CuapteR 7 Organic Reactions and Syntheg, of a Drug Molecy, Learning Objectives After studying this chapter, the students will be able to: + Visualize the basics of organic reaction mechanisms. + Identify different type of reactions. + Define and understand Syl. & Sy2, El & E2 reactions. + Build the concept of addition, oxidation and reduction reactions. + Understand the mechanism of ring opening and cyclization reactions. + Visualize the methods of synthesis of commonly used drugs. Chemistry is the basis of all living beings. ‘The chemical compounds that build a living being can be categorized into organic and inorganic. Compounds containing carbon are known as organic compounds and compounds without carbon are known as inorganic compounds. The organic compounds that are present in a living body or in living matter are known i biological molecules. These biological molecules are of four types, namely, carbohydrates, proteins, lipids and nucleic acids. All activities performed by an individual result from the biochemical reactions taking place in the body. These biochemical reactions are influenced by several electronic factors which include inductive effect, electromeric effect, resonant? effects, and hyperconjugation. A majority of the biomolecules are made of the six major elements, namely, carbon, hydrogen, nitrogen, oxygen, Phosphorus, and sulphur, All organi¢ compounds have diverse physical characteristics and chemical reactivity which enables them to participate in different types of organic reactions and generate suitable products. The effects that influence the structure, Teactivity, or Properties of = ule are called electronic effects. They are neither telated to traditional bond . renee : ‘These effects influence the stability of molecules, ce EOC Scanned with CamScanner7 sae Organic Reactions and Synthesis of a Drug Molecule | 293 14 Inductive Effect pisdefined a the effet that governs the orientation ofthe chemical bond adjacent 0 the a det cons ein, It is denoted by I. In general, the electron clouds of the atoms 1 in a bond tend to place themselves in such a position where they are close to the A eeetonegative stom involved inthe bond (a Types of Inductive Etect « -Teffect fan electronegative atom is bonded to an atom which is less electronegative in comparison, fe former relays the electron cloud towards itself. This results due to the acceptance OF witrawal of electrons and is said to be ~1 effect. Examples of groups or atoms showing Teffect are: NH,", -COOH, -COOR, -NO2, ~CN, ~CHO, ~COR, -F, ~Cl, ~Br, -l, “CF, “OH, -OR, -NHL, ~SH, ete. « Heffect Groups like alkyl group, are less electronegative and are less electron-withdrawing than hydrogen and are hence called electron-releasing, This electron-releasing nature is termed ts elecron-releasing inductive effect or + I - effect. Some groups or atoms showing +1 effect are: -CH3, -CHRp, ~CH)R, -CR;, -COO-, etc. Inductive effect is a permanent effect but is significant only over a short distance and decreases with increasing distance. (b) Relative Inductive Effect Ifthe inductive effect of different groups are to be compared then a series is formed in tems of decrease in -I effect and increase in +I effect. This phenomenon is called relative inductive effect. Generally, hydrogen serves as the standard with respect to which the others are oriented, It is shown by different groups or atoms as follows: -NH, > -NO, > -SO,R > -CN >'-SO,H > -CHO > ~CO > -COOH > ~COC! > “CONH, > -F > -C] > -Br > -I > -OR > -OH > -NH, > ~CeHls > ~CH-CHy 712 Resonance Effect Resonance is defined as the process of expressing the delocalized n-electrons present in a Aoleeule or polyatomic ion. This is applicable for structures in which the bonding cannot be represented by a single Lewis structure. A molecule or ions that contain delocalized dlstrons ig generally represented by several contributing structures. Resonance is also termed as mesomerism, Each of the contributing or canonical structures can be represented ty a Lewis structure. Multiple Lewis structures represent the actual molecular structure of i Species, which is considered to be an approximate intermediate between the involved ‘anonical structures and is known as resonance hybrid. Resonance increases the stability 4 compound, The extra stability thus gained due to delocalization of electrons is called ‘sonance energy. It is calculated from the difference between energies of the actual Molecule and the most stable canonical form. Scanned with CamScanner294 | Engineering Chemistry - I: Concepts and Applications ‘Types of Resonance Effect © +R effect Groups or atoms that donates electrons through resonance exhibit +R effect. The roupy that donates electron and shows +R effect are called +R groups. Example: 1. Resonance in phenol 8b 6-6 2. Resonance in aniline (3 NH, WH, x 3, Resonance in chlorobenzene Other groups showing +R-effect are -OR, -NR;, -NHR, -SH, etc. © -R-effect | Groups or atoms that withdraws electrons through resonance exhibit -R-effect. The grours | that withdraws electron and shows -R-effect are called -R-groups. For example, 1, Resonance in benzaldehyde Scanned with CamScannerOrganic Reactions and Synthesis of a Drug Molecule | 295 .