Dr. Solomon Derese...We will study the chemistry of heterocyclic compounds i.e. Cyclic organic...
Transcript of Dr. Solomon Derese...We will study the chemistry of heterocyclic compounds i.e. Cyclic organic...
UPC 213 (Pharmaceutical Chemistry II)
Heterocyclic Chemistry
Dr. Solomon Derese UPC 213 2
n = 1,2,3, ……
Where Z is different (hetero) from carbon
Course outline
• Introduction to heterocyclic chemistry
• Nomenclature of Heterocycles
• Structure, reactions and synthesis ofaromatic heterocyclic compounds
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Study Nomenclature, Structure, Reaction andSynthesis of aromatic heterocyclic compounds.
Scope of the course
Aliphatic heterocycles
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Aromatic heterocycles
We will study the chemistry of heterocycliccompounds i.e. Cyclic organic compoundscontaining not just carbon atoms, but oxygen,nitrogen, sulfur etc.
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It may seem strange that this rather narrowlydefined class of compounds deserves a wholeunit, but you will soon see that this is justifiedboth by the sheer number and variety ofheterocycles that exist and by their specialchemical features.
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Why bother with heterocycles?
A recent analysis of the organic compoundsregistered in Chemical Abstracts revealed that as ofJune 2007, there were 24,282,284 compoundscontaining cyclic structures, with heterocyclicsystems making up many of these compounds –about two third of organic compounds areheterocyclic.
Most pharmaceuticals are based on heterocycles. Aninspection of the structures of the top-selling brand-name drugs in 2007 reveals that 8 of the top 10 and71 of the top 100 drugs contain heterocycles.
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The history of medicine can be defined byheterocyclic compounds.
As early as 16th centuryhave been used to treatmalaria.
The first synthetic drug(1887) (used forreduction of fevers)
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The first effectiveantibiotic (1938).
The first multi-millionpound drug (1970s),antiulcer drug.
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Approved in 1997 fortreatment of male impotence.
Approved for treatment of Chronic MyelogenousLeukemia (CML) in 2001.
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Nomenclature of Heterocyclic Compounds
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The IUPAC rules allow three nomenclatures.
I. The Hantzsch-Widman Nomenclature.
II. Common Names
III. The Replacement Nomenclature
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n = 1,2,3, ……
The Hantzsch-Widman nomenclature is based onthe type (Z) of the heteroatom; the ring size (n) andnature of the ring, whether it is saturated orunsaturated .
I. Hantzsch-Widman Nomenclature
This system of nomenclature applies to monocyclicthree-to-ten-membered ring heterocycles.
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I. Type of the heteroatom
The type of heteroatom is indicated by aprefix as shown below for commonhetreroatoms:
O OxaN AzaS ThiaP Phospha
Hetreroatom Prefix
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II. Ring size (n)The ring size is indicated by a suffix according toTable I below. Some of the syllables are derived fromLatin numerals, namely ir from tri, et from tetra, epfrom hepta, oc from octa, on from nona, ec fromdeca.
Ring size Suffix Ring size Suffix
3 ir 7 ep
4 et 8 oc
5 ol 9 on
6 in 10 ec
Table I: Stems to indicate the ring size ofheterocycles
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Ring size Saturated Unsaturated Saturated (With Nitrogen)
3 -irane -irine -iridine
4 -etane -ete -etidine
5 -olane -ole -olidine
6 -inane -ine
7 -epane -epine
8 -ocane -ocine
9 -onane -onine
10 -ecane -ecine
Table II: Stems to indicate the ring size and degree ofunsaturation of heterocycles
The endings indicate the size and degree ofunsaturation of the ring.
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Each suffix consists of a ring size root and anending intended to designate the degree ofunsaturation in the ring.
It is important to recognize that the saturatedsuffix applies only to completely saturated ringsystems, and the unsaturated suffix applies torings incorporating the maximum number of non-cumulated double bonds.
According to this system heterocyles are named bycombining appropriate prefix/prefixes with a stemfrom Table II. The letter “a” in the prefix is omittedwhere necessary.
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Saturated 3, 4 & 5-membered nitrogenheterocycles should use respectively thetraditional "iridine", "etidine" & "olidine"suffix.
Systems having a lesser degree ofunsaturation require an appropriate prefix,such as "dihydro"or "tetrahydro".
