Organic Chemistry CHM113M Course Lecture 4 PDF

Organic Chemistry CHM113M Course (Lect. 4) Sem I (2024-25) Instructor: Dr. V. S. Mothika Department of Chemistry IIT Kanpur 1 Chirality without a chiral center Molecules can be chiral without having chiral centers for example when a...

Organic Chemistry CHM113M Course (Lect. 4) Sem I (2024-25) Instructor: Dr. V. S. Mothika Department of Chemistry IIT Kanpur 1 Chirality without a chiral center Molecules can be chiral without having chiral centers for example when a compound has a "screw- like" structure due to restricted rotation caused by connecting bonds or spatial steric crowding They are chiral about an axis and contain two non-superimposable mirror images. This termed as Axial chirality Allenes Spiro compounds Biphenyl compounds Helicenes 2 Axially chiral systems does not need stereocenter Allene Helical (-)-Panacene (biologically active) Vancomycin (Antibiotic) Biphenyl Helical Nanographenes (Electronics) Spiro Zebofloxacin (Antibiotic) 3 Atropisomerism and biphenyls Atropisomerism: It occurs when a molecule experiences a high enough steric strain that creates a barrier between substituents, which prevents pivotal bond rotation and forms different isomers of the compound. Biphenyls dynamically convert between two isomers via a high energy Achiral transition state (TS) Atropisomers are physically separable by chiral HPLC if they have sufficiently high racemization energy and half-life >16.7 min at room temperature. Repulsive interactions Twist angle, θ = 0/180/360° ΔG‡ = 3 kcal/mol High steric strain Good π-conjugation Twist angle At Twist angle θ = 45/135/225/315° θ = 90° Low steric strain No steric strain Good π-conjugation Poor π-conjugation 4 Axially chiral systems does not need stereocenter The TS is achiral due to presence of symmetry. The central bond about which rotation occurs is also called pivotal bond. Maximum steric strain is observed in TS1 and is of highest energy Unlike biphenyl, here the twist angle where the minima is observed is slightly greater than 45° High steric repulsion TS1 TS1 TS2 ΔG‡ = ΔG‡ = 8-10 19-20 kcal/mol kcal/mol (S)- (R)- Isomer Isomer Rotate right Turn molecule hand ring by by 180° 180° around C-C bond 5 Nomenclature system Step 1: Identify the viewing direction. Step2: rank the two substituents on each phenyl ring in the order of priority. Step 3: Look from the side of flat structure along the pivotal bond axis and draw the projection in line form with front ring with thick line and back ring with a circle. Place the substituents on either side as you would see. Identify the movement from the highest priority substitution on the front carbon to the highest priority substitution on the back carbon. If clockwise, configuration is denoted as “R-enantiomer” and if anticlockwise, configuration is “S- enantiomer”. 1 1 Me Me 4 3 H Me Me H4 3 H 2 H Me > H 2 Anticlockwise clockwise (S)-isomer (R)-isomer 6 Nomenclature system Binaphthyls also show atropisomerism. For R/S-configuration similar rules can be applied 2 Ph 4 Ph PPh2 3 PPh2 1 Clockwise BINAP (R)-isomer 1 PPh2 4 Ph PPh2 3 Ph 2 Anticlockwise (S)-isomer 3D models 7 BINAP = 2,2′-Bis(diphenylphosphino)-1,1′- binaphthyl Allenes structure and bonding Allenes are compounds which have two cumulative double bonds (two double bonds adjacent to each other). The terminal carbon atoms are sp2 hybridized while the central carbon atom is sp hybridized. The bonding dictates that the two p-bonds be in perpendicular planes. Blue are σ-bonds Green are π-bonds 8 Chirality in allenes If the two substituents on the terminal carbon atoms are distinct, then the allene is chiral. Plane of symmetry Achiral No plane of symmetry Chiral 9 R, S-Configuration of allenes The “R” and “S” nomenclature applies to allenes as well. A similar method used for naming biaryls can be followed to identify the stereochemical configuration of allenes 1 1 Me Me 3 4 Me H H Me 3 4 H H 2 2 clockwise Anticlockwise (R)-isomer (S)-isomer 10 R, S-Configuration of spiro systems The “R” and “S” nomenclature applies to spiro compounds as well. Here spiro carbon is tetrahedral, depending on viewing direction 1st and 2nd priority is given to both sides of spiro center and then the 3rd and 4th priority order is assigned. 