Org. Chem 3 Lecture Notes PDF

Org. Chem 3 Synthesis of Pyrrole 1) From 1,4-dicarbonyl compounds (Paal-Knorr Synthesis) * Generally Substituted pyrrole may be synthesized through the cyclization of 1,4-diketones in combination with ammonia (NH3) or amines, The ring-closure is proceeded by dehydration (condensation), which then y...

Org. Chem 3 Synthesis of Pyrrole 1) From 1,4-dicarbonyl compounds (Paal-Knorr Synthesis) * Generally Substituted pyrrole may be synthesized through the cyclization of 1,4-diketones in combination with ammonia (NH3) or amines, The ring-closure is proceeded by dehydration (condensation), which then yields the two double bonds and thus the aromatic @ system. The formation of the energetically favored aromatic system is one of the driving forces of the reaction. A , [\)\ + 21,0 R® N R! R=H or Alkyl or Aryl é NH3 PhH, reflux ———— 90% H Me>H n tautomerism to m H%\ AT, N Me ~ Me ek Ve | momteswave N Me aromatic structure Me [y ” Me 2) Pyrrole is obtained by distillation of succinimide over zinc dust. N H Succinimide Org. Chem 3 3) By heating a mixture of furan, ammonia and steam over alumina Catalyst NH 0N ——— (@] Al>Ogz 4) By passing a mixture of acetylene and ammonia over red hot tube. CH CH red hot tube ||| + NH3 + ||| CH CH 5) Knorr-pyrrole synthesis: This involves the condensation of a-amino ketones with a f-diketone or a B-ketoester to give a substituted pyrrole. HaC__O R Flgt A R T, NH, O oA “CHs L5 RS~ CH R'=-COR; [— diketone 6) HANTZSCH SYNTHESIS FOR PYRROLE This is the condensation between halo ketone, B-keto ester and primary amine Org. Chem 3 cl COOEt +I\ o o MECHANISM E10, " REACTIONS AND REACTIVITY OF PYRROLE Pyrrole is a colorless volatile liquid that darkens readily upon exposure to air. Pyrrole is a weak base because the lone pair of electron of nitrogen atom contributes to the (4n+2) 7 electron cloud. It also exhibit weak acidic properties. Acidic properties of pyrrole Due to participation of N lone pair in aromaticity), pyrrole has exceptionally strong acidic properties for instance it can react with strong bases ; Grignard reagent ; potassium metal in inert solvents, and with sodium amide in liquid ammonia, to give salt-like compounds which can be used to alkylate or acylate the nitrogen atom as shown below: Org. Chem 3 CONHPh phenyl isocyanate PhN=C=0 Acylation RX 14 \Se —_— = (/ \5 R= CH; or C,Hs N DMSO ) K or CHsPh 3 Alkylation R RMgX/ Et;O *Pyrrole is sensitive to strong acids. *This is due to protonation occurs at one of C-3 and the resulting protonated molecule will add to another unprotonated pyrrole molecule this continues to give pyrrole trimer. *This reaction is considered as electrophilic addition to pyrrole pvrrole trimer Pymole ) Trimer —. POLYMER Org. Chem 3 Electrophilic substitution in pyrrole *As expected for aromatic compound, pyrrole can react by electrophilic substitution. *In comparison to benzene pyrrole is more reactive thus the substitution is easier and milder reagents can be used. *The increased reactivity is a result of resonance which pushes the electrons from the N-atom into the ring making the c-atoms of pyrrole ring more electron rich than in case of benzene. In fact pyrrole resembles most reactive benzene derivatives (phenols and amines). *Consequently, there are some modifications in usual electrophilic reagents, for instance, sulphonating and nitrating reagents have been modified to avoid the use of strong acids (induce polymerization). Also reaction with halogens requires no Lewis acid. *Electrophilic substitution normally occurs at a carbon atoms instead of at the nitrogen as explained before. *Also it occurs preferentially at C-2 (the position next to the heteroatom) rather than at C-3 (if position 2- is occupied it occurs at position 3). *This is due to attack at C-2 gives more stable intermediate (it is stabilized by three resonance structure) than the intermediate resulted from C-3 attack (it is stabilized by two resonance structure). Pyrrole ring is acid sensitive therefore nitration and other electrophillic substitution reactions are carried out in milder conditions Org. Chem 3 Not formed two resonance structures less satble NITRATION Pyrrole ring is acid sensitive therefore nitration and other electrophillic substitution reactions are carried out in milder conditions (Mixture of nitric acid + acetic anhydrde) acetyl nitrate (CH;-C0),0 + HNO; —> CH;COONO," + CH;COOH Acetyl Nitrate at 5c // \> CH,COONO," N H Acetyl Nitrate AcONO; AGOH, ~10°G_ O\ [ g T ea% 0, 4| + cHy—&—oNo, _(CH,CO50_ e 2 ° N I\ +CHy—C—0ONO,EHCDY L] CH3C0O),0 + N cocH, N7 cocH; oN o NO2 O,N (CH3C0),0 U\ +CH3—C ONO.ZJ—E FS\ N n N R N H R H Org. Chem 3 HALOGINATION The high reactivity of pyrrole ring