CH3
N
N
N
N
N
O
S N N
N
N
4) Presence of saturated atom
When a heterocyclic ring with maximum number of noncumulative double bonds caontains a saturated atom, its position is given the lowest possible locant and is numerically indicated by an italic capital H before the name of the heterocyclic ring system. H N
N
N
N
S O S 4 H -1,4-thiazine -1,4-thiazine 2 H -1,4-thiazine -1,4-thiazine 6 H -1,3-oxazine -1,3-oxazine 2 H -pyrrole -pyrrole
N S 2 H -1,3-thiazine -1,3-thiazine
N 3 H -azepine -azepine
II Trivial System This system of nomenclature is based on the trivial and semitrivial names of the heterocycles which were given before their structural identifications. These trivial and semitrivial names of the heterocycles were given on the basis of their characteristic properties or on the sources from which they are obtained. Therefore, trivial and semitrivial names provide hardly any structural information.
N N H Pyrrole
S
Se
Thiophene
Selenophene
O Furan
N N H Tellurophene Pyrazole
N
N H Imidazole
Te
O Isoxazole
N N N
N
N
N
Pyridine
Pyridazine
N
N
Pyrazine
Pyran
N Pyrimidine
Pyrrolizine
NH
PH
N H Indole
P H Phosphindole
Isoindole
As H Arsindole
Isophos[hindole
N N
N
O N
N H Indazole
Isobenzofuran
N
Indolizine
Purine
N H
N N
N Quinoline
N
N P Phosphinoline
Isoquinoline
N Quinazoline
Phthalazine
N N N
N
N
Cinnoline
O
O
Quinoxaline
Quinolizine
N
Chromene
Isochromene
N N
N
N
N
1,8-Naphthyridine
N
N H B-Carboline
N H Carbazole
Pteridine
N
N
N Phenazine
Acridine
As Acridarsine
N N N
O N
Phenathridine
Phenanthroline
Xanthene
HN
N
Perimidine
III. Fusion nomenclature system The fused heterocyclic system is considered to be constructed by the combination of two or more cyclic structural units. The cyclic structural units contain maximum number of non-cumulative double bonds and are fused in such a way that each structural unit has one bond common with other. Naming 1. The fused heterocyclic system is dissected into its components in which one is base component and other is attached component. 2. The components are given their recognized trivial name. 3. Base component should be a heterocyclic system. If there is choice, the base component is determined by the order of preference. Example: benzothiazole, benzimidazole etc. Selection of base component: i. Order: N, O, S. give examples. O
N
S
O
S
O
N H
S
ii. Component with greatest number of rings: a component with as many rings as possible is selected as the base component. N
N
N
Base component: Quinoline iii. Rings of unequal size: if fused heterocyclic system contains rings of unequal size, the component with the largest size of the ring is selected as a base component. O
S S
O Base component: Thiepine
Pyran
iv. Rings of equal size with different number of heteroatoms: the ring with greater number of heteroatoms of any kind is considered as a base component. N N H O Base component: Oxazole
v. Rings of equal size with equal number of different heteroatoms: the component containing ring with greatest variety of heteroatoms is selected as a base component.
N N N H
O
Base component: Oxazole
If two heteroatoms of same group are present, the component containing the ring with heteroatoms appearing first in the table 1 is preferred as the base component. N
N
S O
S O
N Base component: Oxazole
N Thiazole
vi. Rings of same size with same numbers and same kinds of heteroatoms: The component containing ring with heteroatoms which have the lowest locant numbers is preferred as a base component. N
N S
N N
O
N
N
Base component: Pyridazine
Pyrazole
4. The attached component is added as a prefix to the name of the base component. Pyrazine: pyrazino, pyrazole: pyrazolo, thiazole: thiazolo. However there are some exceptions to this rule. Pyridine: pyrido, Quinoline: Quino, Isoquinoline: Isoquino, Furan: Furo, Thiophene: Thieno, Imidazole: Imidazo. 5. The bonds of the base component are alphabeticed with consecutive italic letters starting with ‘a’ for 1,2-bond, ‘b’ for 2,3-bond, ‘c’ for 3,4-bond, ‘d’ for 4,5-bond and so on. 6. The atoms of ring system of second component (attached component) are numbered in the normal way; 1,2,3,4 .etc., observing the principle of the lowest possible numbering. 7. The atoms common to both rings are indicated by the appropriate letters and numbers and are enclosed in a square bracket and placed immediately after the prefix of the attached component. 4
=
S O Thieno[2,3-b]furan
3 b
5
2 S 1 Attached componet
d
a O e Base component
N
N c
=
O
b
S
O
S a
Benzopyrano[3,4-b]benzothiazine
1,4-benzothiazine
Benzopyran
N
N
=
N N
N a N b
N
Pyrazino[2,3-c]pyridazine
c
N
Pyridazine
Pyrazine
8. Common heteroatom: If a position of fusion is occupied by a heteroatom, both the components are considered to possess that heteroatom. N
N
O
N +
=
N
Imidazo[2,1-b]oxazole
N H
O
9. Numbering of fused heterocyclic system: i. Fused heterocyclic system is numbered independently of the combining components. The numbering is started from the atom adjacent to the bridgehead position with the lowest possible locant to the heteroatom. If there is choice, the heteroatom appearing highest in table 1 is preferred. 4
5
6
3
O 1
7 Benzo[b]furan
2
5
O3
2 8
S 6
N 2 1 3,1-Benzooxazepine 9
5
3
7
5 6
4
4
6N
4 N
5 3
2 N 8 1 Pyrazino[2,3-d]pyridazine
Thieno[2,3-b]furan
3 2
6
7N
O 1
4 N
N 7
S 1
Imidazo[2,1-b]thiazole
ii. Carbon atom common to two rings is given the lowest position, but not numbered. However, the heteroatom at a fusion of two rings (common heteroatom) is numbered. 4 3
7 6
2
1 N
8
5 N
N
N 7 1 Imidazo[12-b]pyridazine
6 5
N 4
N2 3
1,3,4-Triazolo[1,2-a]pyridine
iii. The position of a saturated atom is indicated by an italic hydrogen and is given the lowest possible number locant.