¢ in nitrobenzene 0 3 wr A’ N ~ Pa ~ Pa N N g + — _ rs ¥ Resonance in allyl carbonium ion and benzyl cation | seo cs. cusch-tu, ——~ tu,-cu=cu, Allyl carbonium ion cu, cH, §—6-8-8-4 Other groups showing R-effect are -COOR, ~COOH, -COR, -CHO, -NO3, -CN, SOR, etc. 11.3 Hyperconjugation fan empty, half-filled or partly-filled ¢,,—Hy, to-bonding p-orbital is present adjacent ‘oond ‘0a C-H or C-C o-bond, an interaction ‘ecurs between the bond and the empty Gbital. Due to this interaction, an ex 7 / Subility is provided due to an extended i TE empty 20 obit Molecular orbital. This phenomenon 1S i ‘alled hyperconjugation. ns of a bond participate i istoostene Hence, the In hyperconjugation, the ee ijugation do not exist ahi i eae sul whose electrons undies a bo id resonance’. For examples in ijugation is, also term: Hyperconjugation tthyl radical as shown. H HH ee Ef bb ey 1 He C= a HH H-¢-@ 7 Jol aH ™, | i HH am a o Scanned with CamScanner206 | Engineering Chemistry — 1: Concepts and Applications Hyperconjugation can be divided into two types: * Sacrificial: In this type of hyperconjugation, the number of covalent bonds in the canon, structures is usually less than that of the actual structure. * Jsovalent: In this type of hyperconjugation, the number of covalent bonds in the Cncay Structures is same as that of the actual structure. 7.1.4 Electromeric Effect The complete transfer of shared pairs of x electrons of a double bond or multiple to one of the bonded atoms under the influence of the attacking reagent is known electromeric effect. Since the effect involves complete transference of electrons, it leads to the developm of full positive charge (+) and negative charges (-) within the molecule, Electromeri effect is a temporary effect and operates in presence of attacking reagent and vanj &s soon as the attacking reagent is withdrawn, If a proton (H”) adds to C=C bond, the bond will break and the electron pair will be transferred completely to one of the C a The electromeric effect has no specific direction. Its direction is always that which favours the reaction. (eacking The effect takes place in the direction of the more Nc Lb + pte, ‘E04 electronegative element. It can be represented by the 7 ~~ 7 IN symbol E and is of two types: (i) +E effect (ii) —E q effect. ° +£-effect: When the displacement of an electron pair is away from the atom or group, it is called +E effect. ° —Eeffect: When the displacement of an electron pair is towards the atom or group, its called +E effect. " (atacking These are the factors that determines the nature Nc. LY Ay ee of the organic molecules, their stability and there /“—° reactivity. \ne a” AN CN 7.1.5 Carbocations, Carbanions and Free Radicals A carbocation is an ion containing the carbon atom with a Positive charge along with three bonds such that it posseses six pairs of electrons. Carbocations can be of three types: 1. Primary carbocation: A primary or 1° carbocation is one in which the carbon bearing the Positive charge is attached to only one alkyl group. Example: Ethyl cation (CH,CH;) 2. Secondary carbocation; A secondary or 2° carbocation is the one in which two alli! substituents are attached to the carbon containing the positive charge. Example: Iso-propy! cation (CHCHCH) 3. Tertiary earbocation: A tertiary or 3° carbocation is the one in which the carbon beaité the Positive charge is attached to three alkyl groups, Example: tertiary butyl cation (CiyfcH,) CH, Scanned with CamScannerOrganic Reactions and Synthesis of a Drug Molecule | 297 geability of Carbocations eb of carbocations follows the order- ; R Re > Ret - Rook j y)) Atertiary Asecondary ecoetoa'” | “Srtochy! "Abeer Ions in which the carbon bears a negative charge are called carbanions. Carbanions are rncleophiles in nature and their stability is governed by multiple factors, such as: | 4, Inductive effect: Presence of an electronegative atom or group adjacent to the carbanion | stabilizes it. 1. Hybridization of the carbon carrying the negative charge. 