1 4 3 2 2 (S) 3 1 4 4 3 2 1 (S) 2 1 3 4 Clockwise AntiClockwise (R)-isomer (S)-isomer (S) 11 R, S-Configuration of helicenes The “R” and “S” nomenclature applies to helicenes as well. Step 1 - identify the axis of the helix. Step 2 - look along the axis. If the molecule rotates clockwise as you move from the front to the rear (away from viewer), the descriptor is P or plus. If the molecule rotates anticlockwise direction, it is M or minus. 12 Nucleophilic Substitution Reactions 13 Alkyl halides Tetrahedral ‘C’ ; sp3 hybridized C-X bond is polarized and result partial positive charge on C and negative charge on ‘X’ (X = halogen here). This results in intermolecular dipole-dipole attractions and high boiling point to alkyl halides if compared to alkanes. *ESP map 14 *ESP is electrostatic potential surface; red surface indicates high e− density region Polarity of Alkyl halide bonds Increase in C-X bond length 1.39 Å 2.14 Å 110 57 Kcal/mol Decrease in C-X bond strength Kcal/mol 15 How alkyl halides react Halogen (X) is more electronegative than carbon and the bonded electrons are not shared equally but polarized towards halogen Nu− is nucleophile, X− is leaving group and ‘C’ is electrophilic center Path 1: (SN2) Path 2: (SN1) 16 Bimolecular Nu− substitution reaction: SN2 SN2 reaction, where “S” stands for substitution, “N” for nucleophilic, and “2” for bimolecular. Bimolecular means that two molecules are involved in the rate-determining step. SN2 reaction is a concerted reaction—it takes place in a single step. No intermediates are formed. The nucleophile (OH− here) attacks the carbon bearing the leaving group (Br− here) and displaces the leaving group. Rate ∝ [alkyl halide][nucleophile] Energy (kJ/mol) 17 Stereoelectronics of SN2 The configuration of that product is inverted relative to the configuration of the alkyl halide. Only one product formed since SN2 is concerted reaction LUMO of CH3Br Configuration is inverted 18 Why rear attack preference Back-side attack involves a bonding interaction between the Nu− and the larger lobe of σ* when the nucleophile approaches the front side of the carbon: Both a bonding and an antibonding interaction occur, and the two cancel each other. 19 Factors affecting SN2: Sterics at electrophilic ‘C’ Accessibility of electrophilic ‘C’ center by Nu and reaction rate 20 Effects of sterics at electrophilic ‘C’ center Reaction coordinate diagrams for (a) the reaction of methyl bromide with hydroxide ion; (b) an reaction of a sterically hindered alkyl bromide with hydroxide ion. Transition state energy increases with increase in the steric bulk at the electron carbon center Single step (via formation of transition state) Bonds broken and formed simultaneously 21 The Nucleophile Basicity is a measure of affinity towards proton (equilibrium process)—thermodynamic property Nucleophilicity is a measure of reactivity towards an electrophilic carbon (kinetic property) (irreversible process and measured by rate of reaction) In protic solvents, larger ions with diffused electron density are less solvated and also their HOMO can interact better with LUMO of ‘C’ at larger distances such as TS. Nucleophilicity increases from top to down in porotic solvents Nucleophilicity decreases with steric bulk 22 The Nucleophile Basicity broadly parallels nucleophilicity Less stable anions are stronger Nu− than more stable anions R-O− > RCOO− (Alkoxide) (carboxylate) Nucleophilicity decreases from left to right due to increases in electronegativity of Nu− center Conjugate base is stronger Nu− due to increased electron density on Nucleophilic center 23 Leaving group ability and basicity The weaker the basicity of a group, the better is its leaving ability. Weak bases don’t share their electrons well, a weak base is not bonded as strongly to the carbon as a strong base 24 Good leaving group stabilizes the negative charge A leaving group that can stabilize negative charge better will be a better leaving group. Charge delocalization is an important indicator of relative stability Good leaving groups 1/2 1/2 p-toluenesulfonate anion stable due (OTs) to resonance 25 Converting a bad LG