7
1 O
6
2
5
O 3 4 2 H -Furo[3,2-b]pyran
10. Benzofused heterocycles: i. If a benzene ring is fused to the heterocyclic ring, the compound is named by placing number(s) indicating position(s) of the heteroatom(s) before the prefix benzo-(from benzene) followed by the name of the heterocyclic component. 5
6
H N4
5
4
7
6
3
7
O3 7
8 2
9
1 3-Benzooxepine
1 N
8
6
2 S 8 1 4 H -1,4-Benzothiazine
2
O 3
5
4
4 H -3,1-Benzoxazine
ii. If two benzene rings are ortho-fused to a six membered 1,4-diheteromonocyclic ring containing different heteroatoms, the heterocyclic system is named by adding prefix ‘pheno-‘ to the Hantzch-Widman name of the heteromonocycle. 5 O
6
4
7
3
7
8
2
8
N 1 H 10 H -Phenoxazine 9
5 S
6
N 1 H 10 H -Phenothiazine 9
10
5 O
6
4 3
7
2
8 9
10
10
S
4 3 2 1
10 H -Phenoxathiine
iii. However, the heterocyclic system in which two benzene rings are ortho-fused to a sixmembered 1,4-diheteromonocycle containing the same heteroatoms are named by adding the replacement prefix for the heteroatom to the term ‘-anthrene’ with elision of an ‘a’. 5 S
6
4
7 8 9
10
S
Thianthrene
1
6 3
7
2
8 9
5 N
4
N
10 1 Phenazine
(exception to this rule)
3 2
IV. Spiro and bicyclo heterocycles-replacement nomenclature system The compounds in which two rings are fused at a common point are known as spiro compounds and the common atom which is quaternary in nature is designated as spiro atom. The spiro compounds may be classified according to the number of spiro atoms; monospiro, dispiro and trispiro ring systems. Naming of spiroheterocycles: 1. Spiroheterocycles with one spiro atom consisting of one or both heterocyclic rings are named by prefixing spiro to the name of normal alkane with same number of carbon atoms. The number of atoms in each ring are indicated by Arabic numbers separated by a full stop and enclosed by a square bracket in ascending order and are placed between spiro prefix and the name of the hydrocarbon. The heteroatoms are indicated by the prefixes and are prefixed with their positions to the name of spiro hydrocarbon. 9
10
1
9
10
7
O 6
1 2
2 8
8
3
5 6 7 4 Spiro hydrocarbon
3
5 4
Spiro heterocycle
spiro[x.y[alkane
prefix spiro[x.y]alkane
x= number of atoms other than spiro atom in smaller ring
6-Oxaspiro[4.5]decane
y = number of atoms other than spiro atom in larger ring spiro[4.5]decane
2. The numbering starts from the the ring atom of the smaller ring attached to the spiro atom and proceeds first around the smaller ring and then around the larger ring through the spiro atom. The heteroatoms are assigned the lowest possible number locants. 1
8 7
2
4
6
S 3 5 5-Thiaspiro[3.4]ocatane
If there is choice between two different heteroatoms, the preferential numbering is decided according to the appearance of the heteroatoms. 8
9 S
1
7 4
2
O 3 5 5-Oxa-9-thiaspiro[3.5]nonane 6
3. The heterocyclic ring is preferred over the carboxylic ring of the same size. If both the rings are heterocyclic, the preference is given to the heterocyclic ring with heteroatom appearing first in the preference table.
11 1
10
2 O
9
1 O
9 8
2
3 3 5 S 4 6 1-Oxa-6-thiaspiro[4.4]nonane 7
6
8
5
7
4
4. If the unsaturation is present in a ring, the pattern of numbering remains the same but the direction around the ring remains in such a way that the multiple bond is given as low as possible. However, the heteroatom is preferred over the multiple bond. 10
9
1 O
10
9
1 2
2 8
8
3 5 O 7 4 6 6-Oxaspiro[4.5]dec-9-ene
3
5
6 7 4 1-Oxaspiro[4.5]dec-6-ene
5. when one or both the components of spiro heterocycle are fused polycyclic system, the names of both the components are cited after prefix ‘spiro’ in square bracket in alphabetical order and are separated by the numbers of spiro atom. The components in such spiro heterocyclic system retain their numbering, but the second component is numbered by primed numbers. 4 5
3 2
1 3'
7'
2'
6
H N 1
2
8' 5
4
3
9'
1' 2'
3' O 5' 4' 10' Spiro[piperidine-4,9'-xanthene]
N 1'
6'
Spiro[cyclopenta-2,4-diene-1,3'-3H-indole]
6. If both the heterocyclic components are the same in spiro heterocyclic system, ‘spirobi-’ is prefixed to the name of heterocyclic component. 1 N 2
3
3' 2'
N 1' 3,3'-Spirobi(3H-indole)
V. Bridged heterocycles Bridged heterocyclic systems are named according to the rules for bridged hydrocarbons. The heteroatoms with their locants are prefixed to the n ame of bridged hydrocarbon. Bicyclic systems
1. Bridged heterocyclic system consisting of two rings with two or more common atoms is given the name of acyclic hydrocarbon with the same total number of carbon atoms, which is preceded by the prefix ‘bicyclo-’ with the descending order of numbers separated by a full stop in square bracket indicating number of atoms separating bridged atoms. The prefixes indicating heteroatoms with their locants are prefixed to the name of bridged hydrocarbon. 2. The numbering starts from one of the bridgehead atoms and proceeds through the longest possible route to the second bridgehead atom and then by the second longest route to the first bridge head atom and finally shortest route from one bridgehead atom to the second bridgehead atom. 3. The heteroatom is given number as low as possible. 4. When there is a choice between heteroatom and multiple bond, the heteroatom is preferred. 5. if there is comparision between heteroatoms, the preference of numbering is given according to their appearenece in the preference table and their prefixes with locants are arranged alphabetically. CH2 H2C
CH
Total no of atoms = 10 (decane) No. of rings = 2, prefix - bicyclo
H2C
H2C
CH2
O
CH2
CH
Number of atoms separating bridged atoms in three routes and
CH2
Prefix for heteroatom and its locant: 3-Oxa
3-Oxabicyclo[4.3.1]decane 1 CH
6 H2C
O7
2 CH2
CH 4
7O
6
CH2 3
5
2 4
H2C 4 5 CH
2 CH
4 NH 3 CH2
H2C 9
CH2 8
CH 1
O 2
3
7-Oxabicyclo[2.2.1]heptane
3 CH2
5 CH
6 CH2
1
O7 CH2 5
arranged in descending order = [4.3.1]
4-Aza-2,7-dioxabicyclo[3.3.1]nonane
1 C
10 N
11 NH
HC 9
CH CH O 6 7 8 10,11-diaza-8-oxabicyclo[5.3.1]undec-1,5,9-triene
6 HC
HC 5
1 CH
HN 7
CH 4
2 CH 7-Aza-bicyclo[2.2.1]hepta-2,5-diene
CH 3
Polycyclic systems 1. Polycyclic bridged heterocycles are also named according to the rules adopted for the bicyclic bridged heterocycles. However, the prefix tricycle-, tetracyclo-, etc., depending on the number of rings used. 2. The prefix (cyclo-) is followed by the numbers separated by full stops in square bracket in decreasing order indicating: (i) the number of atoms of two branches of the main ring containing maximum number of atoms, (ii) the number of atoms in main bridge excluding bridgehead atoms and (iii) the number of atoms in secondary bridges.