3, The extent of conjugation exhibited by the carbanion. ifan atom or molecule contains an unpaired valence electron, it is said to be a free radical. | | | These unpaired electrons are highly energetic and hence are extremely reactive. They can fimerise or can undergo chemical reaction. Free radicals generally have a very short life span, A free radical with a single unpaired electron is the hydroxyl radical (HO). Similarly, fee radicals with two unpaired electrons are triplet oxygen and triplet carbene (:CH,) 11.6 Neucleophile and Electrophile ucleus loving molecules. In other words, neucleophiles can donate Neucleophile means m ‘a ; aya arenes st attracted towards positive centers By donating electrons they form aan lent bonds. They are none owe! than Lewis bases. olecules. In other words, electrophiles can accept a E loving ™ Electrophile means cle owards negative centres. They are also called Lewis acids. pair of electrons is attracts HBR tor’s think in molecules? 1. Why does resonance cece ryperconlugation and Isovalent hyperconjugation. 2. Differentiate berwoer Dp ‘single unpaired electron. deol weenie 3. Name a free radicg 4. Electrophiles oct OF cr iGRNRNTRE IS COTE reactions for carbon-carbon. and carbon-heteroatom = class of 7 ful c1888 ©. is also widely used for synthetic transformations hates). Depending on the nature of the nucleophiles and 7 5 a These reactions ™ Fons, The a bond formation reactions as tosy! (eg, leaving ups § Scanned with CamScanner a eae.d Applications 298 | Engineering Chemistry I: Concepts an different mechanisms are possible. These reactions typically occur on reaction conditions, shed to a leaving group: a saturated carbon atom, attacl 7.2.1 Electrophilic Substitution Reactions or atom (generally hydrogen) in a When an electrophile replaces a functional erouP m ally n compound, then the pe of substitution is called electrophilic substitution. Electrophilic ‘substitution is basically of two types, namely, electrophilic aliphatic substitution and electrophilic aromatic substitution, The latter is ‘used to introduce different functional groups in the benzene ring. (a) Aliphatic Substitution Reactions Ifa fumetional group or an atom is replaced by an electrophile in an aliphatic compound then the process is termed as aliphatic substitution. idic medium or in basic medium. Example: Halogenation of ketones can be done either in aci 0 xcept fluorides) can be attached effectively at Orposition In this reaction, the halogens (e of ketones. In acidic medium- ° ae Br 5 ae ° =— Nhe ae ahs Ae Jae + HH H HH In basic medium- % 9 £% Gg 9 Clas af So, \ Ag at A a+ nae ‘ i ne H H (b) Aromatic Substitution Reactions If a functional group or an atom is replaced by an ele: ‘1 0 ctr i i then the process is termed as aromatic substitution SERIE inn aromatic compone aromatic substitutions are discussed below, most important types of © Nitration In this reaction first NO} is formed whi ate H atom, 2 which gets attached to the benzene moiety by replacing Scanned with CamScannerOrganic Reactions and Synthesis ofa Drug Molecule | 299 A H 1 HONE, + Aso, = DLN, + nso: se HW 2 % Ea + Ho, e sa? yd? HSO, = NO! + Ho's uso; — i Hl + ‘NO, NO, NO, 3 oO + NO; — ey — — = # 1, H Ca, CO um + Halogenation inthis reaction X* is formed which gets attached to the benzene moiety by replacing one Hiom, Here, bromination is considered as an example. Step 1 Brot’ + PeBr, —> Br + FeBry H He AL Br ~ ef - a i \ Br Ce es — OT om ¢_FeBr, ), cr i to the benzene moiety by replacing * Sulphonation ic attachs In this reaction, first SO; is formed which BS ove H atom. ot + 80, | Sep 1 2H,S0, <== 805+ HF y H x ite SO; % es $0} —Gt be Crs i. I | Step2 O N V a Scanned with CamScanner300 | Engineering Chemistry ~ 1: Concepts and Applications Step 3 ok SO, aim =O! we 0, SO;H set CT bo = Os v0 © Friedel-Crafis alkylation In this reaction first R’ is formed which gets attached to the benzene moiety by replacing ‘one H atom. Here; propyl cation is considered as an example. Step 1 \-a + Alc, == ‘ex + AICI, iwi H H pa 2H | Hy Oo : at — Foe er Cree \ a a H H H | I Step 3 how \. C(CH,), AlCl, — Cr + AIC + HCI © Friedel-Crafts acylation In this reaction R-C=O is formed which gets attached to the benzene moie by lacing one H atom. — Q Step 1 ya + ald, == fs 0 Step 3 ep ee COR : J, 4 + AIC + HCI Scanned with CamScannerOrganic Reactions and Synthesis Of a Drug Molecule | 301 | No jucleophilic Substitution Reactions , a cleophilic Substitution Unimolecular (S,') Reaction to Unimolecular Nucleophilic Substituti ion. Here onl: Teactant i, controls the rate ofthe reaction. Highly substituted reactants rtidega rn be the in substitution at carbon favors Sy' pathway. The Sy! reactions mi fin ‘The rate constant is dependent on how fast the leaving group can de nis nt of the incoming nucleophile, part. I in actors Affecting Sy' Reactions * pe nature of the substrate, 1 Therate of leaving group departure. }. The nature of the solvent. « Mechanism of ‘Sy! Reactions . | Thefirst step of the reaction involves the formation of a carbocation. This is a slow process due to higher activation energy for bond breaking. Carbocation can be stabilized by the substituents through two important effects (i) hyperconjugation if the carbon is highly substituted or (ji) by resonance. 