Stereochemistry, Reaction, Mechanisms, andsSynthesiss of; Drug, Molecules, ei Outline «yoction * Conformational Isomerism 4 TypesofIsomerism © Organic Reaction Mechanisms {Representation of 3-dimensional © Nucleophilic Substitution (SN) stares Reactions «configurations - D, Land Absolute * Addition of HBr to Propene RS) © Grignard Reagents Chirality © Oxidation and Reduction Symmetry Elements Addition of diborane (hydroboration) + Optical Activity © Synthesis of Aspirin and Paracetamol =a it AV introduction =sszsammemsenmuoamasss Stereochemistry Creic Chemisty is based on the relationship between the structure of the molecule and its popes. Stereochemistry is the branch of chemistry which deals with the structure of the molecule ‘ntive dimensions and stereo isomerism is only a part of this branch of chemistry. __Stereochemistry isthe study of physical, chemical and biological properties of molecules ‘rth respect to spacial arrangements of atoms or groups in a molecule in three dimensions. Zero dimensions ae One dimension Example: HC=C-H a ‘Two dimensions % Example: SC=CC 41 Scanned with CamScanner42 Engineering Chomistry * Three dimensions Example: 7 Away from observes in front of the plane, Stereochemistry is the branch of che ‘mistry which deals with the structure of in three dimensions and stereo isomerism the mo is only a part ofthis branch of chemisy Eo 4.2 Types of Isomerism 2 Sy LR: Compounds having same molecular formulae but possess different (ce) chemical (or) both) are known as isomers and the phenomenon Tipes of isomerism: Isomerism is of two types (a) Structural isomerism (©). Stereo isomerism Structural isomerism ‘ee compounds having same molecular formula but possess different structural arrangemess atoms. This difference may be due to difference in th e le natures of carbon chain (chain isomerisn OF due to the position of the substituent (position ti isomerism) or due to the difference in the ‘ature ofthe functional group (functional isomerism), Properties (eit ther p is known Sic 88 isomerism ‘Chain isomerism: It arises due to the different in the nature of carbon chain, Example: (1) n-butane H,C—CH,—CH,—cH, iso-butane HCC H—CH, on, 2) n-pentane H,C—CH,—cH,_cu,—cu, Wso-pentane HjC—CH—CH,—cH, bi, CH, | heo-pentane H,C_C—_cH, ch, Scanned with CamScanner), Reaction Mechanisms, and Synthesis of Drug Molecules 43 Trarises due to the different in the position of the substituent iodide = WC CH, CH 4 Joopropy! iodide HC es cH, 1 4, bute HC CH—CH,~CH, debutene HAC. CH=CH—CH, : Compounds having same molecular formula but possess different func- x1, ethylalcohol = — HC CH,—OH @imethyl ether =~ HC—O—CH, dehyde =~ H,C-CH;- CHO HyC—C—cn, oO exhibited by the compounds having same structural formulae, molecular different spacial arrangements of atoms or groups. It gives 3-D is e of amolecule. : Stereo isomerism can be broadly divided into two classes. the phenomenon ‘configurational rted only by breaking and making of the bonds. isomerism’. These ‘Scanned with CamScanner44 Fagineering Cherniatry Fxampte: dibromo cinnamic acid coon COOH H—C—Br Br—C—-H H—C—Br Br—C—H COOH COOH Characteristics of enantiomers |. Bhantiomers always exists as discrete pairs 2. They are stable, isolable compounds, that differ from one another in 3 a arrangements of atoms or groups, 3. They cannot be inter converted under ordinary conditions, 4. Enantiomers have identical Properties in all respects except in their inte plane polarized light. 5. They have same melting points, density, solubility, colour and Teactivity acids and bases. 7. Amixture of equal amounts of the two enantiomers is called racemic mixture wx is optically inactive. 8. Enantiomers can be separated by mechanical separation, bio-chemical separ and complex formation. (i) Diastereomers: When the configurational isomers are not the mirror images of each oihex they are known as diastereomers, 1. The two diastereomers have different Properties, 2. They have different melting Points, boiling points and solubilities. 3. They have different chemical Teactivities towards most of the reagents. 4. They can be separated by fractional distillation, fractional Crystallization and phy. Example: |. Maleic acid Fumarie acid *~ COOH H. coon C. H~ coon HOoc~ \u ~cis isomer ~trans isomer ‘Scanned with CamScanneronervstry of f negroes sp acid pane nl CooH H é Br H—C—Br COOH tiomers Br—¢ Br—c COOH Characteristics of enan' j { ; always exists as discrete pairs. |. Bnantiomers 2. They are stable, isolable compounds, that differ from one. arrangements of atoms or groups. 5 They cannot be inter converted under ordinary conditions 4 Enantiomers have identical properties in all respects exce plane polarized light. § They have same melting points, density, solubility, co acids and bases, © They differ in the direction in which they rotate plane | taal the ppl. to exactly the same extent (same angle polarized light to the right (dextro rotatory) Wh the left (laevo rotatory), 1 Ami Mure of equal amounts of the two enantiomers 's is optically inact 8. Bnantinn es Scanned with CamScannerstereochemistry, Reaction Mechanisms, and Synthesis of Drug Molecules 45 5 bromo-2-butanol 1c Hy o, - ao YH HoO-C—H = H—-C—O# el ee H—C-Br H-C—Br ay ” cHy cH goes between enantiomers and diastereomers: Diastereomers 1 “They are non-superimposable mirror They are non-superimposable and non- mages of each other. mirror images of each other. 4, Only one pair of enantiomers are 2. More than one diastereomers are le. possible, 3, Typosraphically they are non- 3. Typographically, they are equivalent. “4, Theyare isometric and geometrically 4. They are non-isometric and i ‘geometrically non equivalent. 5s, They are optically active. 5. They are optically inactive. "6 Enantiomers are related by second 6. These are non related to (6, Ci, Sn). Be kind of symmetry clement (6, Ci, Sn). 