Organic Chemistry 3, Lecture 4, Dr. Yusuf (PDF)

Org.Chem.3 Lec4 Six-Membered Aromatic Heterocyclics: Pyridine (Azine) Six membered heterocyclic compounds: This class of compounds may be considered to be derived from the replacement of a carbon atom...

Org.Chem.3 Lec4 Six-Membered Aromatic Heterocyclics: Pyridine (Azine) Six membered heterocyclic compounds: This class of compounds may be considered to be derived from the replacement of a carbon atom of benzene by an iso-electronic atom. Similar to the five membered heterocyclic compounds, the six membered heterocyclic compounds may also be subdivided in to following categories. a). Heterocyclic compounds with one hetero atom: Common examples of this class of compounds are pyridine, pyran, thiopyran etc (Figure). b). Heterocyclic compounds with more than one hetero atom: Common examples of this class of compounds are pyridazine, pyrimidine, MOLECULAR ORBITAL PICTURE OF PYRIDINE: Six membered heterocyclic compounds (with one heteroatom) are structural = TN 0 @ = [ - = pyridine 4H-pyran 4H-thiopyran pyrazine etc (Figure). \l \‘\J N"'\_/’ pyridazine pyrimidine pyrazinc analogous to that of benzene but with a heteroatom replacing one of the carbon atoms of the benzene ring. Pyridine is the most common example of this class of heterocyclic compounds. 1-Pyridine is a planar molecule like benzene, since all the carbon atoms and nitrogen atom of the pyridine are of sp2- hybridized. 2-The lone pair of electrons of nitrogen atom lies in the plane of the ring. 3-Pyridine is also an aromatic compound with (4n+2) it -electrons (Huckel rule of aromaticity). 4-The nitrogen’s lone pair of electrons is in an sp2 orbital orthogonal to the p orbitals of the ring, therefore it is not involved in maintaining aromaticity but it is available to react with protons thus pyridine is basic Page | 1 Org.Chem.3 Lec4 these e electronsPy are 2 in an sp“ orbital perpendicular to the p orbitals orbital structure of pyridine 5-Pyridine can be represented as a resonance hybrid, of thefollowmg structures. - k£ " \ >’ 2CH;=CH—CHO NH; —> OC"3 — @COOH Acrolein N Comic ) \/hfi;o‘lmic \a@cid VRE3 YQAra'a L~ C_> 3'M;-tphii|(3‘y:cdme - —— Page | 2 Org.Chem.3 Lec4 Properties of pyridine 1-The molecular weight determination method and related analytical studies revealed that the molecular formula of Pyridine as CSHSN. 2-Pyridine was found to be basic in nature since it forms salt with acids CsHsN + HCl ————— CsHsN.HCI Pyridine Pyridinium hydrochloride 3-Pyridine reacts with equimolar amount of methyl iodide to form a quaternary ammonium salt. CsHsN + CHsl ————— [CsHsN* (CH3)]I 4-The molecular formula also indicates that it is a highly unsaturated compound; 5-Pyridine is also found stable towards the oxidising agents. 6-Pyridine exhibits aromatic character like benzene and give electrophilic substitution reactions such as halogenation, nitration and sulphonation. 7- Pyridine is a colourless liquid. Its boiling point is 115.5° C. It has a characteristic unpleasant odour. It is soluble in water and most organic solvents. METHODS OF PREPARATION AND CHEMICAL REACTIONS Following are the general methods of preparation of pyridine: i-From acroline: Pyridine can be prepared by the reaction of acroline and ammonia according tofollowing reaction steps. (Ill) COOH o. nuA kunH l” Acrylaldehyde “xfll\l;'\mhm \u ptinic acid l'\vhhm ii. Hantzsch Synthesis : In this method, the condensation of a beta- dicarbonyl compound, ammonia and an aldehyde lead the formation of 1,4-dihydropyridine derivative. The 1,4-dihydro pyridine derivative on oxidation with HNO3 yields the formation of pyridine derivative. fper, Page | 3 Org.Chem.3 Lec4 iii. From pyrrole: Pyrrole when heated with methylene chloride in presence of sodium ethoxide, pyridine is formed. Z/ \5 + CH,Cl; + 2C,HsONa a | 8 + 2NaCl + 2C;HsOH N = H Pyrrole Pyridine iv. From Picoline: Beta-picoline on oxidation with potassium dichromate and sulphuric acid gives nicotinic acid, which on decarboxylation with calcium oxide gives pyridine. ~ CH,y ~ COOH [ — o1 cao/a CaO/D N = " KaCraOo/H - = SC0; 2 3-Mecthylpyridine : ¢ Pyridine (Picoline) v. Industrial Method: Industrially pyridine is prepared by heating the acetylene, ammonia and formaldehyde dimethylacetal in the presence of alumina at 500° C. CH. Alumina. Il + ~oy + cH©OCH)), R T0C | CH S i = Acetylene Pyridine vi. From 1,5-dicarbonyl compounds: | & | [.T === 1 - 1L === I. I g 4(\/‘\\ NH, OACc o 5 =6 AN vii. Bonnemann cyclization: cH