2, The second step proceeds fast as it involves combination of two ionic substrate and the iM incoming nucleophile. HAC CH, HC He) Slow de oH, ic OH Rate deeming yy o~ “oy, Fat HC step i Hy HC h this example, heterolytic bond cleavage of C-Br bond leads to a tertiary carbocation, hich is subsequently attacked by the nucleophile (hydroxide here). The speed of the action is decided by how fast the carbocation can be generated. The energy profile diagram for Sy' reaction is as follows: Rate limiting ! transit state, j —_ Intermediate eA | RX Reaction coordinats ©) ‘Nucteophitie Substitution Bimoteculsr Gy’) Reaction s to Bimolecular Nucleophi This mechani sm is a concerted lic Substitution. ts in which the bond forming and bond breaking o°cur si Scanned with CamScanner302 | Engineering chemistry - 1: Concepts and Applications to break the bond is comy ied bond formation. The rate of the reaction is foung vary linearly with non me thpe Bch respect to electrophile as well as nucleophile, 1p eucleophile is present in a large excess, the kinetics tends to follow first order even x the mechanism is bimolecular, Nucleophile affects the rate even being in large excess concentration does not vary significantly and rate is found to be determined alone by electrophile. Such a situation is known as “Pseudo first order reaction”. Factors affecting S,} reactions ‘The nature of the substrate. The nature of the nucleophile. . The rate of leaving group departure. .. The nature of the solvent. Mechanism of Sy’ reactions 1. During S,? reaction, neucleophile first approaches the anti-bonding molecular containing the leaving group. 2. The attractive interaction between the donor orbital (filled electrons) and the acceptor (unfilled) results in a new bonding between incoming group and the carbon atom. 3. Simultaneously, the leaving group begins to move away from the carbon centre. Subst may be possible either via front side or backside attack of nucleophile. 4, In Sy? substitution, backside attack is preferred in which approach of the nucleophile i 180° away from the leaving group. being Bond being broken ae NE ie Penre Steg OG HH Thain sate The energy profile diagram for Sy° reaction is as follows: Energy ——> Scanned with CamScannerOrganic Reactions and Synthesis of a Drug Molecule | 303 nucleophilic Substitution Internal (S,') Reaction @ ineral substitution reactions or Sy! reactions 1 eal) found to occur in aliphatic compounds, A Fmation of chlorinated alcohols using SCI, is of the most common examples of S,/ reactions. ater notable example is the decomposition of alkyl cproroformates. ‘These reactions occur with retention i ‘configuaration. There are basically two steps in Ghlorination of alcohols using thionyl chloride. In pe fist step, reaction between SOCI, and the alcohol uss, resulting in alkyl chlorosulfite. The latter is mpinimate ion pair. In the second step, the SO, is tininated followed by its substitution by the chloride gigcent to the sulphite group. Unlike Sy', no real tabocations are produced in Syi reactions, : It is evident that on addition of pyridine; the reaction moves towards inversion since te reaction between pyridine and sulphite’ (intermediate) replaces the chlorine. A e\F we NG of HO: -H OH HOH He Ht 0 Atuek of OF upon SOCI, Epeiedcoronltte 1 t \ es , e/a: f oe 9 1H on oA mA 8 ; se utack carbocation on Departure of leaving group Loss 9fS0,_ Calorie otimimae” on pir 10 form intimate on pir* ; «ss a basic chemical reaction resulting in the h ic i .ddition’ reaction is @ na tematon ened guetta ‘combination of two oF is nea Compounds containing eed those having carbon-hetero dout i wt ke alkenes, alkynes © ition reactions. Addition son double bonds Hk aime (C=N) grou can under sat dtyrton are addition - ee groups, bs! process for example, hydration elimination are reve! mike 224 elimination reactions respectively: Scanned with CamScanner304 | Engineering Chemistry - 1: Concepts and Applications 7.3.1 Addition of Hydrogen Halides In this reaction, an unsaturated hydrocarbon