to good LG 26 Polar protic solvent Protic solvent (e.g., CH3OH, H2O) stabilizes the initial state thus, Nu− itself over TS thus the reaction slows down. On the other hand, protic solvent stabilizes more polar TS if neutral nucleophile is used thus speeding up the reaction. (a) (b) 27 Polar protic solvent hinders SN2 reactivity Protic solvents: Protic solvents (e.g., CH3OH, H2O) are hydrogen bond donors. They solvate and shields the Nucleophile through ion-dipole interactions. Weak bases interact weakly with protic solvents, whereas strong bases interact more strongly because they are better at sharing their electrons. Fluoride ion would be a better nucleophile in a nonpolar solvent than in a polar solvent 28 Polar aprotic solvent good for SN2 reaction Aprotic polar solvents (DMSO, DMF) does not have a hydrogen attached to an oxygen or to a nitrogen. The molecules of an aprotic polar solvent have a partial negative charge on their surface that can solvate cations leaving Nu− behind. Fluoride ion, therefore, is a better nucleophile in DMSO than it is in water. 29 Influence of solvent on SN2 reaction Aprotic solvents raise the energy of Nu− which results in lower Ea and a faster SN2 reaction 30 Unimolecular Nu− substitution reaction: SN1 The SN1 reaction is a unimolecular nucleophilic substitution. It has a carbocation intermediate. Rate = kr[alkyl halide] i.e. doubling alkyl halide concentration doubles rate If precursor is enantiopure, racemic mixture of products obtained Racemic mixture forms. (S) (S) (R) 31 Energetics of SN1 reaction Two transition states (TS) formed: TS1 with Leaving group and TS2 with incoming Nu The lower energy of TS2 over TS1 favors the reaction forward. 32 Stable carbocation formation favors SN1 Alkylhalides that forms stable carbocation reacts faster Stability of carbocation increases with increasing methyl substitution 33 Stability of Carbocations Electron sharing between C-H sigma bond and vacant p-orbital of positively charged ‘C’ stabilizes carbocation No Hyperconjugation in CH3+ Hyperconjugation and Electron pumping into vacant p-orbital of 3° carbocation 34 Stability of Carbocations Electronic effects such as inductive effect, conjugation stabilizes the carbocation 35 Stability of allyl and benzyl carbocations sp2 carbon attached carbocations stabilize by resonance Allyl carbocation: Resonance hybrid HOMO of allyl cation Benzyl carbocation: 36 Aromaticity and Dancing resonance Aromatization stabilizes carbocation Conjugation between bent orbital of cyclopropyl ring and vacant p-orbital of carbocation This is called dancing Resonance Stability increases with addition of each cyclopropyl group 37 Hydride shift in Carbocations Hydride shifts are very fast (faster than SN1) which is partially due to hyperconjugation in the carbocation weakening the C-H bond) More stable 38 Hydride shift in Carbocations 1,2-Hydride shift occurs in SN1 reactions to form more stable carbocation. Below is the hydride shift in SN1 reaction of alkyl halide with H2O 39 Neighbouring group participation Groups remote from a reaction centre can participate in substitution reactions – Neighboring Group Participation (NGP) (or anchimeric assistance): lone pairs of electrons, typically on N, O, S or Hal atoms interact with electron deficient/cationic centres NGP is characterized by reaction rate acceleration SN2 reaction (Inversion) Relative rate 1 Relative rate 600 Double 2-chloroethyl SN2 reaction phenyl sulfide (Retention) 40 Neighbouring group participation SN2 results in inversion in configuration Retention in stereochemical configuration in NGP assisted SN2 is due to double inversion So NGP can manifest stereochemical outcome of the reaction α-Amino acid Overall Retention of stereochemistry α-hydroxy acid 41 Nucleophilic substitution internal (SNi) reaction SNi reactions results in retention of configuration Chlorination of alcohol by SNi is mediated through an tightly held intimate ion pair formation Unlike SN1, no actual carbocation generated rather it is an ion pair (otherwise we get racemized product as like SN1). Rate of SNi = k[ROH][SOCl2] if the alcohol is chiral then this results in retention of configuration (Retention) 42 END 43