CHH + no=n + I red hot tube CH CH viii. By Diels Alder reaction c —CN 300°C. CN.H, CN «f =) — L) = H, = | ~ \ N 1.3-butadiene n\ (‘me'\é\ Page | 4 Org.Chem.3 Lec4 Reactions of pyridine The chemical properties of pyridine are those as would be expect on th is of its electronic structure. The ring ndergoes the substitution, both electrophilic and nucleophilic, typical of aromatic rings; the interest will lie chiefly in the way the ni eact There is another set of reactions in which pyridine acts as a base or nucleophile; A \ oo o™ - a-Basic character of pyridine: Pyridine is basic in nature. Its pKp is 8.75. It reacts with strong acids to form salts. == = (j - HCL | N @~ N (= g H Pyridine Pyridinium Chloride The basic nature of pyridine is due to the 1-freely available lone pair of electrons in sp? hybridized orbital pyridine, which does not participate in the formation of delocalized 1t - molecular orbital. 2- Pyridine is less basic in comparison to aliphatic amines whereas, it is more basic than aniline and pyrrole. This is because the lone pair of electrons in aliphatic amines exists in sp® hybridized orbital.Electrons are held more tightly by the nucleus in a sp? hybridized orbital than an sp? hybridized orbital.The less basicity of pyrrole and aniline can be explained by these lone pair of electrons is involved in the formation of delocalized it -molecular orbital. It undergoes many reactions typical of amines such as reaction with Bronsted acids such as chromic acid and hydrobromic acid. | N I ~ Br, I = = + HBr - ||l o “o e |l @ ) N '?l Br f?l Bry H H b- Reduction: Under catalytic hydrogenation of pyridine hexahydropyridine is formed. It is also known as Piperidine. ~ Ni or Pt | + 3Hz ————————— = * or Na/C,HsOH N Ill Pyridine Piperidine these reactions involve nitrogen directly and are due to its unshared pair of electrons. Piperidine (Kb = 2 x 10%) has the usual basicity of a secondary aliphatic amine Page | 5  Org.Chem.3 Lec4 @n\ f\'\r \ ] A 5 > H 1.2-Dihydropyridine plpcrldlne ‘: 4-,‘"_’4, CHLCH,CH,CH,CHy NH, \Ab ANVo 74 l..s-l)ih:dm,-yrmlne c. Electrophilic substitution Reactions: Pyridine is also an aromatic compound. It is less aromatic than benzene and pyrrole. Pyridine usually considered a highly deactivated aromatic nucleus towards electrophilic substitution reactions. The low reactivity of pyridine towards the electrophilic substitution reactions is due to the following reasons: | = The higher electro negativity of nitrogen atom reduces electron it readily forms pyridinium cation with a. Similarly, @ electrophile itself may also react with pyridine to form corresponding pyridinium ion. This positive charge on nitrogen atom decreases electron density on nitrogen atom, consequently, thmty on Toward electrophilic substltutlon pyridine resembles a highly deactivated benzene derivative. It undergoes nitration, sulfonation, and halogenation only under KO 150, s00° ONO: very vigorous conditions N but does undergo not the 3-Nitropyridine Friedel-Crafts reaction at o _ 4 | msem. (som 3-Pyridinesulfonic acid _gccurs chiefly at the 3 (or B-) 5’3\3'. N S o 3 — A and < position: ) 3-Bromo- and 3.5-Dibromopyridine LRX RCOX, or AICH _.6 reaction Page | 6 Org.Chem.3 _ Lec4 oo DT e~ N stk S0 3 Accounting n on the usual basis of stability”. Attacking at the 4-position yields a carbonium ion that is a hybri of structures |, Il, and Il H_Y H_ Y H Y y H H Electrophilic | C] ® | | | attack at > X 4-position I 11 11 Especially unstable: nitrogen has sextet Whereas attacking at the 3-position yields an ion that is a hybrid of structures IV, V, and VI: 11 9 i Y. 7 3 Y 7 Vi ,\Y lectrophilic Electrophilic attack at N/ H:"‘ N/ \N Y H 3-position v Vv VI Attack at the 2-position resembles attack at the 4- position just as ortho attack resembles para attack in the benzene series All these structures are less stable than the corresponding ones for attack on benzene, because of electron withdrawal by the nitrogen atom. As a result, pyridine undergoes substitution more slowly than benzene. Of these structures, Il is especially unstable, since in it the electronegative nitrogen atom has only a sextet of electrons. As a result, attack at the 4- position (or 2-position) is especially slow, and substitution occurs predominantly at the 3-position In the case of pyridine, a structure in which nitrogen bears a positive charge (1) is especially unstable since nitrogen has only a sextet of electrons; nitrogen shares electrons readily, but as an