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Examples
Oxa+irane= Oxirane Aza+iridine= Aziridine
Oxa+etane=Oxetane Aza+etidine=Azetidine
Oxa+olane= Oxolane Aza+olidine= Azolidine
Thia+irane= Thiirane
Thia+etane=Thietane
Thia+olane= Thiolane
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Azinane Azine
Pyridine
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In case of substituents, the heteroatom isdesignated number 1, and the substituents aroundthe chain are numbered so as to have the lowestnumber for the substituents.
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The compound with the maximum number ofnoncumulative double bonds is regarded asthe parent compound of the monocyclicsystems of a given ring size.
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Partial Unsaturation
Use fully unsaturated name with dihydro, tetrahydro,etc
Azepine 2,3-Dihydroazepine
4,5-Dihydroazepine 2,5-Dihydroazepine
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3
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1-Ethyl-4-methyl-4,5-dihydroazepine
1-Ethyl-5-methyl-2,3,4,5-tetrahydroazepine
When numbering give priority to saturated atoms.
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O OxaN AzaS ThiaP Phospha
Hetreroatom Prefix
Ring size Saturated Unsaturated Saturated (With Nitrogen)
3 -irane -irine -iridine
4 -etane -ete -etidine
5 -olane -ole -olidine
6 -inane -ine
7 -epane -epine
8 -ocane -ocine
9 -onane -onine
10 -ecane -ecine
Type (Z) - PrefixSize (n) - SuffixNature of ring - Ending
Revision
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Rings With More Than One Heteroatom
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Two or more similar atoms contained in a ring areindicated by the prefixes ‘di-’, ‘tri’, etc.
1,3,5-Triazine
If more than one hetero atom occur in the ring,then the heterocycle is named by combining theappropriate prefixes with the ending in Table I inorder of their preference, O > S > N.
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Oxaziridine1,3-Thiazole (Thiazole)
1,4-Oxazine 3-chloro-5-methyl-1,2,4-oxadiazole
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O
S
Se
NB
P
C
Priority of heteroatoms for numbering purposes:
Highest
Lowest
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The ring is numbered from the atom ofpreference in such a way so as to give thesmallest possible number to the other heteroatoms in the ring. As a result the position ofthe substituent plays no part in determininghow the ring is numbered in suchcompounds.
4-Methyl-1,3-thiazole
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There are a large number of important ringsystems which are named widely known withtheir non-systematic or common names.
II. Common Names
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1,4-Dihydropyridine 2,3-Dihydropyridine
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Identical systems connected by a single bond
Such compounds are defined by the prefixes bi-, tert-, quater-, etc., according to the number of systems,and the bonding is indicated as follows:
1
22’
1’
1
2 3’’ 1’’
1’
2’
2’’
4’
2,2' - Bipyridine 2,2': 4',3'' - Terthiophene
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Naming Hetrocycles with fused rings
When naming such compounds the side of theheterocyclic ring is labeled by the letters a, b, c, etc.,starting from the atom numbered 1. Therefore side‘a’ being between atoms 1 and 2, side ‘b’ betweenatoms 2 and 3, and so on as shown below forpyridine.
a
b
c d
e
f
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The name of the heterocyclic ring is chosen asthe parent compound and the name of thefused ring is attached as a prefix. The prefix insuch names has the ending ‘o’, i.e., benzo,naphtho and so on.
Benzo [b] furan
Benzo [b] pyridine
Benzo [c] thiophene
a
b c
a
b
ab
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ca
b
d Benzo [d] thiepine
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In a heterocyclic ring, other things being equal,numbering preferably commences at a saturatedrather than at an unsaturated hetero atom.
3-Ethyl-5-methylpyrazole 1-Methylindazole
1 12
2
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Handling the “Extra Hydrogen”
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Heterocycles with maximum number of double bondswhich can be arranged in more than one way.
Examples
Pyrans
Pyrroles
Double bonds @ 2 and 4
Double bonds @ 2 and 5
Double bonds @ 2 and 4
Double bonds @ 1 and 4
Double bonds @ 1 and 3
Therefore, should have different names.