reacts with the hydrogen halides like HR, yy, H-Br and H-I to form alky! halides. Addition of HBr and HI occurs faster compared to H Fluorine can be added using HF but it is hazardous and hence should be avoided, fy > | | rad + x-Y —— —C-—C-— Pa + XY ; (x * formed: (a) Markovnikov’s Rule When any unsymmetrical alkene is treated with polar reagent capable of producing cat and anion, the electronegative part of the addendum will be attached with double bor carbon atom having least number of hydrogen (i.e., more substituted carbon atom) electropositive part will attach with the less substituted carbon atom. x x CH,CH = CH, + HX — CH; - CH - CH, + CH,CH, - CH, (Major product) (Minor product) I AA “ Se Not formed © Mechanism Scanned with CamScanneroy k Organic Reactions and Synthesis of a Drug Molecule | 305 H H AG Kee HP ‘inane ii — ar, nti-Markovnikov’s Rule or Peroxide Effect oA : an eee oe is treated with HBr in presence of oxygen, hydrogen ie Forza Lepace a like benzoyl peroxide, C,HyCO-O-O-COC;H,, the negetive jt (7 of HBr gets attached to that carbon which has more number of hydrogens. H Ka HBr ws , 1% Benzoyl HN, peroxide ‘ 5 i « Mechanism , 1 Te addition of HBr to an alkene in presence of peroxide is free radical mechanism. In this free radical mechanism, the two important steps are depicted hereunder. () CH,CH = CH, + X° ——> CH,CH - CH, X (i) CH,CH - CH, X + HX —— CH,CH, - CH, X+X° ‘The addition reaction will go to the completion if both of the above steps are exothermic (energy releasing). 1 HF =45 keal mor (exothermic) Gl 96 kcal mot (exothermic) +21 kal mot (endothermic) HBr 21 keal mor" (exothermic) =11 kcal mot (exothermic) a [7 keal mor (endatheric) =27 kcal mot” (exothermic) i cothermic; is evi bole that asly in case of HBr both the steps are ex Fi tts ae : om ako Rule while the other halo acids doesnot. 132 Addition of Water (Hydration) acidic medium, form hydroxy! alkanes, The reaction on reaction with water in Blt iti q are accordance with Markovnikov's addition nile. = iy] CH; slow, ce IN cao tao BT He“ YU " CH, cH, Scanned with CamScanner306 | Engineering Chemistry ~ I: Concepts and Applications Bo Ly Be eS = HC Su Hy CH, H Lega diy it Fea Bl at neta ie 04 CH, La CH, 7.3.3 Addition of Dihalides H cada Dihalides undergo addition to alkenes forms dihalo 1 alkane. This are vicinal dihalides and are formed = +¢l,—> H—C—C. effectively in presence of CH;Cl, or CCl,as / \ it ane H 4H HH 7.34 Oxymercuration and Demercuration Reactions Oxymercuration: Here, an alkene id transformed to an organomercurial alcohol. The react generally occurs in aqueous medium. OAc AC A‘ Hy ee sy ‘y abe pe Np Demercuration: Here, the an organomercurial alcohol is converted to alcohol. Mercurinium fon Reductive elimination Ae one NaBH, pe ad rou HO HO HO Hg(o) Mercuric hydride Markovnikov product 73.5 Catalytic Hydrogenation The addition of hydrogen to unsaturated system occurs in the presence of metals as catalyst Almost all the alkenes can be saturated in very high yield by treatment with hydrogel and a metal catalyst. The hydrogenation of alkenes is an exothermic reaction. Most! hydrogenation reactions are having high free energies of activation. Scanned with CamScanneroo Organic Reactions ‘and Synthesis of a Drug Molecule |207 CH: taht aE CH;-CH,-CH, ysts in catalytic hydrogenation reaction include Hy phi “ Catalysts used ing: Fe sium 2. Adams’ catalyst (PtO,+ oo " aa arene 'H,0) 3. Raney nickel 4. Copper chromite “. tet’s Think does the nature of the substrat stow te affect S,,! reaction? dees the nature of the substrate affect $2 rooted f vot happens when 3-methylbut-I-ene reacts with HBr in pretence of HOz4 y 5 FON REACTIONS = Shereactions in which two substituents are removed simultaneously in either a one- or two- sepmechanism are generally called elimination reactions. If the process occurs in two sieps, jiscalled E1 elimination whereas if it occurs in two steps it is called E2 elimination. 