3. The locations of each secondary bridge are indicated by superscripts to the numbers indicating its length and are separated by a comma. 4. The prefix (tri or tetracyclo) with numbers separated by full stop in square bracket is followed by the name of acyclic hydrocarbon of the carbon atoms equivalent to the total number of atoms in the bridged heterocyclic system. 5. The prefixes for the heteroatoms and the substituents with their positions are indicated and placed as usual. 8 H2C
7 CH
H2C10 9 CH2
6 HC
N5 N4
CH2 HC CH2
CH HC N
CH2
CH
OCH3 CH2
CH2
HN CH2
CH
CH
S
H2C CH2
H2C
CH CH N C6 H 5 3,8 10-Methoxy-6-azatricyclo[4.3.1.0 ]decane 2 1 3 HC CH CH2 HN 3-Phenyl-3,4,5-triazatricyclo[5.2.1.02,6 ]decane 3-Thia-8,10-diazatricyclo[5.3.2.02,6 ]dodecane
Five membered heterocyclic compounds with one heteroatom
The parent five membered heterocyclic rings are pyrrole, furan and thiophene. Pyrrole and thiophene occur naturally whereas furan arises from the decomposition of sugars. The structures of these heterocycles would suggest that they have highly reactive diene character analogous to cyclopentadiene. Rather these compounds give reactions which suggest that they possess considerable aromatic character like benzene. These molecules are characterized by a high degree of reactivity towards substitution by electrophilic reagents rather than addition and also show the effect of ring current in their NMR spectra. From the molecular orbital standpoint these molecules are described as consisting of planar pentagon with sp2 hybridized carbon atom. Each ring atom has one electron remaining in the pz orbital while each heteroatom contributes two such p-electrons to the aromatic sextet. Five membered aromatic heterocycles are considered to be derived from cyclopentadienyl anion and the lone pair on the heteroatom is involved in the cyclic delocalization of pi-electrons. Six pielectrons are delocalized over five atoms. The electron density on each carbon atom in the ring is approximated to be greater than one (6/5=1.2) in comparison to the benzene ring, a pi-neutral system in which one electron is on each carbon atom. The five membered aromatic heterocycles are, therefore, referred to as pi-excessive aromatic heterocycles. The electron donor characteristic of heteroatom can be evidenced by their resonating structures. Fig. These heterocycles are thus endowed with considerable aromatic character and possess high resonance energies. Benzene Pyrrole Furan Thiophene Pyridine Resonance energy (Kcal/mole) 36 21.2 15.8 29 23 The aromaticity falls in the order, thiophene>pyrrole>furan. Since the electronegativities of the heteroatom is in the order oxygen>nitrogen>sulfur, resonance structures 4a-4d are less important in the case of furan relative to pyrrole and thiophene. Oxygen atom is reluctant to release its electrons and as consequence, furan is less aromatic of the tree heterocycles. [The resonance energy in five membered heterocycles follows the order thiophene>pyrrole>furan. The higher degree of stabilization energy and thus aromaticity of thiophene is attributed to the
following reasons: i) release of angle strain due to larger bonding radius of sulfur than nitrogen and oxygen, ii) sulfur being less electronegative, iii) use of d -orbitals of sulfur for bonding.] Additional evidence to support the delocalized structure in these rings is derived from the dipole moments of these heterocycles compared to their non-aromatic counterparts. In the saturated compounds the dipole points towards the heteroatom. As a result the net dipole moment of furan and thiophene is reduced. The lower dipole moments in these heterocycles are attributed to the counteraction of two effects: inductive effect and mesomeric effect. Thus the existence of two opposing structural effects supports the contributing resonating structures involving cyclic delocalization of pi-electrons in the five membered aromatic heterocycles. The tetrahydro derivatives have negative end at the heteroatom because of the electron pull towards electronegative heteroatom due to the inductive effect. In case of pyrrole, thiophene and furan, the inductive effect is still operating, but this effect is superimposed by the mesomeric effect operating in the opposite direction. The larger difference in thiophene reflects the involvement of d-orbitals of sulfur. The direction of the dipole in pyrrole is reverse of that in pyrrolidine and thus very large difference (3.37D) is due to the large contribution of the mesomeric effect. Bond lengths in furan, pyrrole and thiophene. X X-C2 C2-C3 C3-C4 O 1.362 1.361 1.431 S 1.714 1.37 1.42 NH 1.37 1.38 1.417 Single Bonds: C-C=1.48, C-N=1.45, C-O=1.36, C-S=1.75. Double bonds: C=C:1.34, C=N: 1.27, C=O:1.22, C=S:1.64. Ultraviolet spectroscopy Five membered aromatic heterocycles with one heteroatom exhibit a band of moderate intensity followed by a band of moderate intensity at shorter wavelength. A significant feature, the absence of bands due to promotion of an electron from the lone pair orbital (non-bonding) to a pi-orbital of the ring, is attributed to the large s-character due to smaller ring angle in the five membered rings. λ max for thiophene:215 (logε, 3.8), pyrrole:210nm (logε, 4.2) and for furan: 207nm (logε, 3.9). Mass spectroscopy The mass spectrometric analysis of the three five-membered heterocycles exhibits interesting fragmentation patterns. In pyrrole the uneven valence and even atomic weight of the principal isotope 14N produces a molecular ion of uneven mass unless nitrogen carries a substituent. Sulfur has a natural isotope distribution 32S/34S of 25:1 and thus ensures two molecular ions for thiophene, two mass units apart of appropriate intensity ratio. The principal fragmentation patterns for the three heterocyclics are depicted below: It has been noticed that the molecular ions of pyrrole and thiophene are the base peaks in their respective spectra, whereas the molecular ion of furan ia strongest peak (70%) after the cyclopropenyl cation(5) which rather constitutes the base peak. The same ion, cyclopropenyl cation is also an importanmt feature of the spectrum of pyrrole but less so in the spectrum of thiophene. An additional fragment which is of significance for pyrrole and thiophene but absent for furan is 6, formed by the loss of acetylene from the molecular ion. Another ion 7 is much less abundant with furan than for pyrrole and thiophene.
Similarly mass spectrometric spectra are obtained for 2- and 3- alkyl derivatives of these heterocyclic compounds. Besides modest contributions from ions corresponding to 5 to 7, a principal fragmentation pathway is initiated by β-cleavage of the alkyl substituent.
It is believed that the ions 8 and 9 which result after β-cleavage tend to rearrange to a common ion 10 which is generally the base peak. N-alkylpyrrole fragments in contrast in a different manner. In addition to β-cleavage of the alkyl group to yield ion 11, rearranges to pyrridinium ion. The molecular ion also generates N-methyl pyrrole cation which forms the base peak and in addition pyrrolium ion. The fragmentation pattern is shown for N-pentylpyrrole.
