Organic Chemistry Lecture Notes PDF

Org.Chem.3 Effect of electron-releasing substituents at C-2 *The effect of electron-releasing substituents at C-2 position is similar to that of ortho-para directing substituents in benzene and tend to direct incoming electrophile to C-5 position. 1) In the presence of weakly electron-releasing sub...

Org.Chem.3 Effect of electron-releasing substituents at C-2 *The effect of electron-releasing substituents at C-2 position is similar to that of ortho-para directing substituents in benzene and tend to direct incoming electrophile to C-5 position. 1) In the presence of weakly electron-releasing substituents(-CI, -CH3) at C-2 position tend to direct incoming electrophile to C-5 position. 2) But with strongly activating substituents (-OCH3, -NHCOCH3) the substitution may occur at C-3 due to the ortho-effect of electron- releasing substituents E B X R E Ly, ® - 5R X R NO2 BNs” “CHy —_—HNO; (CH3C010 o,NT [\ g7S ey S CH3 Effect of electron-withdrawing substituents at C-2 The effect of electron-withdrawing substituents is similar to the meta- directing effect in benzene. 1) The presence of electron-withdrawing substituent at C-2 causes substitution at C-4 due to directing influence of the substituent. 2) But the directing effect of substituent competes with the -directing effect of heteroatom which causes substitution to occur at C-5. The formation of 2,5-disubstituted furan is rationalized by the most powerful directing effect of oxygen in furan than that of sulfur and nitrogen in thiophene, and pyrrole respectively. Q\ C nitration 2 nitration —_— 2 nitration Q\ NO. 2 H Org.Chem.3 Effect of electron-releasing substituents at C-3 * The presence of electron-releasing substituents at C-3 will reinforce the -directing effect of ring heteroatom with the substitution at C-2 *|f the electron-releasing substituent is alkyl, the reactivity of -positions (C-2 and C-5) does not differ appreciably and in case of the sterically hindered alkyl group or incoming electrophile, the substitution atC-2 is restricted and occurs at C-5 CH3 3 wmo (i) HCN/HC1 O acetylation _ CHa—fi o o Effect of electron-withdrawing substituents at C-3 *The effect of electron-withdrawing substituent at C-3 is similar to the meta directing effect in benzene and is reinforced by the a-directing effect of ring heteroatom. Thus, the combined effect of both the effects; meta-directing effect of the substituent and directing effect of the heteroatom, causes substitution to occur at C-5 most favourably w W W w w X=NH,QorS W = electron-withdrawing group (~CHO) Furan and thiophene Reactivity Order in Five-Membered Heterocycles *The reactivity of five-membered heterocycles towards electrophiles depends (1) on the electron availability on the ring carbon atoms or (2) mesomerically electron release from the heteroatom and (3) the greater stabilization of transition state. 2|Page Org.Chem.3 * The order of reactivity in five-membered heterocycles is : pyrrole > furan > thiophene > benzene (for comparison). *The order of aromaticity is Benzene > thiophene> furan > pyrrole *The greater reactivity of pyrrole towards electrophiles is attributed to the greater electron releasing ability of trivalent nitrogen (when linked by three bonds) making ring carbon atoms electron rich and to the greater stabilization of transition states involving positive charge on the tetravalent nitrogen atom i) @ii) *Furan is also reactive (although less than pyrrole) towards electrophiles (preferably at C-2) 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 resulting from the electrophilic attack on furan is, therefore, less stable than that of pyrrole. Thus, furan is less reactive towards electrophiles than pyrrole as phenol is less reactive than aniline Org.Chem.3 Lec3 *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 (mesomeric electron release from sulfur) is smaller Dmtranon (i) acetyl nitrate (ii) pyridine than that of oxygen because of not effective overlapping of differently sized p-orbitals of carbon and sulfur than in carbon and oxygen. The relative reactivity of thiophene and furan can be shown by the following reaction in which nitration with mild nitrating agent occurs only in furan nucleus at C-2 Reactivity Comparison with Benzene The electrophilic substitution in thiophene is much easier than in benzene. Benzene is much less reactive than the five- membered heterocycles towards electrophiles. The reactivity depends on: (i) The stabilisation energy and (ii) The stability of transition state. The lower reactivity of benzene towards electrophiles is attributed partly to the greater resonance stabilisation energy of benzene. The higher energy of the transition state of benzene than the structurally related transition states of five-membered heterocycles is also responsible for the lower reactivity of benzene. The stability order of the