43 Representation of 3-dimensional Structures ™ Thecarbon atom to which all the four atoms or group attached are different is called asymmetric ‘carbon atom. The compounds having one asymmetric carbon are chiral or optically active. ‘Compounds containing two asymmetric centres may be chiral or achiral. Achiral compounds show various conformations. The representation of conformations can be done in different ways. Wedge Representation Inthis method, the four bonds of the chiral carbon are represented by four line e thick line indicates the bond directed towards the eye of the viewer. The normal line indicates the bond that les in +4 plane of the paper. The dotted lines indicates the bonds behind the plane of the ‘Paper. cH Hy C Cc FAIRS aa. He coon OF H cucu, © C(CH3)(OH)(H)(COOH) (C(CH3)(CH2 CHs)(CD(H) Scanned with CamScanner46 Engineering Chemistry Fischer Representation It isa simple method to give planar representation to the enantiomers, The four bon, nted by horizontal and vertical lines, The interaction ofthe arbon. The horizontal lines represent bonds gj chiral carbon are repre: and vertical lines represents the chiral towands the viewer The vertical lines represent the bonds directed away from the viewer, CH; i Cl C(CH3)(CH CH3\(H)(CL) CH, CH, Newman Representation x = method, oe ay oa “presented by a point. The three atoms or ‘TOUps attaches this carbon y Points radiating from this oint. The oth hich is simated away is represented by ¢¢ ioe sare reps abn to . Its e edge ofthe circle, 2 HCl Is three bonds are representer by three lines Tadiating from th y H H HC a Hc: Ms cin GH HC ey St taggered form Eclipsed form 0 which s connecrne © Act. The remaining groups are indi bond in Tbk ahd een ens Te on lines represen the me, OF groups abs’ SONS projects above or below this plane. Thick Br0ups below the plage ve the plane while dotted lines represent the atoms oF Scanned with CamScannerereocreren. Reaction Mechanisms, and Synthesis of Drug Molecules a7 Staggered form Eclipsed form sn sbstances are capable of rotating the plane of polarised light either towards left or ‘These substances are said to be optically active. This propriety is known as ty. Due to optical activity, two types of compounds are formed. These substances spe ontically active, Substances which turn the plane of polarised light towards right « isomers and substances which turn the light towards the left are called laevo Tne process is called optical isomerism. The optical isomerism is due to the presence =c carbon atom. A carbon atom connected to four different groups is called « Lactic acid (CH, CHOH - COOH) H H . C aie eo = | Sou COOH COOH Dextro lactic acid Laevo lactic acid two isomers are related like an object and its mirror image, such compounds are wn as enantiomers. The phenomenon is called enantiomerism. eonmgen : F in in which two carbon atom are joined by a single bond. One of sloms is kept fixed and the other carbon atom is rotated about the single Bond. Due i the atoms attached tothe carbon occupy different positions in space depending rotation, ‘Scanned with CamScanner48 Engineering Chemistry Staggered form (trans) Staggered confirmations are more stable than eclipsed confirmations. In eo} Sreater repulsive force operates. Ipseq fron, 4.4 Configurations — D, L and Absolute (R, S) === Arrangement of atoms or groups in a stereoisomer is called configuration, Example: CooH 1. Lactic acid -H OH Ithas one chiral centre. Therefore it has stereomer. CH = 2 stereo isomers. i Z They are CooH CooH H OH HO H CH3 CH3 Dextro lactic acid itrorLaevo lactic acid 2. Glyceraldehyde CHO CHO Ht OH HO H CHOW CH)OH Dextro/D(+) isomer Epevorl.(") isomer These are two configurations to represent the molecule (a) Relative configuration (D, L system) (b) Absolute configuration (R, S configuration) Scanned with CamScannerquresmreriaty, Reaction Mecherterne, and Syritesie of Drug Molecuiee m 49 fectual arrangement of atoms ot groups in space are studied with reference to a in D and L. system, usually glyceraldehyde is used as standard with reference 10 is assigned to isomers PHO cHo u Ou HO—}—H CH0H CH;OH DE) Glyceraldehyde L (-) Glyceraldehryde © jon in which —OH group is on the right is called D(+) Giyceraldehyde, other which contain —OH group on the left side of the molecule is called L-isomer. Configurations ‘are characterized by arrangement of atoms or groups of a compound. This is called the configuration of the stereoisomers. ‘compound may have same configuration but different sign of rotation and hence @ “is best recognized by the configuration not by sign of rotation. ¢ chosen as an arbitrary standard and the configuration of different Yelative to that of glyceraldehyde, Therefore, itis called relative configuration ‘of this configuration relative to some compound. c hhas -OH group on the right, H (hydrogen) atom on the top and ~CH,OH at the bottom. This was given the i OH group on the left, H (hydrogen) atom on the rightSeperate, Rewston Wectentere, and Syritecie of Drug Mutecuten = 49 we configuration ‘ype actual arrangement of atoms or groups in space are studied with reference f * Dandl system, usually glyceraldehyde is used as standard with reference t© configuration is assigned to isomers. HO CHO H OH HO H (CH)OH CH:OH D(+) Glyceraldehyde LQ Glyceraldehyde which —OH group is on the right is called D(+) Glyceraldehyde, —OH group on the left side of the molecule is called L-isomer. en ‘are characterized by arrangement of atoms or groups of a compound. This called the configuration of the stereoisomers. may have same configuration but different sign of rotation and hence a ‘best recognized by the configuration not by sign of rotation. sen as an arbitrary standard and the configuration of different to that of glyceraldehyde, Therefore, it is called relative configuration n relative to some compound. de has OH group on the right, H (hydrogen) atom on the ‘at the bottom. This was given the configurational 1 ‘on the left, H (hydrogen) atom on the right ‘Scanned with CamScanner4.10 Ml Engineering Chemistry Absolute configuration Sequence rules 7> assign configurational symbols R, S to an organic compound, sequence rules Ifthe sequence is clockwise the configuration is “R’ (Rectus is right) and if the s clockwise, the configuration is ‘S’ (synistrous is left). are