11 E1 Eliminations tis a two-step reaction. First step is si abocation intermediate. Subsequently, nthe carbocation. As in Sy' only one 0 stp, i., unimolecular reaction. imilar to that of Sy! reaction, i.e., the generation of hydrogen is abstracted by the base rather than ack the substrates is involved in the rate determining HON H H Br it Her _ =C. wont Py, name ne Pf wh he H CH +H,0+Na +BF CH, ent of 1d subsequent ™ the B hydrogen 2” ion is a sIOWET Attack of base or solvent molecule on i Formation as oe see bit develops @ ee ‘on between ‘eactve sae col to the ining SEP’ Cie () Conditions for EL Mecbanis™ ign conte 08 * Scanned with CamScanner308 | Engineering Chemistry — I: Concepts and Applications © Use of polar solvents (which can stabilize the resulting carbocation in addition to stabi, 4 polar transition state involved in the heterolytic bond cleavage. The energy profile diagram for E1 reaction is as follows: Reaction coordinate 7.4.2 E2 Eliminations This reaction involves one step (in other words, no intermediates are involved). It is bimolecular reaction, i.e., both substrate and nucleophile participate in a single step. base abstracts the B hydrogen Br and leaving group simultaneously a BONEOH, UX + FOH + BE + Nat leaves such that it forms a Propene 4 multiple bond between, a and B carbon atoms. In the example given above, sodium ethoxide acts as the base, abstracting B-hydrogen, Bromine is the leaving group. q HO: A He-e—en, HC, CH, ‘CH, 1p (a) The Sequences of Events Involved are: 1 (The attack of ethoxide on B hydrogen and its abstraction as a Proton is the first event. (ii)As the new double bond is created, the C-Br bond begi i rare to eee CBr on begin break away (leaving group) Scanned with CamScannerOrganic Reactions and Synthesis of a Drug Molecule | 309 profile di re enesy profile diagram for E2 reaction is ag follows: Transition state Reaction coordinate 143 Elcb Eliminations his reaction also occurs with removal of groups or atoms from the reacting molecule like £] and E2 but differs in the fact that here, instead of carbocation, a carbanion intermediate js formed. Only one molecule is involved in the rate determining step. ElcB means Unimolecular Elimination that occurs via conjugate base. This reaction is generally utilized when a poor leaving group, such as an alcohol, is involved. This poor leaving group makes the direct El or E2 reactions difficult. 181 Oxidation Reactions Inorganic chemistry, the gain of oxygen © There are several reagents by which oxi PCC (pyridinium chlorochromate) is one $ of primary and secondary alcohols. : 9 i "pec, DCM, pe a ol a 0 PCC, dry CHC!» fF snp AcOH en or loss of hydrogen is often referred to as oxidation. dation of organic compounds can be carried out, ach efficient reagent used widely for oxidation “~~~ on Scanned with CamScanner310 | Engineering Chemistry - I: Concepts and Applications Another idant is PDC (pyridiniumdichromate). PDC is less acig than PCC. Fn coi eed for oxidation of those aloohols which may g,® Pete to acids. Seti NO oy {seq PDC wont, DEM, 25°C 90% Manganese can function as oxidant when it is in +7 oxidation state. KMno, i, such oxidant. It is a very strong oxidizing agent. KMnO, is also used to oxidize pyr alcohol and aldehyde to corresponding carboxylic acid. Primary o =o- or = Co oO co= cs Ou 0 crs KMn0, No reaction | 9 CH Oo = Cre (a) Baeyer Villiger Oxidation Ketones can be chlooperberane seid (mCPRAY et treating a ketone with a peroxy acid like me reaction occurs through a tetrabedal Teaction is called Baeyer-Villiger oxidation- ‘ i acid. intermediate, and results in-release of a ca" Scanned with CamScannerOrganic Reactions and Synthesis of a Drug Molecule {au 9 a 0. PaCOOo! Oo ancy ee oo a a Bacyer-Villiger 9 CHy {CH, onion oy, AA CHAM CHy ~O’ | Major product 0 Jones Oxidation ip Jones oxidation, Ketones aré formed from secondary alcohols and carboxylic acids are famed from primary alcohols. Primary allylic and benzylic alcohols forms aldehydes. mixture of chromium oxide, sulphuric acid and acetone is called Jones reagent and it rates carboxylic acids from primary alcohols and ketones from secondary alcohols that dp not contain acid sensitive group. 9 (C104, 09. 1,50, a teetone on Se C10, a9, H,S0, acetone R R’ - () Oppenauer Oxidation Oppenauer Oxidation or Meerwein-Ponndorf-Verley (MPV) reduction is an aluminium- catalyzed hydride shift reaction in which a hydride is shifted from the a-carbon of an alcohol component to the carbonyl carbon of a second component. The reaction occurs through a transition state (six-membered). The reaction is termed as Oppenauer Oxidation ifaldehydes or ketones are formed as the desired product ole iH SL AMOR), RoE OR SR IR having relatively low reduction. potentials, non ed as the hydride acceptor in this oxidation. Non-enolizable ketones like benzophe! MN also serve as the carbonyl substrate Us: Scanned with CamScanner312 | Bngineering Chemistry ~ I: Concepts and Applications 7.5.2. Reduction Reactions os A : in of hydrogen is often referred to ag In organic chemistry, the loss of oxygen or gain of hy Fe If reagents like LiAlH,, NaBH, NaH, ee. are applied to aldehydes or ketones, “et get converted to their corresponding alcohols. The et are owed in i na at a low temperature. Carboxylic acids are converted to alcohols either by Using Lag