transition states has been observed to be as follows NH> = '\5 H *Furan is not very aromatic therefore if there is a possibility of forming stable bonds such as C-O bonds by addition, this may be preferred to substitution i.e. tendency to give addition products rather than substitution products increses as aromaticity decreases. *The order of aromaticity is Org.Chem.3 Benzene > thiophene> furan > pyrrole In comparison to benzene the order of reactivity in electrophilic substitution is as follows: Pyrrole > Furan > Thiophene > Benzene *The 2 & 5 () positions are more reactive than 3 & 4 (f) Positions as in pyrrole the intermediate results from electrophilic attack at C2 can be stabillized by three resonance structure while the intermediate results from the attack C3 is only satbilized by two resonance structures. Thus the former is more preferred Synthesis of Furan and Thiophene PO " Il».SO4 l 4 Dicarbonyl compound 2) | | HLS / weak base /@\ R s R R R H. H,SOL/A @\ zno/400'¢ f\ [CHO - 3HO fe) CHO (o) Furfural Pentose EtO,C EtO,C __pyridine /\L \]\; 0 - HCL.- Hx /U 1- Addltlon Reactions a) Oxidation /\_/\/\ _Br,/ CH;OH HQH ) MeO O OMe cis / trans 2,5-Dihydro-2,5-dimethoxyfuran *This reaction involves electrophilic addition of bromine in presence of methanol at 2 & 5 positions which is followed by substitution by methanol. Org.Chem.3 *Thiophene is oxidized by peracids to thiophene-1-oxide and 2- hydroxythiophene oxide. Raney Ni / Hy (o) 2-Methvltetrahvdrofuran On the other hand thiophene can not be reduced under the same conditions due to sulphur poison the catalyst and desulphurisation occurs with ring opening. *However, partial reduction can take place by metals in acidic medium. !/ \E Raney Ni/ H, / \ + NiS S Zn / HCI1 s CH>CHg3 c) Diels- Alder Reaction: *Reaction of thiophene with maleic anhydride requires more drastic conditions than in case of furan and pyrrole (high pressure and temperature), this is because it is the most aromatic thus it is the least reactive as a diene. *The order of reactivity in D.A reaction is as follows: Furan > N-alkyl pyrrole > Pyrrole > Thiophene. Org.Chem.3 100 c + Q pressure o H3CO, 3 CO N “/ CN Znl, H3CO O = Catalyst | GN — QeHCI unsatble Heterocvelic 2-Electrophilic Aromatic substitution Reactions of furan 1) Nitration Furan is nitrated with mild nitrating agent, acetyl nitrate, at low temperature. The reaction proceeds by an addition-elimination mechanism involving an intermediate, 2,5-addition product. In certain cases, the intermediate 2,5- addition product , may be isolated, if a base (pyridine) is not used to eliminate acetic acid. (Mixture of nitric acid + acetic anhydrde) acetyl nitrate (CH4-C0),0 + HNO; —> CH;COONO," // \5 CHiCOONOy' oy@Noz g pyridine // \\. o 10°C H : ™ _ACcONO,, 07 @ (Acz0, HNO;) NO, AcO isolable pyridine, heat -AcOH o8d o O [\ Note:Electrophilic substitutions in 2,5-disubstituted heterocycles normally occur at the 3-position 7|Page Org.Chem.3 Lec3 *in some cases, specially with furan, electrophilic substitution occurs with the displacement ofX-substituent (carboxyl, acyl or halogen) HNO NO. /@ O! AC, /©< ’ — HC” X “cooH COOH | Hc” 0" “No, {OOR, -Cl, -Br 2) Sulfonation Furan and its simple alkyl - derivatives are decomposed by the usual strong acid reagents, but the pyridine — sulfur - trioxide complex or dioxane can be used, and provides 2-sulfonic or 2,5-disulfonic acid depending on the reaction conditions, disubstitution of furan occurring even at room temperature. 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. CI(CH,)-Cl, 1t fl 80%. HOS—\g~ ~SOsH H,SO, + SO, ——————— /@\ o 3) Halogenation *Furan reacts vigorously with chlorine and bromine at room temperature to give polyhalogenated products, but does not react at all with iodine. *The milder conditions are required for the formation of monobromo- and monochloro-furans. Bromination of furan by bromine in dimethylformamide at room temperature — smoothly produce 2 - bromo - or 2,5 - dibromo - furans. * dioxane-dibromide (Br2 + dioxane) at -5°C gives 2-bromofuran 8|Page Org.Chem.3 Mechanism: (] N\ 2z dioxan, 5'97@%5’ —HBr M\ 2 Br oe H H Q\B’ d 80% r Note: Bromination of furan substituted with an electron-withdrawing substituent at the position-2 generally provides 5-bromo derivative involving an electrophilic substitution mechanism. zjig - CICH,—CH,Cl 7\ 0~ “COOCH4 Br o COOCH 3 ST s W O COOCH 3 XK COOCH & \ COOCH 3 O e (¢) 0 - O D, (64 %) (29% (7%) Q\coocm oo qfl\ 4) Friedel-Crafts Acylation The acylation of furan with acid anhydrides in the presence of mild catalysts such as phosphoric acid or boron trifluoride etherate results in exclusively 2-acylfuran. The acylation of furans can be performed also with Ac,0-SnCls, although trifluoroacetic anhydride does not require any catalyst. Org.Chem.3 H;PO, or 4 \ + (CH,CO),0 - = BF3—-Et,0 O [/ \;+ (CH,CO0),0 —hECe Z ; O Ac30, SnCly, / \ H3PO, cat., 20 T (