1
13
H and C NMR- ring current The ring current effects are increase with the size of the ring and are higher for the six membered ring compared to the five membered ring. The effect of the ring current are quantitatively be observed by comparing aromatic with nonaromatic compounds. The proton chemical shift depends on the density of the electrons at a ring carbon to which hydrogen is attached. Ring current follows the order: benzene>pyridine>thiophene>pyrrole>furan. H NMR spectra of the parent five membered aromatic heterocycles exhibit two multiplets of which one at the lower field (high δ value) is assigned to the α protons. The chemical shift for β protons, except for pyrrole, increases with decreasing electronegativity of the heteroatom. H/C Pyrrole Furan Thiophene H-2 6.68 7.29 7.18 H-3 6.22 6.24 6.99 13-C C2 118.5 142.6 125.4 C3 108.2 109.6 127.2 I. Synthesis of Pyrroles, Furans and Thiophenes 1. Pyrroles Pyrrole was isolated in pure form from bone oil in 1857. It also occurs in coal tar and in products derived from proteins. This ring system is incorporated as a basic structural unit in porphyrins; porphin(haem0 and chlorin (chlorophyll) and corrins (vitamin B12). 1.1 Ehrlich test Reaction of pyrrole (or alkyl pyrrole with free 2-or 3-position) with 4-dimethylaminobenzaldehyde in the presence of hydrochloric acid produces purple coloration due to the formation of cation ####. 1.2 Synthetic methods: i) From ammonium mucate : The ammonium salt dissociates into the free acid which dehydrates followed by decarboxylation and cyclization with ammonia yields the parent compound. This method was applied for the ppepareation of N-substituted pyrroles but the yields were found to be disappointing. ii)Paal-Knorr Synthesis
This is the most general method and it involves the condensation of 1,4-diketone with ammonia or primary amine. Pyrrole itself is formed from succinaldehyde and ammonia whereas 2,5dimethylpyrrole is obtained from acetylacetone and ammonia (used as ammonium sulfate). This method is widely applicable for the preparation of substituted pyrroles. H3C
CH3 O
(NH4)2SO4
H3C
NH3
O
CH3
N H
iii) (3+2) cyclizations reactions. a) Knorr Pyrrole synthesis : Reaction of α-amino ketones or α-amino β-keto esters with β-diketones or β-keto esters. H3C
R
O +
R
H3C
1
1
H+ CH3COOH
R
CH3
O
NH2
R
CH3
N H
R=H, CH3, COOC2H5; R 1= COCH3, COOC2H5
The reaction is considered to proceed with the formation of enamine intermediate involving attack of nucleophilic amino group on the electrophilic carbonyl carbon. Subsequent cyclization takes place with the nucleophilic attack of β-carbon of enamine on the electrophilic carbon of carbonyl group. b) Reaction of α-amino ketones with alkynes H3C
O
COOCH3
H3C
COOCH3
R
COOCH3
+
R
NH2
COOCH3
N H
iv) (2+2+1) Cyclization reactions a) The Hantzsch synthesis : Reaction of β-keto esters with α-haloketones or aldehydes in the presence of ammonia or primary amine. The reaction proceeds via enamine intermediate which on C-alkylation and N-alkylation by α-haloketone leads to the formation of corresponding pyrrole.
H3C
H5C2OOC
Cl
H5C2OOC
+
R
O R
NH2
2
O
H3C
N
CH3
R
b) Reaction of Benzoin with benzyl aryl ketones in the presence of ammonium acetate.
-
-
-
Ar
OH
-
Ar
Amm.Acetate -
-
-
Ar
Ar
O
O
Ar
-
Ar
Ar
Ar
N H
NH3
2. Furans Furan 2-carboxylic acid was first obtained by Scheele in 1780 from the dry distillation of mucic acid. Furan was obtained later in 1870 by heating barium fureate with soda lime. Furan is a colorless o liquid, b.p 31.5 C. It possesses chloroform like odor and is soluble in most organic solvents but is only slightly miscible with water. 2.1 Synthetic methods i) Commercial method (From aldopentoses or Ketopentoses) Acid catalysed consecutive dehydrations of aldoses or ketoses result in the formation of αketoaldehydes via 1,2-enediol. The resulting α-ketoaldehyde undergoes acid catalysed cyclization o involving carbon-oxygen bond formation to provide furfural which on steam distillation at 400 C in the presence of oxide catalyst gives the corresponding furan. HO CH
R
HO
OH H+
CH
HC OH CH OH CHO
-H2O
R
CH
CH
CH OH
C
OH R
CHO
CH
CH
OH
H C
C R
HO
O
CHO
R
CH OH
C
HC
H+
O
CHO
-H2O
R
Distill
C
C
-H2O
CH2
CH
CH
H+
CH
Ag2o
CHO
O
CH
CH OH
C
CH
CH
CHO
CH
C R
O
O
ii) From 1,4-diketones – Paal-Knorr synthesis Acid catalysed intramolecular dehydrative cyclization provides furans. The reaction proceeds with the intramolecular addition of enolic –OH group of one carbonyl group to the other carbonyl group. Although sulfuric acid is generally used, the other reagents such as zinc chloride, acetic anhydride, phosphorous pentoxide and phosphoric acid are also used to cause cyclization and dehydration of 1,4diketones.