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This is a special problem resulting from isomerism in theposition of the double bonds which is sometimes referredto as “extra-hydrogen” and this can be addressed bysimply adding a prefix that indicates the number of thering atom that possesses the hydrogen using italic capital‘1H’ ‘2H’ ‘3H’, etc. The numerals indicate the position ofthese atoms having the extra hydrogen atom.
1
2
1 2
3
4
2H-Pyran4H-Pyran
The saturated position takes priority in numbering.
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4-Methyl-2H-oxete
1
23
4
1 2
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2-Methyl-2H-oxete
1H-Pyrrole(Pyrrole)
3H-Pyrrole 2H-Pyrrole
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In replacement nomenclature, theheterocycle's name is composed of thecarbocycle's name and a prefix that denotesthe heteroatom.
III. The Replacement Nomenclature
Thus, "aza", "oxa", and "thia" are prefixes for anitrogen ring atom, an oxygen ring atom, and asulfur ring atom, respectively.
Notice that heterocyclic rings are numbered sothat the heteroatom has the lowest possiblenumber.
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REACTIONS AND PROPERTIES OF AROMATIC HETEROCYLCES
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N..
Pyridine
Pyridine is aromatic asthere are six delocalizedelectrons in the ring.
Six-membered heterocycles are more closelyrelated to benzene as they are aromatic on thebasis of their p-electron systems without the needfor delocalization of heteroatom lone pairs. Theempirical resonance energy for pyridine is about 28Kcal/mol, only slightly lower than that for benzene.
SIX MEMBERED AROMATIC HETEROCYCLES
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Pyridine has divalent negatively charged N, which isa stable condition for N. The positive charge isdispersed to carbons around the ring, specifically toC-2 and C-4.
Structure of Pyridine
The net effect is to reduce the p-electron density inthe ring relative to benzene, and as result pyridineis electron deficient compared to benzene.
As a result, unlike benzene pyridine is polarmolecule due to the electronegative nitrogen.
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Six membered heterocycleswith an electronegativeheteroatom are generallyelectron deficient comparedto benzene. Such compoundsare classified as p-deficient.
Electron-withdrawing heteroatoms decreasethe p-electron density at the carbon atomsand are thus p-deficient relative to benzene.
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Structure of five membered heterocycles
The five-membered aromaticheterocycle ring has a p-electronexcess (six on five atoms), while inbenzene, the p-electron density isone on each ring atom.
Five membered heterocycles with an electronegativeheteroatom are generally electron rich compared tobenzene (six electrons for five carbons). Suchcompounds are classified as p-excessive.
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36 kcal/mol
29 kcal/mol
22 kcal/mol
16 kcal/mol
The ease with which the lone pairelectron is released is directlyrelated to the electronegativity ofthe heteroatom. Thus the lowerthe electronegativity of theheteroatom, the higher thearomaticity.
The degree of aromatic characterin a five membered ring isdetermined by the ease withwhich the lone pair may bereleased into the delocalizedsystem.
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Aromatic Heterocycles
p- Excessive p- Deficient
This classification is not trivial; there is a vastdifference between the properties of the two typesof aromatic compounds.
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Reactions of p-deficient heterocyclic aromatic compounds
A hallmark of p-deficient heterocyclic systemsis their low reactivity with electrophilicagents, slower than benzene. For example,pyridine is less reactive than benzene by afactor of 106 when subjected to conditions ofnitration. The reactivity is on the order of thatof nitrobenzene, which is well known torequire much more drastic conditions thanthose for benzene itself.
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For example, 3-bromopyridine is formed whenpyridine is reacted with bromine in the presence ofoleum (sulfur trioxide in conc. sulfuric acid) at 130°C.
Conversely pyridines are susceptible to nucleophilicattack.
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The reactivity is greater than that of benzeneand is in roughly the same range as found forbenzenes bearing electron releasing groupssuch as in aniline. The greater electron densityin these rings accounts for this higherreactivity.
A significant feature of the p-excessive ringsystems is that they undergo electrophilicaromatic reactions faster than benzene.
Reactions of p-excessive heterocyclic aromatic compounds
These heterocycles undergo electrophilic aromaticsubstitution reactions much faster than benzeneunder similar conditions. The reasons for this are:
I. The resonance energy of the heterocycles is lessthan that of benzene, i.e. less aromatic thanbenzene.
II. The five-membered aromatic heterocycle ring hasa p-electron excess (six on five atoms), while inbenzene, the p-electron density is one on eachring atom.