or by three molecules of BH. : 9 don Me Oh, OCR on : Another very selective reagent is diisobutylaluminium hydride (DIBAL-H) and is ayy commercially available. Esters and nitriles are converted to aldehydes using this reage, The ideal condition for the,reaction is an inert and moisture free atmosphere, COMe _ DIBALH 0 0 a ~“e Me Me of Me NaBH, is such a reducing agent that can convert aldehydes or ketones to alcohols. Non-conjugated aldehydes or Ketones are reduced more rapidly and easily than conjugated aldehydes or ketones. The reaction can be performed effectively in solvents like THF, DME, diglyme, hydroxyl solvent and water. ROH f aoc ie NaBH, |, OX on b THE, reflux NH (a) Clemmensen Reduction When any aldehyde or ketone is boiled with zinc ie acid the nascent hydrogen obtained during the reacti apa ieee ion reduces the carbonyl group of aldetyd or ‘ketone to methylene group (=CH,) to produc e | group of ade? known as Clemmensen reduction, Produce corresponding alkane. This reductio® a ) Zn(Hg) HUH oO Zo(Hg) ra, HCl COMe com OMe 163 Epoxidation ‘ides ot oxiranes are three-membered cycli ect cyclic structures of oxygen at one of its vertices carbon atoms on the other two vertices, It is an important method for preparing and two i epoxides by reaction with peracids, RCOSH. | > 5 * Nene’ + RA A Do=cc + R-C-00H — {4 Oe on Atkene Peroxyacid Epoxide “sd 9 pte den Cera | H 2, canner tite | « Mechanism of epoxidation | | xX - Spee po ages | ‘0. | 0: yr p c oxy RO « Ring opening reactions of epoxides we i in hii i The reason for their reactivity lies in the Epoxides contain highly reactive carbon atoms. on fo reactiv fact that on ag ‘an epoxide ring, there is substantial ring strain, This also favours the nucleophilic attack. R OH OUR R ‘ RA . 3K . i wor y has been opened, | Niu ee member sine Hi ng beng energy cing sai0) t Scanned with CamScanner316 | Engineering Chemistry ~ I: Concepts and Applications "96? DRUGS AND THEIR'SYNTHESIS yy or. PEO A drug is any substance that, when inhaled, injected, smoked, consumed or absorbed, a temporary physiological or sometimes psychological, change in the body. Drugs are t chemicals which have very low molecular masses but can interact with macromol targets resulting in biological response. Biological responses that are therapeutic and Use generally occurs due to compounds called medicines which are used in treatment Of diseases, There are different types of drugs. Drugs can be classified on the basis of: (a) pliarmacological effect (b) drug action (©) chemical structure (@) molecular targets The same drug can be synthesized by a variety of methods. Some of the most commonly’ used drugs and their methods of synthesis are discussed below. 7.7.1 Aspirin Aspirin (acetylsalicylic acid) is a synthetic organic compound produced from salicylic acid, It is found naturally in the bark of the willow tree. It was known to.be used by the ancient Greeks and Native Americans, to obtain relief from fever and pain. It was first synthesized by a German chemist named Felix Hoffman in'1897. Aspirin is generally prodticed by adding an excess of acetic anhydride (C,H,0;) to a measured amount of salicylic acid (C;H<03) in presence of concentrated sulphuric acid (H,SO,). H,SO, acts as a catalyst here. The mixture is heated in order to obtain acetylsalicylic, acid (CoH,O,) and acetic acid (C,H,O,). The product obtained is washed with water to remove the excess acetic acid and is crystallized. ° ° ll l oH CH, oben, ? + , + CH,—C_oH Gon ac G08 : ° 6 0 Salicylic acid Acetic anhydride Acetylsalicylic acid Acetic ac (CHO) (CH03) (GH,0) (CHO) 7.7.2, Paracetamol Paracetamol or APAP results in relief from pain and fever. It is also called acetaminophe?- Paracetamol is prepared by reaction of 4-aminophenol and aceti¢ anhydride. When the reaction is complete, the product is isolated and purified, Scanned with CamScannerOrganic Reactions and Synthesis ofa Drug Molecule | 317 OH OH oH il. H,50, NO, NaNO, + NO, OH OH 9 A oH ‘NaBH, 0 Ao NO, NH, Xr 113 Ranitidine Ranitidine is commonly known as Zantac. It is a medicine that decreases the production of acid in the stomach. Taken orally or intravenously or even intramuscularly, Ranitidine teats peptic ulcer, gastroesophageal reflux and Zollinger-Ellison syndrome. It is prepared by reducing furfural followed by treatment with dimethyl amine and formaldehyde in acidic hedium. The product is further treated with cysteamine hydrochloride and N-methyl-1- nethylthio-2-nitroethenamine to form the product. . 0. 0. 2 0. Hi cat. HSCH,CH,NH, ‘aq. HCI MeS\_/NHMe No, yee —— | . 