H+ -H2O
O
O
O
iii) The Fiest-Benary synthesis The reaction of α-halo aldehydes or ketones with β-keto esters in the presence of a base, sodium hydroxide or pyridine, results in the corresponding furans involving aldol type condensation. The ester anion attacks the carbonyl group of α-halo compound followed by the formation of an intermediate and cyclization takesplace by intramolecular displacement of the chloride ion and finally loss of water. H3C
H5C2OOC
CH3
Base
+
H3C
Cl
O
H3C
H5C2OOC
O
O
iv) Cyclization of sulfur ylides The reaction of sulfur ylides with β-diketones or β-keto esters produces furans. The reaction proceeds with O-phenacylation of β-diketone or β-keto ester and involves cyclization followed by dehydration. But the reaction of phenacyl halide with β-diketone or β-keto ester provides isomeric furan involving C-phenacylation. O C6H5COCHS(CH3)2
H3C
C
C
CH
H2C
CH3COCH2COCH3
-H2O
Cyclization HO
O
+
COCH3
H5C6
CH3
C
CH3
O
C6H5
COCH3
H5C6
O
CH3
O
COCH3
C6H5COCH2Cl + CH3COCH2COCH3
H 5 C6
O
CH3
v) Cyclization of phosphorous ylides The reaction of sodium salt of α-hydroxy ketone with β-ethoxyvinyltriphenylphosphonium salt gives phosphorous ylide which undergoes intramolecular Wittig reaction providing dihydrofuran and subsequently furan with the loss of ethanol. O
R
H 5C 6
+
ONa H 5C 6
R
H 5C 6 PPh3Br OC2H5
H 5C 6
O
3. Thiophenes Thiophene was first discovered by Victor Meyer in 1882 as contaminant of coal tar benzene. The discovery of thiophene was based on the fact that the indophenine test (blue color with isatin and
conc.sulphuric acid) given by commercial benzene, depended on the presence of thiophene. But the pure benzene obtained by decarboxylation of benzoic acid d id not give indophenine test. o o o o Thiophene is a colorless liquid, b.p 80 C (benzene 84 C), the freezing point is -33.3 C (benzene 5.5 C). it is miscible with water, but soluble in most orgnic solvents. 3.1 Synthetic methods i) Paal-Knor synthesis-from 1,4-diketones This is the most general method for the preparation of substituted thiophenes and involves the reaction of 1,4-diketones with phosphorous pentasulfide. R
R O
P2S5
1
95OC
O
R
R
S
1
ii) The Hinsberg method It involves the condensation of α-diketones with dimethyle sulfides containing methylene groups activated by the electron-withdrawing groups (-COR, -COOR, -CN as in bis-keto sulfides, thidiacetates and thioacetonitriles) in the presence of alcoholic sodium ethoxide to provide thiophenes involving aldol type condensation.however with thiodiacetonitrile the product vary with substituents on α-diketones. When the substituents are alkyl or phenyl, 5-cyanothiophene-2-carboxamides are obtained, but with alkoxy group 3-hydroxy-2,5-dicyanothiophenes are produced. R1
C
C
O
O
R2
C2H5OH
S
R2
C2H5ONa
+
COOR
R1
COOR
COOR
S
COOR R1
R2
R 1=alkyl or aryl
R1
C
C
O
O
R2
+
NC
S
NC
C2H5ONa
CONH2
S HO
C2H5OH
CN
R2
R 1 = OCH3
NC
CN
S
iii) (3+2) cyclization reactions a) Reaction of dimethyl fumarate with mercapto esters. H3COOC CH CH H3COOC
C +
HS
O
H3COOC
O CH2
OCH3
CH3ONa
CH C
-CH3OH H COOC HC 3
S
NH2OH/HCl
N
H3COOC
CH2 H3COOC
CH C HC S
OH
H3COOC
NH2
Reduction
CH2 Aromatization H3COOC
S
b) Reaction of α,β-unsat. carbonyl compounds with ethyl mercaptoacetate in presence of a base. The reaction proceeds by nucleophilic attack of the thiolate anion at the β-carbon followed by an internal Claisen type condensation with the formation of C-S and C-C bonds. R
2
C R
1
COR
COOC 2 H 5
3
+
C
H 2C
R
R
3
(C 2 H5 ) 3 N
SH
Cl
2
R
1
COOC 2 H 5
S
c) Reaction of activated alkynes with α-mercapto ketones or esters This reaction involves Michael-type nucleophilic addition of the thiolate anion to an alkyne and cyclization of the resulting carbanion to provide thiophenes. COOC2H5 C
O C
+
C COOC2H5
HS
CH2
OH
OCH3 CH3COONa
H5C2OOC
S
COCH3
II. Reactions of pyrroles, furans and thiophenes Five membered heterocycles with one heteroatom, pyrrole, furan and thiophene, are π-excessive and are characterized by their ability to undergo electrophilic substitution reactions on the ring carbons rather than to undergo addition reactions. The electrophilic attack on the heteroatom is rare in the neutral heterocycles due to the mesomeric electron release from the heteroatom. The heteroatom bears partial positive charge and hinders the attack of electrophile, while the negatively charged carbons facilitate the attack of electrophiles to occur at the ring carbon atoms. These heterocycles are less reactive towards nucleophiles and are restricted to undergo deprotonation at the nitrogen or carbon atom. However, the cation formed by the electrophilic attack on the neutral heterocycle reacts readily with weak nucleophiles resulting in addition or ring opening reactions. Five membered heterocycles undergo Diels-Alder reaction with varying degree of reactivity which can be correlated with aromaticity. Electrophilic substitution reactions: The general mechanism of electrophilic substitution reaction in five membered heterocycles is similar to that in benzene and involves the attack of electrophile in the first step with the formation of σ-complex, which subsequently looses a proton in the second step with the formation of substituted product. They undergo electrophilic substitutions involving electrophilic attack at the α (C-2 and C-5) and β (C-3 and C-4) positions of higher electron density. The resonating structures with unlike charges separated (iii and iv) are less stable and contributing less to the resonance hybrid than those in which unlike charges are not much separated. Secondly the intermediate obtained by electrophilic attack at the α-position has three resonationg structures, while the intermediate with electrophilic attack at the β position is stabilized by only two resonating structures (C4=C5 double bond between C-4 and C-5 remains mesomerically intact and does not participate in delocalization). The intermediate with electrophilic attack at the α-position is more stable than that with electrophilic attack at β-position.
Reactivity order in five membered heterocycles: The reactivity of five membered heterocycles towards electrophiles depends on the electron availability on the ring carbon atoms or mesomerically electron release from the heteroatom and the greater stabilization of transition state. The order of reactivity is : pyrrole > furan > thiophene > benzene. The greater reactivity of pyrrole towards electrophile is attributed to the greater electron releasing ability of trivalent nitrogen making ring carbon atoms electron rich and to the greater stabilization of transition states involving positive charge on the tetravalent nitrogen atom Furan is also reactive (although less than pyrrole) towards electrophiles and the reason is the same as for pyrrole. Since oxygen is more electronegative than nitrogen and withdraws electrons from the ring carbon atoms, the positive charge is less readily accommodated by oxygen atom than by nitrogen atom. The transition state with oxygen atom positively charged is therefore less stable than that of pyrrole. Thus furan is less reactive towards electrophiles than pyrrole as phenol is less reactive than aniline. Thiophene is less reactive than even furan towards electrophiles. The sulfur atom is less electronegative than the oxygen atom and therefore withdraws electrons less readily from the ring carbon atoms. Moreover +M effect of sulfur is smaller than that of oxygen because of not effective overlapping of differently sized p-orbitals of carbon and sulfur than in carbon and oxygen. The trend of reactivity in these heterocycles can be clearly shown by their reactions with maleic anhydride. Pyrrole is sufficiently reactive towards electrophiles and reacts readily as nucleophile with the formation of a substituted product. But furan undergoes Diels-Alder reaction as conjugated diene with maleic anhydride with the formation of cycloaddition product. Nitration i.Acetyl nitrate
O
S O
NO2
O
S O
ii.Pyridine O HC
+
N H
C O
HC
HC
N H
C
CH2 COOH
O O O + HC HC
O
C O C O
COOH
O
C
C O
C
C O
Thiophene does not react with maleic acid even as a conjugated diene. Moreover, the relative rates of the reactions of five membered heterocycles with trifluroacetic anhydride also indicate their reactivity sequence: pyrrole > furan > thiophene.