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Reaction with bromine requires no Lewis acid andleads to substitution at all four free positions.
no Lewis acid
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FIVE MEMBEREDAROMATIC
HETEROCYCLES
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a-substitution b-substitutionThe Substitution is regioselective to the a position; whenthese positions are occupied, the b-position is substituted.
X = O, S or NH
Electrophilic aromatic substitution reaction of fivemembered aromatic heterocycles
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WHY?The +ve charge is better resonance stabilized whenthe substitution is at the a-position than at b-position.
A more stable intermediate carbocation having 3resonance forms.
only 2 resonance forms
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Common reactions of pyrrole, furan, and thiophene
Electrophilic aromatic substitution reaction is easyand is preferred at a-position; also easy at b-position.
The following reaction are common to the three fivemembered aromatic heterocycles.
A. Electrophilic Aromatic Substitution
Z = O, S, NH
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C. Vilsmeier-Haack reaction
B. Substitution at a-position via a-lithiated Intermediates
Z = O, S, NR
Vilsmeier reaction (Vilsmeier‐Haack reaction) allowsthe formylation (addition of -CHO) of heterocyclicmolecules. The formylating agent, chloroiminiumion, is formed in situ from N,N‐dimethylamide andPOCl3.
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Z = O, S, NH
Example
Vilsmeier-Haack reaction
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Mechanism
Chloroiminium ion
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The reaction of electron rich heterocycles withformaldehyde and primary/secondary amineforming an amino alkylated heterocylcic compoundis called the Mannich reaction.
D. Mannich reaction
Z = O, S, NH
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Mechanism
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Furans are volatile, fairly stable compounds withpleasant odours. Furan itself is slightly soluble inwater. It is readily available, and its commercialimportance is mainly due to its role as the precursorof the very widely used solvent tetrahydrofuran(THF).
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By analogy with benzene, furanundergoes reactions with electrophilicreagents, often with substitution.However, it can also react by additionand/or ring-opening depending onreagent and reaction conditions.
Reactions of Furans
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Electrophilic Aromatic Substitution Reaction
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Halogenation
Furan can be halogenated at a-position. Bromination andiodination are easy to control as only one halogen atomsadds to furan. In the case of chlorination, di-substitution hasbeen known to occur.
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AcylationAcetyl groups in the presence of phosphoric acid (or a Lewisacid) add at a-position of furans.
In general, position 2 (a-position) is more reactive thanposition 3. When position 2 is blocked, b-acylation canproceed smoothly.
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n-Butyllithium in hexane metalates furan inthe 2-position, while excess of reagent athigher temperature produces 2,5-dilithiofuran.
Metalation
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Addition reactions
Furans yield the corresponding tetrahydrofurans bycatalytic hydrogenation.
In some addition reactions, furans behave as 1,3-dienes. For example, furan reacts with bromine inmethanol in the presence of potassium acetate togive 2,5-dimethoxy-2,5-dihydrofuran by a 1,4-addition:
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Ring-opening reactions
Furans are protonated in the 2-position, and not onthe O-atom, by BRÖNSTED acids:
Concentrated acid
Dilute acid
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Thiophene prefers reactionswith electrophilic reagents.Additions and ring-openingreactions are less importantthan with furan, andsubstitution reactions aredominant.
Some additional reactions, such as oxidationand desulfurization, are due to the presenceof sulfur and are thus confined to thiophenes.
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Electrophilic substitutions
Thiophene reacts more slowly than furan but fasterthan benzene. Substitution is regioselective in the 2-or in the 2,5-position.
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Reactions with nucleophilic reagents
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Thiophenes are oxidized by peroxy acids to givethiophene 1,1 –dioxides:
Oxidation
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Pyrrole reacts with sodium, sodium hydride or potassium ininert solvents, and with sodium amide in liquid ammonia, togive salt-like compounds:
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Electrophilic substitution reactions on carbon
Nitration
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Halogenation
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6-Membered Aromatic Heterocycles
Containing one
Heteroatom
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Pyridines
Pyridine is the simplest heterocycle of theazine type. It is derived from benzene byreplacement of a CH group by a N-atom.
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The structure of pyridine is completely analogous to that ofbenzene, being related by replacement of CH by N.