pro quence is ay, Rule! Fre order of the priority is determined on the basis of the atomic numbers of atoms that ag diretly atached directly tothe chiral earbon. Greater atomic number results n high, a The order ofthe priority is Br> OH> CH, > H. Br Br nf He | cl configuration “ Priority: 1, Br, Cl, H Rule I In the presence of two isotopes of same clement, the heavier isotope will have higher priority -Deutero ethyl bromide. H D At. wt. of ‘D’ is greater nc c= than that of ‘H”. So deutero ik if gets preference S-configuration Rule Il If the two atoms attached to the carbon are the same, rule (1) is not applicable. Priority in such cases is determined by comparing the next atom in the group. Example: Secondary butyl bromide H3C- H)C: Priority ~ Br, —CH, - CH,, —CH,, —H. ‘The relative priority of methyl, ethyl groups are taken, Scanned with CamScannerStereochemistry, Reaction Mechanisms, and Synthesis of Drug Molecules _ 41 H é: Inmethyl —C—H_ and H i, Inethyl —C— as c Since carbon has higher atomic number than H, ethyl group gets higher priority over ~ methyl group. _ Rule IV | {f chiral carbon is attached to doubly or triply bonded atom then the atom is considered equivalent to two or three singly bonded atoms in determining priority. — Ais equivalent to sh A = Ais equivalent to —COOH >—CH, > —H ‘Scanned with CamScanner42 @ Now the molecule is viewed from the opposite side ofthe lowest priority y, OH > C,H, > —CH,. In the molecule, the fourth priority group i.e, —CH, is not placed at the bottom Se ee four (even number) interchanges, the new Projection of the @ CH; 4 1 @ @Q ne—f—8 =D el @ oH > 4 Second interchange 1 Order of priority eee ee —— — OH > —CHO > —CH,OH > —H tion 3b a ‘Scanned with CamScanner| a yi stereochemistry, Reaction Mechanisms, and Synthesis of Drug Molecule = y cH Br Br, Cl, CH, H | Rs. - ad,on Sa (S- conf) Interchange the groups bonded to asymmetric carbon. It must be done in pairs to avoid the configurational change. NE = weet cus (S-config) H Priority NH, > C,H, > CH, > H. ® ’ CHO OH No U OH = HOK,C. cHO gfth ou H Clockwise is R-conf. Priority OH > —CHO > —CH,OH > H. . D,—L-tartaric acid Neon cooH H0-¢ Val OH 4 con = wos H = Hooc G as G mi ES pal G On H—C—OH | Hon = HOC ic Coon So cooH Ee Means hand. Just like our right hand is a non-super imposable mirtor image of Le, non-super i ieee 7 : lanar molec eee rr image is called chiral. Planar molecules are achiral i ‘Scanned with CamScanner4.14 BB Engineering Chomistry (a) (a) " i Wy | oy (by | dy «” ) () 1 mirror = and II are non-super imposable mirror images, In organic molecules, chirality is due to the Presence of tetrahedral cay carbon to which four different atoms or groups are attached, Enantiomery molecules having atleast one chiral center, A molecule is said be chiral if it contains (i) at least one asymmetric carbon ang ij) should not contain any of the elements of symmetry, : Mb On/ A ren a6 peoMible 1p 4.6 Symmetry Elements There are three elements of symmetry (i) plane of symmetry (ii) centre of *y (iii) alternating axis of sym: 1. Plane of symmetry: The plane that splits an object into two identical halves is ale 4 plane of symmetry. For instance, palm of our hand cannot be divided into tro cx. halves and hence it does not have a plane of symmetry. Therefore, itis chiral CH, <*-*** PLANE OF SYMMETRY 2, Center of symmetry: It is a point in a molecule. A line drawn through this point fro any alom or group to the end results in the presence of identical group or atom at te opposite end, GOH HO, re is CHIRAL CENTER ime CHIRAL CENTER HOF = % ‘O.H n-fold aternating axks of symmetry: If a molecule is rotated by an angle of 27)” a through an axis followed by reflection across a plane which stands perpeodiu! © this axis results in an identical structure, This results in an n-fold axis of symsmetY the mosecule ‘Scanned with CamScanner4.15 stereochemistry, Reaction Mechanisms, and Synthesis of Drug Molecules _ ———éia F cl : 90° Hq 90° pe ae a & t t ' © (ropa! Aci ly semesters n of rotating plane polarised light is known as optical activity. The compounds Ten property are known as optically active compounds. midy of optically active compounds shows that only those compounds which pos: Jmposable mirror image of original molecule are able to rotate the plane polarised ‘onder to exhibit optical activity, the compound must be chiral (cheir means hand) our dis the mirror image of right hand and these two are non-super imposable. ntically active compounds does not possess any of the element of symmetry. m which are mirror images of each other are known as enantiomers (enantio = ‘merol = parts). They resemble each other in their physical and chemical properties that, they rotate the plane polarised light in opposite directions. st chiral compounds have a chiral center in which an atom (carbon) is bonded to four ent atoms or groups. If groups attached to carbon are the same the molecule is no longer nd optical activity disappears. Glycolic acid Propionic acid Isobutyric acid CHy CHy HO—C—H H—C—H HyC—C—H COOH coon coon active Inactive Inactive Inactive 10 represent the three dimensional structure of a molecule on two dimensional paper, rojection are used, They are Fischer projections Newman projections, saw horse and wedge representation, * Projections are used for representing, configurational (optical and geometrical) ¢wman projections are used to represent conformational isomers Projection can be explained by taking lactic acid as an example HC CHOH cooH Scanned with CamScannerCH CH3 According to the Fischer projection, the molecule has to be oriented in such a Way the chiral carbon lies in the plane of the paper and the two horizontal bonds (on both leh ‘abt side) are above the plane of the paper, while the other two vertical bonds projected bunt the plane of the paper. In this, the vertical bonds are shown by dotted line and horizontal bg are shown by wedge. Optical isomerism Plane polarized light: Ordinary light consists of waves vibrating in all planes perpendicular the line propagation. When such a light is allowed to pass