(CF3CO)2O
X
75oC
X
+ CF3COOH COCF3
X = NH X=O X=S
5
530x10 140 1
Reactivity comparison with benzene Benzene is much less reactive than the five membered heterocycles towards electrophiles. For 9 example thiophene is brominated 10 times more rapidly than benzene. The reactivity depends on (i) Stabilization energy and (ii) the stability of the transition state. The lower reactivity of benzene towards electrophiles is attributed partly to the greater resonance stabilization energy of benzene. The higher energy of the transition state of benzene than the structurally related transition states of fivemembered heterocycles is also responsible for the lower reactivity of benzene. The stability order of the transition states has been observed to be as follows. Pyrrole ~ aniline > furan ~ phenol > thiophene > benzene
1. Protonation Pyrrole Pyrrole is extremely a weak base because the lone pair of electrons on the nitrogen atom is involved in the cyclic delocalization and is less available for protonation. Moreover pyrrole is a weaker base than pyridine and even than aniline in which lone pair on the nitrogen atom is involved in the resonance and not essentially contributes to the aromatic sextet. The protonation of pyrrole at nitrogen or carbon (C-2 or C-3) of the ring reduces its basicity and destroys its aromaticity. However, C- and Nalkyl substituents enhance the basicity of pyrrole but the electron-withdrawing substituents on the ring make pyrrole a weaker base. The protonation of pyrrole at nitrogen is most rapid than that at C-2 and results in thermodynamically more stable 2H-pyrrolium cation (than 1H –pyrrolium cation), although C-3 is protonated but to a lesser extent. Moreover, the pKa (-3.80) of its conjugate acid corresponds to the protonation preferentially at C-2 rather than at nitrogen atom. Pyrole on treatment with mineral acid under carefully controlled conditions produces a trimer, 2,5di(2-pyrrolyl)pyrrolidine. The formation of trimer is considered to involve an electrophilic attack of less thermodynamically favored but more reactive β-protonated pyrrole on neutral pyrrole. Reaction with bases: The pKa for the loss of the N-H hydrogen of pyrrole is 17.5, and is relatively a weak acid. It is a weaker acid than phenol but corresponds to acid strength in ethanol. It reacts with potassium but not with sodium to liberate hydrogen and to form corresponding salt. The acidity of pyrrole can be enhanced by putting electron withdrawing groups at 3-position because in that case the anion can be stabilized by resonance. Furan Protonation of furan generates reactive electrophilic intermediate which participates in polymerization and the ring opening reactions. Furans substituted with electron withdrawing group 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. 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 in the formation of a ring opened product succinaldehyde. However furans with methanolic hydrochloric acid also undergo ring opening reactions involving β-protonation.
Thiophene Thiophene is very stable to aqueous mineral acids, but not to the strong acids. Thiophene undergoes protonation exclusively at position-2 with the formation of thiophenium ion when treated with fluorosulfonic acid. The thiophenium ions are generally unstable and polymerized at moderate temperatures. However, the reaction of thiophenes with hydrochloric acid and aluminium chloride results in the formation of stable α-protonated thiophenium ions. The reaction of thiophene with 100% phosphoric acid gives a trimer involving α-protonated thiophenium ion. 2. Nitration Pyrrole Because of the sensitivity of pyrrole ring to oxidation and acid catalyzed dimerization and polymerization, pyrrole is not nitrated under strong acidic conditions. The reaction of pyrrole with nitrating mixture results in its extensive decomposition. Pyrrole is nitrated by nitric acid in acetic o anhydride at low temperature (- 10 C) with the formation of 2-nitropyrrole as a major product together with 3-nitropyrrole. O HNO3 + (CH3CO)2O
H3C
O
C
NO2 + CH3COOH NO2
O +
N H
H3C
C
O
NO2
(CH3CO)2O
+
O
10-20 C
N H
NO2
N H
Nitration of substituted pyrroles under same condition also provides 2- and 3-nitro derivatives but the formation of 3-nitro derivatives is favored with increasing steric effect of the substituent at the position-1. NO2 O +
N
H3C
C
O
NO2
(CH3CO)2O O
10-20 C
N
R
+ NO2
R
N R
Nitration of pyrroles substituted with electron withdrawing substituents at C-2 generally produces comparable amounts of 4- and 5-nitro derivatives, where as with electron releasing substituents at C-2, the 3-,4- and 5-nitropyrroles in a ratio 3 : 2 : 5 are obtained. O2N
O + H C 3
N R
COCH3
C
O
NO2 (CH3CO)2O
+
N R
COCH3 O2N
N R
COCH3
+ H C 3
N
O 2N
O 2N
O
NO2 (CH3CO)2O
O
C
+
R
R O 2N
N
H
+
R
N
H
R
N H
H
Furan o Furan is nitrated with mild nitrating agent, acetyl nitrate, at low temperature (- 5 to -30 C) . The reaction proceeds by an addition-elimination mechanism involving an intermediate, 2,5-addition product. In certain cases, the intermediate may be isolated, if a base (pyridine) is not used to eliminate acetic acid. O + H3C
O
C
O
NO 2 HNO3 + Ac2O -10to -20OC
NO2
O
O OHC
O
+ H3C
C
O
NO2
CH(OCOCH 3)2
Fum.HNO3 + Ac2O -10to -20OC
OHC
+
NO2
O
OHC
O
NO 2
Thiophene Thiophene undergoes nitration predominantly at an α-position with the formation of 2o nitrothiophene, when treated with mild nitrating agent, acetyl nitrate, at 10 C. Although small amount of 3-nitrothiophene is also obtained, the α-selectivity in nitration decreases with the strong nitrating agents. NO2
O S
+ H3C
C
O
NO2
10OC
+ NO2
S 95%
S 5%
NO 2
+
S
HNO3
H2SO4
S 85%
+ NO2
S 15%
The nitration of thiophenes substituted with electron releasing group (with +I effect) at C-2 provides 3-nitro- and 5-nitrothiophenes. But when the substituent is with considerable steric hindrance, the nitration occurs exclusively at C-5.
NO2
R
S
H2SO4
+ HNO 3
+
R = alkyl group
+
HNO3
R
S 30%
H2SO4
O 2N
C(CH3 )3
S
O 2N
R
S 70%
C(CH3) 3
S
Thiophenes substituted with electron releasing substituents (+M effect) involve nitration at the αand β- positions, but in halothiophenes nitration takesplace exclusively a t C-5. NO2 + HNO 3 OR
S
H2SO4
+
O 2N
OR
S
S 20%
80% +
H2SO4
HNO3
O 2N
X
S
OR
X
S
X = halogen
Thiophenes with electron withdrawing substituents at C-2 undergo nitration at C-4 and C-5 positions providing 4-nitro and 5-nitro derivatives. O 2N
S
+ HNO 3 COOH
H2SO4
+
O 2N
COOH
S
S
75%
COOH
25%
3. Sulfonation Pyrrole Pyrrole and its N- and C-alkyl pyrroles can not be sulfonated under ordinary conditions as these are polymerized by concentrated sulfuric acid. These are, therefore, sulfonated by mild sulfonating agent (pyridine-sulfur trioxide) of low acidity. The reaction of pyrrole with pyridine-sulfur trioxide complex o at 100 C provides pyrrole-2-sulfonic acid. 100oC
+
N H
+
N
SO 3
-
N H
SO 3
HCl
+
N H
N H
SO3H
Pyrroles substituted with electron withdrawing substituents require vigorous reaction conditions (chlorosulfonic acid, conc.sulfuric acid and oleum). If both the α-positions are blocked, the sulfonation occurs at the β-position.