The key differences are:
I. The departure from perfectly regular hexagonalgeometry caused by the presence of the hetero atom, inparticular the shorter carbon-nitrogen bonds,
II. The replacement of a hydrogen in the plane of the ringwith an unshaired electron pair, likewise in the plane ofthe ring, located in an sp2 hybrid orbital, and not at allinvolved in the aromatic p-electron sextet; it is thisnitrogen lone pair which is responsible for the basicproperties of pyridines, and
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III.A strong permanent dipole, traceable to thegreater electronegativity of the nitrogencompared with carbon.
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I. The heteroatom make pyridines very unreactiveto normal electrophilic aromatic substitutionreactions. Conversely pyridines are susceptible tonucleophilic attack. Pyridines undergoelectrophilic substitution reactions (SEAr) morereluctantly but nucleophilic substitution (SNAr)more readily than benzene.
II. Electrophilic reagents attack preferably at the N-atom and at the b-C-atoms, while nucleophilicreagents prefer the a- and c-C-atoms.
The following reactions can be predicted forpyridines on the basis of their electronic structure:
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In reactions which involve bond formation using thelone pair of electrons on the ring nitrogen, such asprotonation and quaternisation, pyridines behave justlike tertiary aliphatic or aromatic amines.
Electrophilic Addition at Nitrogen
Reactions of Pyridine
When a pyridine reacts as abase or a nucleophile itforms a pyridinium cation inwhich the aromatic sextet isretained and the nitrogenacquires a formal positivecharge.
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Protonation at Nitrogen
Nitration at Nitrogen
Pyridines form crystalline,frequently hygroscopic,salts with most protic acids.
This occurs readily byreaction of pyridineswith nitronium salts,such as nitroniumtetrafluoroborate.
Protic nitrating agents such as nitric acid of courselead exclusively to N-protonation.
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Acid chlorides and arylsulfonic acids react rapidlywith pyridines generating 1-acyl- and 1-arylsulfonylpyridinium salts in solution.
Acylation at nitrogen
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Alkylation at nitrogen
Alkyl halides and sulfates react readily with pyridinesgiving quaternary pyridinium salts.
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Electrophilic substitution at Carbon atoms of the pyridine ring
Electrophilic substitution of pyridines at a carbon isvery difficult. Two factors seem to be responsible forthis unreactivity:
I. Pyridine ring is less nucleophilic than the benzenering; nitrogen ring atom is more electronegativethan carbon atoms and therefore it pulls electronsaway from the carbon atoms inductively leaving apartial plus on the carbon atoms.
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II. When pyridine compound is exposed to an acidicmedium, it forms pyridinium salt. This increasesresistance to electrophilic attack since the reactionwill lead to doubly positive charged species.
Less reactive than pyridine
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When an electrophile attacks the pyridine ring, onlyposition 3 is attacked.
Hint: draw resonance structures that result fromelectrophilic attack at various positions. The positivecharge residing on an electronegative element withsextet configuration is unfavoured.
Why?
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For example, 3-bromopyridine is formed whenpyridine is reacted with bromine in the presence ofoleum (sulfur trioxide in conc. sulfuric acid) at 130°C.
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Mechanism of bromination of pyridine
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Pyridine can be activated to electrophilicsubstitution by conversion to pyridine-N-oxides.
A series of preparatively interesting reactions onpyridine can be carried out by means of pyridine N-oxides such as the introduction of certain functionsinto the ring and side-chain which cannot beachieved in the parent system by direct methods.
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The activating oxygen atom can be removed byreacting the pyridine N-oxide withphosphorous trichloride.
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In such reactions there is a balance between electronwithdrawal, caused by the inductive effect of the oxygenatom, and electron release through resonance from thesame atom in the opposite direction. Here, the resonanceeffect is more important, and electrophiles react at C-2(6)and C-4.
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Thionyl chloride, for example, gives a mixture of 2-and 4-chloropyridine N-oxides in which the 4-isomeris predominant.
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However, pyridine N-oxide reacts with aceticanhydride first to give 1-acetoxypyridinium acetateand then, on heating, to yield 2-acetoxypyridinethrough an addition-elimination process.
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When a similar reaction is carried out upon the 2,3-dimethyl analogue, the acetoxy group rearrangesfrom N-1 to the C-2 methyl group, at 1800C, to form2-acetoxymethyl-3-methylpyridine.