system causes it to undergo halogenation at all the strongly activating positions. The special reagents with mild conditions are, therefore, required for the halogenation of pyrroles. O 42—> H -0°C SOCI, @ —_—— o) N Cl H Only monohalogenaed product pyrrole substituted with electron-withdrawing substituent undergoes bromination providing monobrominated pyrrole Qhm2=e., T N TC00CH; CH,000H COOC,Hs COOC;Hs with bromine in carbon tetrachlorlde, 3-br0m0pyrr01e is obtained by the isomerization of thermodynamically less stable 2-bromopyrrole Br [N o2 e [@N Br }——1/ \S N H H H Although the 2-bromo and 2-chloropyrrol can be directly prepared by using N-halosuccinimides (o] OUQ N-Bromo succinamide (N.B.S) Org. Chem 3 Lec 2 Todination of pyrrole substituted with electron-withdrawing substituent at the position-2 results in substitution at the position- 4. (/ \5 + I = N H COCH 3 H COCH 3 Sulfonation : Pyrolysis sulfonated by mild sulfonating agent (pyridine-sulfur trioxide) of low acidity. The reaction of pyrrole with pyridine-sulfur trioxide complex at 100°C, a 90% yield of the corresponding pyrrole-2-sulfonic acid is obtained, after acidification. £ O‘“’C @so(j L. sog Pyrroles substituted with electron- withdrawing substituents require vigorous reaction conditions SOzH pyridine-SO; / \ e R N R 100°C R N H H Friedel-Crafts Acylation: Direct acetylation of pyrrole with acetic anhydride at 200 °C leads to 2-acetylpyrrole as main product, together with some 3-acetylpyrrole, but no N-acetylpyrrole.” N-Acetylpyrrole can be obtained in high yield by heating pyrrole with N-acetylimidazole. or pyrrole with acetic anhydride in the presence of sodium acetate provides N-acylpyrrole [ I C—CHy o [/ \5 + (CH3C0O),0. 200°C @—g—cua + 1/ \S + CH;COOH N N N H aceti¢'anhydride H H 2-acytal pyrrole 3-acytal pyrrole 90% 10% O CHg‘-CO N CHj3— CO Org. Chem 3 Lec 2 N-Acylpyrroles can be obtained by the reaction of alkali metal salt of pyrroles with an acyl halide + RCOC| ————» Z/ N\> 1 M COR Vilsmeier reaction : The Vilsmeier reaction (reagents: POCI3, and N, N-dimethylformamide) gives 2- formylpyrrole Me, o (/ \> - \N—< + POCI4 4 \L\C//O N| me H N “u H H 2-formylpyrrole (1H-pyrrole-2-carbaldehvde) Friedel-Crafts Alkylation: Because of high reactivity of the pyrrole ring, Friedel-Crafts alkylation of pyrrole with alkyl halides and highly reactive allyl- and benzyl halides results in polyalkylation under milder conditions. Therefore, it is not possible to obtain monoalkylated product. 7\! + Y"H3 - 100°C E il o o D Reaction N I H CHj CHy /Zj(CHJ + Complex mixture (excess) HC” TN on, CH3 I poly-mthylated pyrroles Friedel-Crafts alkylation of pyrrole Grignard reagent produces 2- alkylpyrrole via 1-alkylpyrrole involving Hofmann-Martius rearrangement Q + CH 51 & Z/”\S s H Org. Chem 3 Diazo Coupling Pyrrole undergoes diazo coupling reactions very readily with benzenediazonium salts providing 2- aza- or 2,5-bis(aza)- pyrroles depending on the reaction conditions. The rate of the reaction is faster in an alkaline media as it involves pyrrolyl anion and results in the formation of 2,5-bis(aza)- pyrrole CgHs—N=N—CI (/ \5 N=N—CgHs (aqu. C,H5OH) N / ¥ H 4N CH,COONa N H CgHs—N=N—OH \L—V CGHS—N=N‘O—N=N705H5 (aqu. C;HsOH) N Iy H NaOH If both the X-positions are occupied, diazo coupling occurs at the B position N=N—CgHs HsC”™ RN — “N” 'CHj; Ha N H H RING OPENING REACTION OH fl NH,OH / EtOH < u Reflux OH OXIDATION REACTION @ [o] flo N CrOg / CH3COOH N REDUCTION REACTION Zn / CHyCOOH Org. Chem 3 RESEMBILANCE WITH PHENOL :- 1-RIEMER TIEMANN REACTION On reaction with CHCl3 and strong alkali Pyrrole is giving two type of reactions. The first one is the formylation at position 2 and other one is formation of 3-chloro OH o o OH CHC, CHO CHO r H CHCI; / KOH 7.\.. —_— —_— ?\CHCIQ CHO pyridine. In both the cases carbine is generated; second one is carbine insertion reaction. OH CHCly aq. NaOH 70°C benzal chloride salicylaldehyde (main product) ———® CHCl; / KOH J.\ ” “CHCl, ——————» BN“\“ CHO y H 2- KOLBE SCHMITT REACTION RESEMBLANCE WITH AMINES, HOFFMANN MARTIU REARRANGEMENT (). ™, Org. Chem 3 MECHANISM Reaction of pyrrole with aldehydes and ketones * Aldehydes and ketones condense with unsubstituted pyrrole at a- position in acidic medium to give dipyrryl methane. The condensation may continue to give tetramer (4 pyrrole rings connected by methine bridge). The tetramers are known as porphyrinogens, they are stable, planar structures that can accommodate a wide range of metal ions. o {/ \5 + /U\ HC1/ 100 C / u R RE N A R! and R? = H or CHj R Dipyrryl methane Org. Chem 3 REACTION WITH BUTYL LITHIUM On reaction of pyrrole with butyl lithium (strong base) 2-lithiopyrrole, organo metallic compound is formed.