Furan Furan is sulfonated with the complex of sulfur trioxide with pyridine or dioxane and provides 2sulfonic or 2,5-disulfonic acid depending on the reaction conditions. However furan substituted with an electron withdrawing substituent at the position-2 can be sulfonated by oleum with the formation of 5-sulfonic acid derivative. + C5H5 N-SO3
-
O
HCl
+
C5H5 N-SO3
SO3 .C5H5N H
O
SO3H HCl
O
HO3S
H2SO4 + SO3
COOH
O
HO3S
SO3H
O
COOH
O
Thiophene Thiophene is sulfonated readily with 95% sulfuric acid at room temperature with the formation of thiophene-2-sulphonic acid. This reaction, indeed, provides the basis for its isolation from coal tar benzene. Sulfonation of 2-halothiophenes with 95% sulfuric acid occurs exclusively at an α-position. The reaction of thiophene with chlorosulfonic acid affords thiophene-2-sulfonyl chloride in low yield. + H2SO4
H2SO4
30-40oC
S
SO3H
S
; S
X
;
HO3S
S
X
+ ClSO3H
CHCl3
S
SO2Cl
S
4. Halogenation Pyrrole The high reactivity of pyrrole ring system causes it to undergo halogenation at all the strongly activating positions. It is very difficult to prepare the mono-halopyrroles except under very special conditions. The halopyrroles are very unstable compounds and decompose readily in air and light. In substituted pyrroles the vacant position is generally attacked during halogenation. Chlorination of pyrrole with sulfuryl chloride (SO2Cl2) in ether results in polychlorination providing mono, di, tri, tetra- and penta chloropyrroles depending on the quantity of sulfuryl chloride. Bromination of pyrrole with bromine and acetic acid gives 2,3,4,5-tetrabromopyrrole, but pyrrole substituted with electron withdrawing substituent undergoes bromination giving monobrominated pyrroles. However bromine in carbon tetrachloride, 3-bromopyrrole is obtained by the isomerization of thermodynamically less stable 2-bromopyrrole. Br + Br 2
Br
Br
CH3COOH
Br
N H
+
; Br
N H
N H
Br 2
CO2C2H5
CH3COOH
Br
N H
+ CO2C2H5
N H
CO2C2H5
Iodination of pyrrole with iodine in aqueous potassium iodide provides tetraiodopyrrole. However iodination of pyrrole substituted with electron withdrawing substituent at the position-2 results in substitution at the position-4. I + I2
N H
I
I
KI
; I
N H
I
N H
+ I2 COCH3
KI
N H
COCH3
Pyrrole-2-carboxylic acids polysubstituted by electron withdrawing substituents undergo iodinative decarboxylation to provide the corresponding 2-iodopyrroles. R
COOC2H5
R
COOC2H5
KI
CH3CO
K 2CO3
COOH
N H
CH3CO
I
N H
Furan Furan reacts vigorously with bromine and chlorine at room temperature with the formation of polybromo- or polychloro- furans. o Chlorination of furan with chlorine in the presence of dichloromethane at -40 C provides 2chlorofuran as a major product. If the electron withdrawing group is present at the position-2, only 5chloro derivative is obtained. Cl + Cl2
CH2Cl2
O
+
Cl
O
Cl
+ Cl
O
Cl
Cl
O
;
+ Cl 2 COCH 3
O
CH2Cl2
Cl
O
COCH3
o
Bromination of furan with dioxane-dibromide (Br 2+dioxane) at -5 C gives 2-bromofuran. o But the bromination of furan in methanol at -10 C in the presence of a base provides 2,5-dimethoxy2,5-dihydrofuran involving an attack of nucleophile on the cations rather than an elimination of a proton (write mechanism). + Br 2
O
H
CH3OH -10OC
Br
+
O
H
CH3OH
H H3CO
O
-Br
Br
CH3OH
H +
H3CO
O
H
H H3CO
O
OCH3
Bromination of furan substituted with an electron-withdrawing substituent at the position-2 generally provides 5-bromo derivative involving an electrophilic substitution mechanism.
O
+ Br 2 COCH3
ClCH2CH2Cl
Br
O
COCH3
Thiophene Thiophene undergoes halogenation preferentially at an α-position. Thiophene reacts with chlorine to yield a mixture of substituted as well as addition products. Chlorination with an excess of chlorine in the presence of iodine as catalyst yields hexachlorothiophene. Bromination of thiophene by molecular bromine in acetic acid-ether mixture or in carbon tetrachloride results in the formation of 2-bromothiophene. The reaction of thiophene with N bromosuccinimide also provides 2-bromothiophene. But bromination of thiophene in the presence of a base yields mainly 2,5-dibromothiophene.
CH3COOH +
S
Br 2
ether/CCl 4
O S +
N
Br
Base
+ Br 2
;
Br
S
Br
S
Br
O
Iodination of thiophene with iodine in the presence of mercury (II) oxide gives mainly 2iodothiophene (70%). The acid catalysed reaction of thiophene with iodine and iodic acid also produces 2-iodothiophene, in better yield (75%). + I2
HgO
+
S
I
S
I
I
S
5. Acylation Pyrrole Acylation of pyrrole produces N-acyl or C-acyl pyrroles depending upon the reaction conditions. o Acylation of pyrrole with acetic anhydride at 100-150 C affords 2-acyl and 2,5-diacylpyrroles, but pyrrole with acetic anhydride in the presence of sodium acetate provides N-acylpyrrole. O H3C +
N H
O H3C O
O H3C
100-150 oC
+
N H
COCH3 CH3CO
N H
COCH3
+
; N H
O
CH3COONa
H3C
N O
COCH3
General methods used for C-acylation are: i) Houben-Hoesch reaction The reaction of pyrrole with aliphatic nitrile and hydrochloric acid (RCN/HCl) in the presence of lewis acid introduces an acyl group at the α-position of pyrrole nucleus. However, if both the α positions are occupied, the acylation occurs at the β-position. The rate of acylation is decreased, if the electron withdrawing substituent is present at the α-position. + RCN + HCl
N H
Lewis acid
H2O
N H
C R
NH2Cl
N H
COR
ii) Gattermann formylation The reaction of pyrrole wit zinc cyanide and hydrochloric acid results in C-formylation involving attack of imidoformyl electrophile at the position-2. if both the α-positions are occupied, C-formylation occurs at the β-position. But the electron withdrawing substituent at the α-position inhibits formylation. C-Formylation is very significant reaction in pyrrole chemistry because of the use of pyrrole-2carbaldehyde in porphyrin synthesis.