0. ‘ NHMe yr ~ NO, tin the 774 Chloroxylenol Sorrel is an. anise Pn sold ud (0. It is very safe and effectv® fr also exhibits disinfectant behavior and is ako names PONEX or parachlorometaxylenOl. I trumens. tis widely available nd for cleaning Md wound cleaner. It is prepared ice used against skin infection at 1d disinfectant an ; epar s sini and is henee used os py ide in CCl, medium. Sulphur dioxide ting 3,5-dimethylphen’ . jducts. 2nd hydrochignie acid are formed as side PO list of essential medicines issued by jpular brands like Dettol. It is Scanned with CamScanner318 | Engineering Chemistry ~ 1: Conoepts and Applications OH OH +80,c, + +80, + HCI CH, ~~ CH, Sebturytchonise CH, 3,5-Dimethylphenol ‘4A-Chiloro-3, 5-dimethylphenol 7.15 Morphine Morphine is a pain relieving medicine when ingested orally, intravenously or rectally, acts directly on the central nervous system and reduces the feeling of pain effectively is found naturally in many animals and plants. It is effective for both chronic and pain, It is used during labour pain and myocardial infarction. It takes 20 minutes to effect if taken intravenously and 60 minutes if taken orally. The effect lasts for about 37 hours. The process of laboratory synthesis occurs in a number of steps im accordance the following pathway: HOO 7 a aC HC Cr (beat NH HC. Mi L, (2) POCIMeCN ba (@)NaCNBHBH, HC OH HC” be () LINHyTHFABUOH N. (1) HOCH, CH, OH/THF/CH,S0,H SApaCODA ae. \cHO ‘@aloNac (2) POCHO/EOAc/D (2) CH,CONHBr/0°C 85%) C oo H,C\p, OH Oo . 0. Br 6 “CHO HO’ (1) HCO,H/H,O (2) NH,F/HF/CF,SO,H N HC 0 CHO OH Contd. i. Scanned with CamScannerOrganic Reactions and Synthesis ofa Drug Molecule | 319 Z 70. Br (Br HO CHOHMCVa HO Sona oed NH/H,0/-PrOH @) HYHOACTHCHO Co" " O° io oO CH, o HO. 5S steps 0. Soa nef \ X N 0 CH; CH, Dihydrocodeinone Morphine 116 Penicillin Penicillin (PCN or pen) is an antibiotic and is very effective against infections caused by staphylococci and streptococci. It is one of the first antibiotics that were very effective against bacterial infection. It belongs to a group of antibiotics including penicillin G that is used intravenously, penicillin V that is taken orally, benzathine penicillin that is used intramascular and procaine penicillin. It can be prepared as follows: ° o 7 CHO Me M® CoH AcONs_ ae N . cy BIOH. HO oe ‘CO,-Bu «HS NIGH x Scout Me Me NHNH, Dioxae, 1,0 CO;H CO,H Me Och HN BN Ye + ay -Bu0,C AS Me =. ,.Bu0,C._}-s M* pro CHCl au : x PhO’ HN a Contd. CHC, Scanned with CamScanner320 | Engineering Chemistry ~ I: Concepts and Applications aH OH Me 0, xo, ° Me he Fano ro SN Ds Me On NaH Dioxane, HO Na | NH H | Po (#}Penicilin | 7.1.7 Phenelzine Phenelzine acts as an inhibitor and is non-selective in nature. It belongs to the hydrazine Class and is an irreversible monoamine oxidase inhibitor (MAOM). It is widely used as an Antidepressant drug. It is readily available as:15 mg tablets; doses are usually in the range from 30 to 90 mg per day. . It can be prepared by treating (2-Bromoethyl)benzene with hydrazine. H Br NANu, o~ + HANNA, —> Oo~ BB. vers think 11. Why do ring opening reactions of epoxides require less energy? 12. Name the drug used for treating peptic ulcer disease. 13, Name the drug contained in the antiseptic named ‘Dettol’, 14. Why is morphine considered more eff than ether corresponding drugs? ° : ; organic reactions and the principles and mechanisms underlying them. The factors that influence the chemical reactions and their stability includes inductive effects, mesomeric effects, electtomeric effects and hyperconjugation, There are different types of chemical reactions. The substitution reactions include Sy', S,? ans SN reactions. Similarly, El, E2 and Eleb reactions occur under elimination reactions. Both Sy! and El are unimolecular reactions and take place in two steps. Sy? and E2 reactions are bimolecular and take place in @ single step. Additional reactions occur in accordance to Markovnikev or anti-Markovnikov addition Tules depending on steric factors, reagents involved and on other factors like stability, RINNE satan FReHoeS aad a a This chapter highlights the different types of reducing to Diels ion of Particular groups. Ring opening and Is-Alder reactions. In this reaction, the @ ring. Similarly, epoxide rings can be ring closure/cyclization can be done in accordance m-bonds are rearranged which results in the formati Scanned with CamScannerOrganic Reactions and Synthesis of a Drug Molecule \se. opened by applying suitable i se 2 Toman, Bra hich he Druts are of different types and can be used eet ten se ‘cal response are called medicines The methods are Ae ; + Paracetamol, phenelzine, chloroxylenol, ‘morphine, Scanned with CamScanner