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Resonance stabilized
Anion Chemistry of Pyridine
Works for 2(6)- and 4-alkylpyridines not for 3(5)-alkylpyridines, why?
The negative chargegenerated on thecarbon goes to theelectronegativenitrogen, which canbetter accommodateit.
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Nucleophilic substituition of pyridine
a) X=Hb) X=Good leaving group
X=H, Substitution with “hydride” transfer
Nu: NaNH2 - aminationNu: BuLi, PhLi etc - alkylation / arylationNu: NaOH - “hydroxylation”
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At high temperature the intermediate anion canaromatize by loss of a hydride ion, eventhough, it is apoor leaving group.
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b) X=LG, The nucleophilic substitution is much morefacile when good leaving group such as X:Halogen (F>>Cl,>Br,>I), -OSO2R, -NO2, -OR, areemployed.
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-H: is a bad leaving group
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Halogenopyridines can undergo metal-halogenexchange when treated with butyllithium. Thelithium derivatives then behave in a similar mannerto arylithiums and Grignard reagents and react withelectrophiles such as aldehydes, ketones and nitriles.
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Synthesis of Heterocycles Compounds
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:Nu
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Synthesis of Furan,
Pyrrole
and
Thiophene
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:Nud+ d+
Furans, pyrroles and thiophenes from 1,4-dicarbonyl compounds: Paal Knorr synthesis
:Nu = RNH2, H2S
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Furans, pyrroles and thiophenes from 1,3-dicarbonyl (b-ketocarbonyl) compounds
acidic hydrogens React with
electrophiles
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Feist–Benary synthesis of furans
The Feist-Benary synthesis is an organicreaction between a-haloketones and b-dicarbonyl compounds to give substituted furans inthe presence of base.
a-haloketones
X = Cl, Br, I
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Knorr-pyrrole synthesis
This involves the condensation of a-amino ketoneswith a b-diketone or a b-ketoester to give asubstituted pyrrole in the presence of a base likepyridine.
a-amino ketones
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Fiesselmann synthesis
1,3-Dicarbonyl compounds or b-chlorovinylaldehydes react with thioglycolates or other thiolspossessing a reactive methylene group to givethiophenes in the presence of pyridine.
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Synthesis of Pyridine
:Nu = RNH2
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I. Reaction between a 1,5-diketone and ammonia
Ammonia reacts with 1,5-diketones to give unstable1,4-dihydropyridine, which can be easilydehydrogenated (using nitrobenzene or nitric acid)to give pyridine.
1,4-dihydropyridine
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II. The Guareschi synthesis
Unsymmetrical pyridines can be synthesised from areaction between a b-dicarbonyl compound and a b-enaminocarbonyl compound or nitrile.
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III. The Hantzsch synthesis
Symmetrical 1,4-dihydropyridines, which can beeasily dehydrogenated (to form pyridines), areproduced from the condensation of an aldehyde,ammonia, and two equivalents of a 1,3-dicarbonylcompounds (commonly a β-ketoester) which musthave a central methylene.
The product from the classical Hantzsch synthesis isnecessarily a symmetrically substituted 1,4-dihydropyridine. Subsequent oxidation (ordehydrogenation) gives a symmetrical pyridinecompound.
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STEP I
The reaction is believed to proceed via KnoevenagelCondensation.
STEP II
A second key intermediate is an ester enamine,which is produced by condensation of the secondequivalent of the β-ketoester with ammonia:
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STEP III
Further condensation between these two fragmentsgives the dihydropyridine derivative:
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MECHANISM
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Nifedipineis in a group of drugscalled calcium channelblockers. It works byrelaxing the muscles ofyour heart and bloodvessels. Nifedipine is usedto treat hypertension (highblood pressure) andangina (chest pain).
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OXAZOLE
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IMIDAZOLES
THIAZOLES
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Diazepam (Valium) used for the treatment ofanxiety disorders. Diazepamalso is used for thetreatment ofagitation, tremors, delirium,seizures, and hallucinationsresulting from alcoholwithdrawal. It is used for thetreatment of seizures andrelief of muscle spasms insome neurological diseases
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Antifungal drug
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ClopiracNonsteroidal Antiinflammatory Drug)
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