through NICOL prism, its vibration in all planes are cut off except one plane. Such a light whose vibrations occur only in single plane is known as plane polarized light (Fig. 4.1), Ordinary light NICOL prism Plane polarized light Fig. 4.1 Plane polarized light Optical activity: The phenomenon by virtue of which certain substances exhibit remarkable ability to rotate plane polarized light is known as optical activity and the substances are know? as optically active substances. Substances which rotate the plane of polarized light in clockwi¥ direction are known as dextrorotatory, indicated by “d” or “+ve” form (Latin: dextor meats ight) and those which rotate the plane of polarized light in anticlockwise direction arc kno" as levorotatory indicated by “C” or “-ve" form (Latin: leavous means left). Polarimeter: The instrument used for measuring the angle of rotation Jarized light is known as Polarimeter. It consists of two NICOL prisms which are Sa by keepin oy axes of polarization parallel to each other. The space in-between is ued to keep the samp? tube carrying the liquid or solution of the substance whose optical activity is to be studied. T™ schematic diagram of a Polarimeter is shown in Fig. 4.2. roa Light ¢_ =] @ source Light a {ager source N L Polarizer Sample tube Analyzer Fete. ‘Schematic diagram of a Polarimeter ‘The magnitude of rotation depends on the 1. nature of substance, ‘Scanned with CamScanner‘soroochemistry, Reaction Mechanisms, and Synthesis of Oruy Molecules Wl 4.17 tration of solution, h of sample tube containing solution, nature of solvent, ture of solution, and wavelength of the Hight used (usually, D-lines of sodium having wavelength 949.3 nm is wed), rotation: Optical activity is reported in terms of specific rotation which is jos of a particular compound, It is defined as the rotation in degrees observed when light is passed through | dm of solution having concentration of 1 g/ml ata 4 Ay tag ot io temperature and wavelength, This is usually expressed as below Done onal ds "ixe sis the D-lines of sodium having wavelength 589.3 nm, 1 is the temperature (°C), Lis the Polarimeter tube, c is the concentration of solution (g/ml). bi of optical activity: The only necessary, inflexible, and sufficient condition to s views ‘activity is that the geometrical structyre should not superimpose on its mirror by in singe erimposibility can be verified with the help of symmetry elements such as plane, ‘sod axis. The molecule that lacks all the elements ‘of symmetry, i.¢., asymmetric, is non-superimposible mirror image and is optically active. Subsequently, it has 4 that the malecules which are devoid of only plane and center of symmetry are also ‘sctive, Such molecules are known as dissymmetric molecules. Thus, all asymmetric are dissymmetric but the reverse is not true, However, both of them are optically be in recent practice, a new term has replaced the use of as ic and dissymmetric simply relates optical activity to rnon-superimposibility of mirror images and not to of elements of symmetry, reference o organic molecules, those molecules that contain o east one chiral carbon active, Chiral earbon is that which remain attached to four different atoms or groups. ‘Scanned with CamScanner4.18. [Engineering Chemistry atoms lie in planes perpendicular 4, , each hey groups which remain attached to the trigonal “ other, The result is that allenes nether possess plane nor a center of symmetry. Howey. « possess non-superimposible mirror image. , ‘The same is true for allenes containing even number of double bonds. Therefore, they ae optically active. In contrast, those contain odd number of double bonds that do not exhibit oc isomerism. This is because atoms or groups present on the terminal carbons lie in the same plane Fischer projections Fischer projections, devised by Emil Fisher in 1891, are 2-D projection formulae of 3-D organic molecules. Following conventions are made for getting the Fischer projections. 1. The molecule having a chiral center is viewed such that two of the groups attached to the carbon remain horizontal and point toward the observer, while the other two are vertical and point away from the observer. ‘The different atoms or groups attached to the chiral carbon are then projected on the plane of the paper in the form of a cross. The chiral carbon lies at the intersection of horizontal and vertical bonds. 3. When the molecule contains two or more chiral carbon atoms, each carbon is viewed individually in similar manner. 4. Usually, the main carbon chain is written vertically with the most prior atom or group at the top. The chain is numbered as per the IUPAC system of nomenclature ‘The complete procedure is described as follows: coon coon COOH c H OH BH ag oH wd Sow | on cH, 7a Lactic acid 4.8 Conformational Isomerism Conformational isomerism refers to any one of the infinite a a the atoms of a molecule that can arise from rotation i spain ange ‘be confused with configuration isomerism, which is the bes of molecule that can be changed only by breaking and spatial fal arangements ‘atoms ‘The stereo isomers which are non-super spb ies By ak aes toe lapis emi owe car aoe ge ingle bond are Known as conformational isomers and the phenomen? i > ‘Scanned with CamScannerei tereochemistry, Reaction Mechanisms, and Synthesis of Drug Molecules i 4.19 cyclo alkanes CHs CH; H He H i iH! Is (staggered) (cclipsed) ‘ut cis of ethane the two carbon atoms remain connected by a o-bond. If one of the methyl ‘ethane is kept fixed and the other is rotated about the C-C bond, one can get 2 ements which are known as conformations of ethane. The energy required for called torsional energy, which is very small (~12.5 kJ/mol). The two extreme gurations are staggered and eclipsed. q HH H H H H H H Staggered Ectinecd conformation, the CH bonds (dihedral 3 along the C-C bond / “In eclipsed conformation, 12.gfed/mol | 150°. The potential energy © / ‘S minimum for the nation, ‘The and reaches at a Hl a RM & 4 ‘eclipsed conformation, a ey of latter is due tothe 0 180 a intermediate Dihedral angle as skew Potential energy Fig. 4.3 Potential energy diagram ot ethane in Fig. 43, ‘Scanned with CamScanner4.20 Mi Engineering Chemistry wield oH yntauns Conformations of n-butane Conformations of n-butane can be discussed by considering n-butane as dimethy. shown here. By fixing one of the “C” atoms (say C, or C,) and rotating the other ary! « bond, one can get several conformations. The six important conformations are as fy." °° 8 Follows? CH; CH, CH; H CH, H CH; 60° 60° H " chair on | H H H H H u | # H 1 ml I H ‘Scanned with CamScannerstereochemistry, | 19.32ki/mol, Reaction Mechanisms, and Synthesis of Drug Molecules 4.21 E . 