H2O
Zn(CN)2 HCl
N H
N H
CO2C2H5
N H
NH OHC
N H
HCl
R
R Zn(CN)2
CO2C2H5 R
Zn(CN)2
R
CHO
R
N H
N H
HCl CO2C2H5
No Reaction
R
iii) Vilsmeier-Haack reaction It is the most effective method for C-formylation and acylation of pyrroles in which pyrrole is treated with phosphorous oxychloride and N,N-dimethylformamide. The reaction proceeds with Cformylation at the position-2 involving immonium ion as an intermediate. However the reaction of N-substituted pyrroles with DMF and POCl3 provides 2-and 3-formylpyrroles and their ratio depends upon the steric effect of the substituent present at the position-1. The peresence of bulky group at position-1 causes Vilsmeier-Haack formylation to occur at the position-3. CHO CH3COONa
DMF
N H
POCl3
H2O
N H
+
N H3C
CH3
N H
CHO
DMF
;
POCl3
C(CH3) 3
C(CH3) 3
iv) Friedel-Crafts acylation Generally pyrroles are sufficiently reactive and are acylated by acyl chloride without using Lewis acid because Lewis acid promotes polymerization of pyrrole. Pyrroles substituted with electron releasing substituents and the pyrroles which are susceptible for acid catalysed polymerization are acylated by acyl chloride in the presence of pyridine. The addition of pyridine facilitates acylation due to the formation of very reactive electrophile, N-acylpyridinium. Furan The acylation of furan with acid anhydrides in the presence of mild catalysts such as phosphoric acid and boron trifluoride etherate results in exclusively 2-acylfuran. The acylation of furans can be performed also with acetyl p-toluenesufonate or Ac2O-SnCl4 although trifluoroacetic anhydride does not require any catalyst. + (CH3CO)2O
O
H3PO4 or BF3-Et2O
O
COCH3
The acylation of 3-methylfuran with acid anhydride and phosphoric acid gives 2-and 5-acyl derivatives in 2:1 ratio. If both the α-positions are occupied, acylation takes place at the β-position.
CH3 + (CH3CO)2O
H3PO4
;
+
O
COCH3 CH3CO
O
COCH3
CH3
CH3
O
H3C
+ (CH3CO)2O CH3
O
SnCl4
H3C
O
CH3
The acylation of furans, containing ester group at the position-2, with acid anhydride and boron trifluoride etherate affords 5-acyl derivative, while with acid anhydride-tin(IV) chloride the acylation occurs at both the C-4 and C-5 positions. The acylation at the position-4 is probably because of coordination of the catalyst to the carbonyl oxygen of an acid anhydride. RCO + (RCO)2O BF3-Et2O
O
;
COR
COOCH3
O
SnCl 4
+ (RCO)2O
COOCH3
COOCH3
O
+
C6H6 COR
COOCH3
O
O
COOCH3
Thiophene Thiophene is polymerized when treated with acetyl chloride in the presence of aluminium chloride, but undergoes acylation exclusively at an α-position when catalysed by acid anhydrides in the presence of phosphoric acid or by acid chlorides in the presence of stannic chloride. The reactivity of α-position in thiophene is much higher than that of the β-position towards acylations. Thiophenes substituted with electron releasing substituents such as methyl, tert-butyl or thiomethyl at the position-2 undergo acylation exclusively at the position-5. The presence of phenyl group at the position-3 activates already activated α-position and also to the adjacent β-position to some extent and both α- and β-substituted products are formed. But the acylation of 2-acylthiophenes in the presence of Lewis acid occurs at the position-4 probably because of co-ordination of Lewis acid with oxygen of an acyl group. + CH3COCl
SnCl4
COCH 3
S
S
+ (CH3CO)2O R
; S
SnCl4
CH3CO
S
R
CH3CO CH3CO
SnCl4
S
+ (CH3CO)2O
+ CH3COCl
+
S
COCH3
;
S
COCH 3
AlCl3
S
COCH 3
S
Thiophene undergoes Vilsmeier formylation at an α-position when treated with DMF in the presence of POCl3.
III. Reactions of pyrrole 1. Hydroxymethylation (Mannich reaction) Pyrrole undergoes Mannich reaction with formaldehyde and primary or secondary amine in the presence of an acid with the introduction of functionalized alkyl group at the α-position. The reaction is considered to involve electrophilic attack of iminium electrophile which ios produced in situ from the reaction of formaldehyde with amine in the presence of an acid. The product of Mannich reaction is synthetically useful as it undergoes a number of transformations providing important compounds.
+ CH2=O + (CH3)2 NH
N H
+
N H Mannich base
CH2N(CH3)3
H2O/H+
KCN
CH3I
H+
CH2N (CH3)3I
N H -
-
N H
CH2CN
N H
CH2COOH
OH
N H
CH2OH
Reactions with aldehydes and ketones The reaction of pyrrole with aliphatic aldehydes and ketones in the presence of an acid gives unstable and highly reactive electrophile, azafulvenium cation, which on subsequent reaction with pyrrole eventually leads to the formation of polymeric products; cyclic tetramer with acetone, while linear tetramer with aldehyde. The presence of two methyl groups force pyrrole ring into coplanar conformation and leads to the formation of a cyclic tetramer in the reaction with acetone. But the reaction of pyrrole (with single free position) with formaldehyde in the presence of acid medium provides bis(2-pyrrolyl)methane. Similarly, the reaction of pyrrole with aromatic aldehyde and acid in the presence of air results in the formation of cyclic tetramer, tetraphenylporphyrin, involving highly reactive and unstable azafulvenium cation. H3C
H3C CH3 + O
N H
CH3
H+
H + N
H3C CH3 CH3
OH
N H
CH3
-H2O
NH
N
CH3
CH3
HN H N
H3C H3C
CH3 CH3
The reaction of pyrrole with aromatic aldehyde substituted with electron releasing substituent at p position is facilitated and produces purple red colouration due to the formation of resonance stabilized azafulvenium cation, which is the basis of Ehrlich test. However the reaction of pyrroles (having single free position) with aldehydes and ketones in the presence of hydroiodic acid and hypophosphoric acid results in an alkylation at the vacant position involving reduction of the reactive intermediate, azafulvenium cation. 2. Reactions with electron deficient species Reactions with carbenes i) The reaction of pyrrole with dichlorocarbene, generated from chloroform and strong base, results in the formation of pyrrole 2-carbaldehyde involving electrophilic attack of carbine at the α position of pyrrole; and the ring expanded product, 3-chloropyridine, involving the insertion of carbine into the C2-C3 bond of pyrrole. When the carbine is generated from chloroform with a strong base, equal amounts of both the products are obtained. But the formation of ring expanded product is favoured, if carbine is generated under weakly basic or neutral conditions. ii) The reaction of pyrroles with carbenes, generated by light or copper catalysed decomposition of diazoesters or diazoketones, provides α-substituted product. iii) The reaction of N-methylpyrrole with ethoxycarbonylcarbene proceeds via a cyclic intermediate with the formation of predominantly 2-substituted product. But the reaction of 1-