electronegative atom it resists the removal of electrons Page | 7 Org.Chem.3 Lec4 It is important to see the difference between substitution in pyridine and substitution in pyrrole. In the case of pyrrole, a structure in which nitrogen bears a positive charge is especially stable since every atom has an octet of electrons; nitrogen accommodates the positive charge simply by sharing four pairs of electrons: H H v v attack mlLass at position st 3 7 N/ 4 N D _H HY H ' " Q> N > H @, H attack atposmion2 [/ \ :H 4. S < “@H N 0 3] N Y w More stable ion Nucleophilic substitution in pyridine 7 S5 =y )-SD Here, as in electrophilic substitution, the pyridine ring resembles a N benzene ring that contains strongly electron-withdrawing groups. "“S? Nucleophilic substitution takes place readily, particularly at the 2- and 4- positions. For example: O _180-200°C NH, Q Br NH> N Z-Bronu)p_\ndlng 2-Aminopyridine Cl NH»> @ - NHs,, T180—200 T °C 5 @ N N 4-Chloropyridine 4-Aminopyridine The reactivity of pyridine toward nucleophilic substitution is so great that even the powerfully basic hydride ion, :H-, can be displaced. Two important examples of this reaction are amination by sodium amide (Chichibabin reaction), and alkylation or arylation by organolithium compounds. (‘ IR >==¢/\ (Chollte = o ‘1441"\/“1 :w‘( — Page | 8 n(vul(@\,\l\_: > 2 Org.Chem.3 Lec4 @ + NatNH, et | [0 LN @ + Na® NH,™ + H:H N X NH, NN Sodium NH, N - 2-Aminopyridine NH Na" + NH N Sodium salt of 2-aminopyridine N Pyridine Phenyllithium Li 2-Phenylpyridine As we have seen, nucleophilic aromatic substitution can take place by a mechanism that is quite analogous to the mechanism for electrophilic substitution. Reaction proceeds by two steps; the rate of the first step, formation of a charged particle, determines the rate of the overall reaction. In electrophilic substitution, the intermediate is positively charged; in hucleophilic substitution, the intermediate is negatively charged. The ability of the ring to accommodate the charge determines the stability of the intermediate and of the transition state leading to it, and hence determines the rate of the reaction. Nucleophilic attack at the 4-position yields a carbanion that is a hybrid of structures |, Il, and Il S i H “ Nj%l > Especially stable: negative charge on nitrogen Attack at the 3position yields a carbanion that is ahybrid of structures IV, V, and VI: H o H H H z = z = 7 Nucleophilic | = S -..o attack at N H” "N N4 3-position v v VI Page | 9 Org.Chem.3 Lec4 (As before, attack at the 2-position resembles attack at the 4-position.) All these structures are more stable than the corresponding ones for attack on a benzene derivative, because of electron withdrawal by the nitrogen atom. Structure Il is especially stable, since the negative charge is located on the atom that can best accommodate it, the electronegative nitrogen atom. It is reasonable, therefore, that nucleophilic substitution occurs more rapidly on the pyridine ring than on the ben- zene ring, and more rapidly at the 2- and 4-positions than at the 3-position. The same electronegativity of nitrogen that makes pyridine unreactive toward electrophilic substitution makes pyridine highly reactive toward nucleophilic substitution. -Reaction with potassium hydroxide OKOH /320 @ __ keto-enol @ tautomerism (o} N” N wO=—H N H 2-Hydroxy pyridine Ty 2-Pyridone Reaction with organometallic compounds lithium reagents Butyllithium v ~c 2:-Butvlpvridine i- Reaction withSodium amide: NH‘ NaNH, / S l + NaOH TA mo H,O - R* N NH, Pyridine as a nucleophile : (reactions on N atom) As a tertiary amine pyridine has nucleophilic properties thus it reacts with electrophiles: Page | 10 Org.Chem.3 Lec4 [ N/ ( - ~ ne H Ci | ~ Pyridinium chloride ) CHyCOOOH T CHyl =g t I rt l 8 N N. Pyridine-N-oxide CHy 'l N-methyl pyridinium iodide Notes about basisty of pyridine:- Benzene is a stronger acid than an alkane, as shown by its ability to displace an alkane from its salts; this, of course, means that the phenyl anion, Cs Hs™ is a weaker base than an alkyl anion, R-. R:"Na® + CH;:H — R:H + CH,:" NA Stronger Stronger Weaker Weaker base acid acid base In the same way, acetylene is a stronger acid than benzene, and the acetylide ion is a weaker base than the phenyl anion. CgHs: Na* + HC=C:H — C¢Hs:H + HC=C: NA' Stronger Stronger Weaker Weaker base acid acid base Thus we have the following sequences of acidity of hydrocarbons and basicity of their anions: Acidity HC=C:H > C¢Hs:H > R:H Basicity HC=C:"