7 60 180 300 Dihedral angle Fig. 4.4 Potential energy diagram of n-butane ‘we observe the above potential energy diagram, the following conclusions can be L Hier, all the tree peaks are not present atthe same height, one peak is present at a ‘higher height than the other two present at same height. ‘The three valleys are also not present at the same height. Two are present at one height and the third one at lower height. n-butane, the most preferred conformation is the anti-conformation. Therefore, © will tend to remain mostly in this conformation. Reaction Mechanisms NARA ‘eaction, the reactant molecule undergoing attack is called as substrate and the = is known as the reagent. The substrate and the reagent interact to yield tha Teaction, 1S Br+ Nao 18° _. 41, OH +Nabr bette eager products 4n organic breaking and making of new bonds of carbon Or ee erode on often called ea its ‘Scanned with CamScannerone fragment the mechanisr le rates and occut 10 the substrat lectron pair i ir is calle jectrons t ings an el a pair of el gent electron Pal it that bri hat takes a te. jc. A reagent tl (or) takes a ait hile and the roa : ‘con is electrophilic: called nucleo} STectrophile and the Teae (b) Homolytic ‘mechanism qfabond breaks in such & way that, each fragment gets an electron, the mechanism is known! omolytic (01) free radical mechanis™- ig (oo beat Lb ight (oF) eat A+B A — B Grperoxides free radicals eee jucts of homolytic fission are free radicals. They are electrically neutral and hav ‘unpaired electron. Free ‘adicals are extremely reactive, because of the tendency F th electron to become paired at the earliest opportunity. ed ring. There are? ove in a clos tions: . Pericyclic reactions i isa tid pe of iectaie in which electrons m or radicals. Reactions of this type are called pericyclic reac! ‘Example: Diel’s - Alder reaction aA & +l = diene dienophile is Fe) ‘ iduct Midas 's - Alder reaction is th iti Alder ection he ation of alkene (dienophile) to a conjuested ee formation “hence it is also called as cyclo addition Sie Sra Scanned with CamScannerccnemitry, Reaction Mechanisms, and Synthesis of rug Molecules 4.23 action is a single step reaction without any intermediates (concerted . a i ot orgen vests a8 > dito eaetions substitution reactions eon reactions and ic Reactions ‘proadly classified into four types. They are o P ent reactions, ( Rearangem jon reactions iin which the substrate and the reagent add up to form a product is called addition "Addition reactions generally takes place in compounds containing multiple bonds. hone fragment, the mechan ctr negative) regative) —, >C=0, —c: at measurable aes nd ocus reactions may be electrophilic (or) nicleopilc. pair of electrons tothe sis Aiton actions may be electrophilic (or) ncleophil tat rings an clecton prs lic addition: This is the characteristic reaction of unsaturated hydrocarbons, pat takes an electron pairs cad ¢ Addition of HBr on ethylene. The electrophile approaches the multiple borid and carbonium ion. @ 2 ton, the mechanism is knowns H,C = CH, +H —> H,c_ Cn, Thecarbonium ion combines with the nucleophile to give addition product. oe are electrically neural and hve because of the tendency of it @ 2 HC ~CH, + Br —> H,C CH, —Br dic addition: The nucleophile being rich in electron density brings its pair of atbon atom joined bya double bond. The ‘electrons of the doable ben aos 0 ‘Bor electronegative atom. in a closed ring. There 2° * AdGition oF HCN to carbonyl compounds led pericyeic reactions. etl) to a conjugated diem * ‘dition reaction. ‘Scanned with CamScanner4.24 GE Engneering Chemistry Ha d He On ‘ HON C / ~~ ” HyC~ CN HC 4 ON rn ‘a | Na+ Jo=0——> nu—¢ 6 o> Nu— dog (Substitution reactions Saibsttution reaction is the one in which an atom or a group in a molecule is replaced by .,., atom or group. a Nucleophilic substitution: The nucleophilic brings an electron Pair to the substrate ‘and te leaving group departs with an electron pair. a Exampie: R-X+NG—> R-Nut:& Ss (H,0),C-Br+:0H — (H,O);C OH +: Br ‘Electrophilic substitution: The attacking species is an electrophile and the leaving group ‘ 204 HC: + Cl — OH, + HCI HC+CLCl — HCCL+ er ‘Scanned with CamScannersiereochemistry, Reaction Mechanisms, and Synthesis of Drug Molecules Ml 4.25 a . He HC. cH, (6H, > ac Cn Nye? - H,C=CH, -—; Hcz Ht; Hchemistry 4.26 Engineering C ; = 4.10 Nucleophilic Substitution (SN) Reaction: nucleophilic substitution is a fundamental class of substi ins emistry, nuc e jn organ ae cleophile initiates the process. A typical nucleoph ie sy bu 1 ich an electron-ric re " reaction is shown as follows: reacti I R—C—L—™, RCN + | ” be R $4 died nucleophilic sup, enn Ml related compounds. According to them there are ty, _ mechanisms at work and both ofthem competing with each othe, vz substitution Mele ‘unimolecular (S.1) and substitution nucleophilic bimolecular (Sy2) mechanism, In rarely another mechanism is encountered which is known as Christopher Ingold in 1935 stu ade substitution nucleo ites {Syi) mechanism, . Bimolecular nucleophilic substitution (Sy2) mechanism {et ws consider the nucleophilic substitution reaction of a ‘ypical alkyl halide say neal bromide in aqueous NaOH solution, y CHSBr+ OH —5 CHON+ By Substrate Nucleophile Product Leaving group Ina biomolecular reaction, the rate of reaction depends both on the Concentration of tie substrate and nucleophile. Mechanism Kinetics data reveals that the rat te depends on Concentration of both substrate and nucleophile, Rate « [CH3Br] [OH] To fit into kinetic data Ingold Suggested a concerted mechanism. In this Path, the ucleophile attacks the C stom from the side opposite to that of leaving group to form the transition state (TS). In Ts, both nucleo] hile and leaving group, ie, Of] and —Br cay Partial negative charges as —OH has started to share its electrons, while —Br has started ne along with its shared pair. Carbon atom is sp? hybric “H” atoms and catbon lie idized in this state, Thus the three in one plane with “C—OH” and “C—Br" bonds lying perpendicular tothe plane. The TS Subsequently collapses to form, the products, The energy required to break ee" bond is compensated by the “Sneray released during the making of the “C.-OIP H Se— pr Ho® (w Ip On ‘Transition state Scanned with CamScannerstereochemistry, Reaction Mechanisms, and Synthesis of Drug Molecules 4.27 nemistry rns always proceed with the inversion of configuration, as nucleophile always attacks sya e I Ge srear backside of the leaving, group. This is popularly known as Walden inverscoe zion which can be compared to the turning inside-out of an umbrella in strong wind. conjigurar i he experimental evidence At be gathered by carrying out substitution at an optically active Moon and measuring the specific rotation of both substrate and product. However, one problem still persists that optical rotation and configuration of two different s are not necessarily related. Hughes and Ingold came with an innovative solution to establish the inversion of configuration. They allowed optically active 2-iodooctane to with sodium iodide carrying isotopically labeled I* in dry acetone solution and observed of I* with ordinary I along with loss of optical activity of substrate. Again the rate ‘of loss of optical activity was observed to be twice that of isotopic exchange. The rate law had the Sy2 path for the reaction. They explained the facts by saying that the nucleophile from backside bringing the inversion of configuration. Since the rotation of inverted molecule exactly cancels the rotation of unreacted molecule, the rate of loss of activity is twice the rate of isotopic exchange. Inverted product 1) mechanism Unimolecular nucleophilic substitution (Sy! ~ Letus consider the nucleophilic substitution reaction at a tertiary Carbon center. To be precise, say substitution reaction of /-buty bromide in aqueous NaOH. (CH,),C Br+ OH — (CH,),COH + Br Mechanism - From Kineties it has been found that rate is Rate « [(CH,),CBr] : ets To fit into kineti two-step mechanism has been proposed. First step involves ai of the eee an. eos carbocation. This is the slow step, i.¢., rate- trolling step. The second step involves the attack of nucleophile to the electron-deficient to form the product. proportional to only substrate concentration. HjC HAC, Cs s ~w 8 HC So Br Slow. ° +Br® Aw Scanned with CamScannersons always proceed with the j . Se cocisito of the leaving. me ¢ nflguration, as nucleophile always attacks _ jo pion which can be Compared to the iyyri,® POPUlatly known ax Walden pension, (pho vexial evidence can be gathers by ait inside-out of an umbrella in strong wind pend measuring the specific rotation of both TYING Out substitution sub cit the inversion of configuration They oe sodium iodide carrying isotopically tat Mm at an optically active strate and Product, allowed Optically active 2-iodooctane to aan: 41° iv dey a0 ers * with ordinary 1 al it “d'1* in dry acetone solution and observed Aw Fobra With 1088 of optical Activity of substrate, Again the rate activity was observed to be 1 ‘ the Sy2 path for the reaction. They estes Of isotopic exchange. The rate law had from backside bringing the inve ied the facts by saying that the nucleophile Coys meee + H Inverted product nucleophilic substitution ($1) mechanism der the nucleophilic substitution reaction at a terti reaction of t-butyl bromide in aqueous NaOH. (CH)),C Br + OH-—5 (CH,),COH + Br- Carbon center. To be precise, tics it has been found that rate is proportional to only substrate concentration, «((CH),CBr] fit into kinetic data, a two-step mechanism has been proposed. First step involves substrate fo g an intermediate carbocation, This is the slow step, i.e., rate- involves the attack of nucleophile to the electron-deficient HyC. CH; x +Br® CH; Intermediate carbocation ier CH: +0H 0 =e : CH; ‘Scanned with CamScanner4.28 Engineering Chemistry Stereochemistry In the intermediate, the Carbon atom is sp? hybridized. The three groups which Fema; to “Carbon” lie in one plane while the unhybridised empty p orbital remaing cm tay, to the plane, As both lobes seem to be equally available for the attack of nucleon Mtigyl Proxiuct is expected to be completely racemic. However, in real practice the pr °Phile, oduct facemized with higher percentage of inverted configuration. The reason being Tea Pang after departure remains in close proximity of carbocation forming ion Pair Which "882 asymmetrically solvated carbocation (I), This ion pair prevent: a s front side attack le forming inverteq igh then leaving group is replaced by solvent the result being nucleophilic attack takes place from back sid; carbocation (I) is stable enou Of carboe, f racemizat ation 10n, y Scanned with CamScannergrereocneristry, Reaction Mechanisms, and Synthesis of Drug Molecules Mf 4.29 vm CH, Bg ‘ - | Br > CH, — Ct — cH, —> cH, — C— , — Cs LA ® - Is H ¥° carbocation 2° carbocation eis os CH —C—CH —CHs 4 CH —C— CH CH; ¥° carbocation bu 3° alcohol Reactions stions are identified as the reverse of addition reactions. Such reactions are broadly ‘or 1,2-elimination and «t-elimination, The first one involves loss of two atoms OF C> atoms, resulting in the formation of a double or triple bond among them. ‘proton is lost from one carbon, i.e. B-carbon, whereas a nucleophile from he ch is referred ot-carbon. In the second category, both the atoms (or groups) the se carbon atom. This is known as mination reseions ‘bimolecular (E,) or unimolecular (E,) path. reaction of a primary alkyl halide,4.30 Engineering Chemistry eae ds on the concentrations of both the substrate and the is Gi Lined Gaia, 8 Concerted mechanism hes been proposed Which j aneetin efumiien hy bine froma f-onrbon end sicaaltinsoes rel from the a-carbon along with the pair of bonding electrons. Br 4 “OCH, 2B, mechanism: Let us cane elimination in butyl bromide. Here ate depeng ‘on the concentration of only substrate. (CBy);C— Br —GHOH (oy, ),C= CH +C,H,0H . Mechanism l o O Mgp Nee N s/s oto ary Prien 27 i if. R— 7 oS — UN a \C F R fa S Adduct Alcohol To fit into kinetic a two- ‘ ica. idence of ci pean has, been proposed. In the frst step, Sestons to form a carbocation Thee is the a es ay along withthe bond carbocation . e 4 proton to solveny controlling step. Subsequently, he it OF Some other Proton acceptor, ch, Slow HyC—o chy +Br ‘Scanned with CamScanner @ €30 WH Engineering Chemistry Mechanivm i The rate depends on the concentrations of both the substrate and the base +, amto the kinetic data, a concerted mechanism has been proposed which invol,,.. ‘abstraction of proton by base from B-carbon and simultaneous release of RUcleophitg from the o-carbon along with the pair of bonding electrons. *Br H. g N /i H \ J H Fe Gn Sahn + C,H5OH + Bp H fd a\ H H H H + —0CH; 2. _E, mechanism: Let us consider the elimination in t-butyl bromide. Here rate depen on the concentration of only substrate, (CH;)yC — Br —GEOE , CH,), C= CH, +CHjOH Mechanism oe 9 O MgBr OH Nb b- ee: x 4 C=O +R —> Co —» ‘Cc Wom — \ 7 a aN inks eae hy, ,C Act Alcohol Mechanism EIS SEERA estan cians ic 0 ‘Scanned with CamScannerqereochemisty, Reaction Mechanisms, and Synthesis of Drug Molecules 431 ation elimination reactions of unsymmetrical substrates usually yield a mixture of all shle products. There are two imperil rules to govern orientation. i) Saptvelf rule: It states that neutral substrates capable of forming double bond © Gn either side of the chain prefer to yield most substituted alkene, '-< the loss Gf the B-hydrogen occurs preferably from the most substituted position. This 1 valid for E, and most of the E, reactions. The reason is attributed to the relative ability of alkenes. It is a well established fact that the stability of double bond increases by alkyl substitution on the doubly bonded carbon atoms. oa, CHy CH; | =CH— CH E cH. Boeeces tn H Major ‘Scanned with CamScanner4.32 IR Engineering Chemistry Major Y N(CH,))|OH + N(CH), + H,0 | / ¥ |, cep +N(CH,), + Ho, + 4 N(CH); |OH Elimination vs Substitution Ss! and E, reactions, S.2 and E, reactions occur simultaneously and compete with eas ote Wf attacking reagent is a good base, i.e., electron pair donor to hydrogen, then it easily ap nl ‘he B-carbon to cause elimination. However, at the same time if it is a good nucleophile ix. electron pair donor to electron deficient carbon, then it attacks the -carbon to bring Substitution ‘The following factors decide the ratio of elimination and substitution. 1. Structure of reactant: In general, proportion of elimination increases With increase hain branching of the reactant, The reason is two-fold. The reason may be attibung to the enhanced stability of highly substituted alkenes. In case of E, and S.1 Teactions, with bond ane from 120°to 109.5° brought about by the substitution. However elimination cg a om Cay. Pos Major. N(CH,)+H,0 a A N(CH3)3 Jow C2 Elimination vs Substitution S,,] and E, reactions, $2 and E, reactions occur simultaneously and compete with each Ifattacking reagent is a good base, i.e., electron pair donor to hydrogen, then it easily ab: the B-carbon to cause elimination. However, at the same time if it is a good nucleophil electron pair donor to electron deficient carbon, then it attacks the o.-carbon to bring substi The following factors decide the ratio of elimination and substitution. 1. a z reactant: In general, proportion of elimination increases with in ar oT ort reactant, The Teason is two-fold. The reason may be at ae stability of highly substituted alkenes. In case of E, and Syl re ugh carbocation intermediate which has a planner structure W! angle of 120°, With i - A A angle from 120° to iO in branching, the intermediate hesitate to decreas?’ ; brought ab ee : easily be ” out by the substitution. Hi -elimin: Y be brought about as it does not involve any change ie ee angle HC, ao: Scanned with CamScannerR istry, Reaction Mechanisms, and Synthesis of Drug Molecules 4.33 ysolvent: Bimolecular reactions are usually favored by decrease in polarity Nature of 3 ofthe s he Has, te effect is more pronounced in E, reactions. Therefore. jess polar solvents favor bimolecular reactions as well as E, over Sy2 reactions »: Activation energy of e 4 ature: Activation energy of elimination reactions is usually higher than those for g substitution reactions, Therefore, el slimination 4S spondiny correspon ated temperature favor eo account of Sy2 and 1 ‘Two-step mechanism Unimolecular reaction Partially racemized product with higher percent of inversion The carbocation formed may undergo rearrangement Favored by highly polar solvents Favored by mild nucleophiles Rate is mainly decided by electronic factor ait Addition of HBr to Propene Addition of | ‘hydrogen halides to Alkenes ‘lkenes react with FIX to form alkyl halides, The reaction is commonly known as hydro ion. ‘Anhydrous HX gas (X = Cl, Br, 1) is directly passed into the alkene dissolved in inert solvent. H,C—CH, +H#X———> H,C—CH, X @ If HX adds on to a symmetrical olefin, only one product is obtai sééed to unsymmetrical olefin, different alky! halides are produced. HC: CHz- CH: X n-propyl halide ined (1). But when HX is H3C - CH=CH? + HX! HyC- ues x {go-propy! halide Frick ne, tn avonot Xt lenin cnasrmnsia SGINETNO. Markownikoft’s eee tiers! HX ar ofthe nen aac 0 carbon of the bond which bears least number of hydrogen ‘roms. In the above case isopropyl halide the main product. Scanned with CamScanner‘Scanned with CamScanner4.34 Engineering Chemistry Mechantem The mechanism of addition of HX to olefin is quiet similar With that of halogen i Addit: ion Example: Addition of HBr to propene various steps involved in the mechanism a, Step I: HBr molecule approaches the x elec IeNt takes place due to the greater clectro negativity of bromine than that Of hydroge, Pla tron cloud of the olefin pettnane 5 HBr H+ Br As a result, the +8 of hydrogen atom of Bromine atom, thus forms a x-complex. The r If the olefin in question is unsymmetrical, two carbonium ions are stable carbonium in predominates. ‘bromide ion. ‘Step II: The second step consists of rapid combination of more stable Carbonium a it f HBr reaches closer to the x electron -complex is then conve into carbone, Onin, formed ang the Mi hy 8 8 H-Br H3C—CH=CH) + HBr —__» HyC—CH=CH, complex lod S 8 H3C-CH,-CHy H3C—CH—cu, Mprimary) _2°(secondary) H3C-CHp-CHy-Br rere H3C—CH—cy, (less stable) (more stable) z The predominance of stable secondary carbonium ; ominance lum ion and hence the format isoroyi rea is strongest evidence to Markwonikof's nie. Thea be further suppored won on unsymmetrical olefin onthe bai of et CH; CH; HC C=CHy ce oy iso butane ! . I ‘thas been observed: eee Gui observed ta, an (ort ropen, in presence of right (or) peoxie ernie yields diferent produ “ts stats 28° Adds to the olefin ining sence of ‘Scanned with CamScannerisms, and Synthesis of rug Molecules 4.85 f cjoreochomisty, Reaction Mech a nis yee are relatively unstable compounds: ‘They undergo thermal (or) photo chemical dissociation to produce alkoxy rad al ie s al produce alkoxy radic Ro. The radical then attacks HBr to form Br radical. Peroxides are the initiators of free radicals. Initiation homolysis * ———> 2R0 alkoxy ideal RO+HBr ROH +Br ‘The peroxy compound undergo homolysis to from alkoxy radical. It reacts with HBr to give bromine radical. R—O—O—R Propagation: 2, The Brattacks the olefin to form the more stable bromo alkyl free radical R—CH—CH)—Br 2° (more stable) Br+R—-CH=CH; R—CH—CH2 Me 1° (less stable) 3. The free, radical reacts with more HBr to form anti-Markownikoff’s product and another Br can further propagate the reaction. R—CH—CH,Br+ HBr — RCH, CH, Br+Br Termination It occurs by the combination of bromine radicals with themselves (or) with alkyl radicals by coupling (or) by di ionation of alkyl radicals. Br+Br— Br, R+R——>R-R of HBr, the free radical addition of HI and HCL 1o olefins In contrast to the addition normally does not takes place. . , This can be explained vo he basis of energy changesasociated with the propagating steps of the radical chain. eS nc, © As oe oe x-cl a : i AE =~26k-cals e X=Br AE=—Sk-cals ‘Scanned with CamScanner4.36 Engineering Chemistry wes eri ot eer oC X-CH,: CH, +HX ——> XH,C—CH, +X () sia X=Cl AE=+5k-cals X= Br, AE =-11 k-cals In the case of HCl, the first step is exothermic hence addition takes place easily. Wh; the second step is endothermic, the al is unable to decompose HCl. Hence, Polymerization, begins to compete with simple addition. For addition of HBr, both the steps are exothermic, and, addition occurs rapidly, For HF, second step is endothermic. For HI, first step of propagation is endothermic. Thus, HI does not add to an olefin by free radical mechanism. Organometallic Compounds Organometallic reagents contain a carbon atom bonded to a metal a R= Organic compound Polar bond M=Metal Most commonly used metals in organometallic compounds are lithium, magnesium and copper. Other metals ~ Si, Sn, TI, Al, Ti and Hg are also known. R — can be alkyl, aryl, benzyl, groups. ‘R’ groups are Sp? hybridised and the metal M (Li or Mg) ‘sp’ hybridised. Because metals are more electropositive than carbon, they donate electron density towards carbon, so that carbon bears partial (8) negative charge and metal bears (8°) parti iti charge. Scanned with CamScannerermic. endothermic. Thus, HI does not add to an o} ise junds contain a carbon atom bont Organometallic Compo ded to a metal Reh oM 2M \ R= Organic compound M= Metal \ —C | Polar bond in organometallic compounds are li pin. Magnesium ayq i, Iso known. R — can be alkyl, ary} tals — Si, Sn, T! , Ti and Hg are al ; kyl, ary pet eae ci soups ae Sp? hybridised and the metal M (Li or Mg) ‘sp’ hybis Because metals are more electropositive than carbon, they donate electron, den: towers carbon, so that carbon bears partial (5) negative charge and metal bears (5°) parti I posit charge. Most commonly used metals it Example: I i R-Mg—X RCo Organo Lithium Organo magnesium: Organo lithium reagent cuprate or Grignard reagent The more polar the carbon — metal bond, the more reactive the organometallic reagent. 4.12 Grignard Reagents STA SR A TES Since Mg is very electropositive, organo magnesium reagents (RMgx) contain polar carbon ~ metal bonds and therefore very reactive reagents. Organo magnesium reagents are called Grignard reagents after victor Grignard who recei oat these reagents, ee eived noble prize in chemistry for his work on Scanned with CamScannerpreparation BE aed ts are typically prepared - etal i a peat of dry ether. by reaction of an alkyl halide with the corresponding R—X+Mg— ther Rote H3C—Br + Mg—(Gi#.0 SR ~ H3C—Mg—Br Methyl magnesium 4 bromide E Grignard reagents are usually prepared in the presence of diethyl ether as solvent. It is ght that, the two oxygen atoms of ethers form complex with magnesium atom, there by silising the reagent. Cr Calls Scanned with CamScannera0 © enepnaering COA. ra Wy ry Wie ROW plhonide 4 W iy ane ; eH # y gh + Rn Me ugh alkoxide bY 1,0 and forms an alcobol addition prodicy 11) Provonation of net ase cin forms anew O H bor is ©) O- , eo tn, p-c—H + OW r-C-H —@ pr Protonation RY (or) Re cHOH 2° alcohol + When Grignard reagent is added to formaldehyde. HCHO, primary alcohol is for gf on fa wt ere ye si HO, yp | Hq Me [| new C—C bond ae RMX (or) R—CH,0H 1° alcohol + with other aldehydes, it forms 2° alcohols + with ketones, Grignard reagent forms 3° alcohol A a oH epow RY-Mex R |} new C—C bond (or) R;C—OH 3° alcohol ‘Scanned with CamScanner(or) Ces — CH CHy 2° al D5, Reaction with aci eee forms t-alcohol ° new C—C bond I HC - CH:MgCl 1,0 ee) sects wel Lo mone Cl cho Cc new C—Chond a Reaction with ester it forms tertiary alcohol 0 OH HAC : cout biti, 1:0 ec