Organic Synthesis - Chemistry
Organic Synthesis1
Organic Synthesis Series of reactions by which a set of organic starting materials is convertedto a more complicated structure A successful synthesis: Provides the desired product in maximum yield with a maximum control ofstereochemistry at all stages Should not produce or release byproducts harmful to the environment (“green”synthesis) Best strategy is to work backward from the target product2
Retrosynthetic Analysis: Analysis of Target Molecule1. Count the carbon atoms of the carbon skeleton of the target molecule Challenge - Determining how to build the carbon skeleton from available startingmaterials Only method to date for forming a new C—C bond is the alkylation of acetylide anionswith methyl or 1 halides2. Analyze the functional groups What are they, how can they be changed to facilitate formation of carbon skeleton,and how can they then be used in forming the final set of functional groups in thetarget molecule?3. Work backward Use retrosynthesis Retrosynthesis: A process of reasoning backward from a target molecule to aset of suitable starting materials An open arrow to symbolize a step in a retrosynthesistargetmoleculestartingmaterials3
Organic Synthesis of 2-Heptanone Analysis Synthesis4
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Reactions of Functional Groups in Complex Molecules Synthesis of fexofenadine illustrates twoimportant points about how functionalgroup analysis is used to developsystematic syntheses of complexmolecules Alkyne was the only functionalgroup to react under theconditions used, and it reacted asexpected Other functional groups oftenhave an influence over theregiochemistry or stereochemistryof a reaction9
Sample Synthesis Problem (from old exam) You should be able to find at least three completely different synthetic routes for the following problem!Show all reagents and intermediates for the multi-step synthesis below. You may use any organicor inorganic reagents in your synthesis, but you must begin with the indicated starting material.You do not need to show any mechanisms. The correct answer will require fewer than 5 steps. Starting material10
Organic Synthesis Using Alkynes Provide a synthetic route to the following product from starting materials that contain nomore than 2 carbons:11
Example An acid-catalyzed domino reaction that ultimately leads to the synthesis ofprogesterone is depicted in the image12
We focus on the acid-catalyzed stepthat leads to cyclization of the fourring system, which is characteristicof steroids Assume that this reaction is initiatedby protonation of the 3 alcoholfollowed by loss of water to give acarbocation The series of reactions initiatedby this carbocation givescompound BTandem reactions, cascade sequencesJohnson’s elegant cation-π cyclization13
Solvents in Organic Chemistry The vast majority of organic reactions are carried out in a solvent, a liquidthat is used to dissolve the reactants, reagents, and products. Eachsolvent can be characterized based on three properties: whether it ispolar, whether it is protic, and whether it is a donor: polar or nonpolar:polar - dielectric constant greater than 15nonpolar - dielectric constant less than 15 protic or aprotic:protic - solvent acts as hydrogen bond donoraprotic - solvent cannot act as hydrogen bond donor donor or nondonor:donor - solvent can share (donate) lone pairnondonor - solvent cannot share (donate) lone pair14
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Haloalkanes, Halogenation, and RadicalReactions16
Structure of Halides17
Haloalkane, Haloalkene, and Haloarene Haloalkane (alkyl halide): Contains a halogen atom covalently bonded toan sp3 hybridized carbon General symbol - R—X Haloalkene (vinylic halide): Contains a halogen atom bonded to one ofthe carbons of a carbon-carbon double bond Haloarene (aryl halide): Contains a halogen atom bonded to a benzenering General symbol - Ar—X18
Alkyl Halides, Alcohols19
Nomenclature — Halides20
HalidesAlcohols/ThiolsEthers/SulfidesEpoxides21
Nomenclature - common name and IUPAC System Haloalkanes Treated as an alkyl group; fluoro-, chloro-, bromo-, and iodo- and list them inalphabetical order with other substituents Haloalkenes Number the parent chain to give carbon atoms of the double bond and substituentsthe lower set of numbersIUPAC nameCommon name22
Common Names of Haloalkanes and Haloalkenes Haloform: Compound of the type CHX3 where X is a halogenCH2Cl2CHCl3CH3CCl3CCl2 CHClDicholormethane(Methylene roethane(Methyl chloroform)Trichloroethylene(Trochlor) Perhaloalkanes or perhaloalkenes - Hydrocarbons in which all hydrogensare replaced by halogens23
Test Yourself Write the IUPAC name and, where possible, the common name of eachcompound Show stereochemistry where relevant24
Test Yourself What is the IUPAC name of the following ethyl-isoheptane25
Physical Properties — Halides26
Polarity of Haloalkanes Magnitude of a dipole moment depends on: Size of the partial charges Distance between the partial charges Polarizability of the unshared electrons pairs on each halogenδ δC X27
Haloalkanes - Boiling Point Haloalkanes are associated in the liquid state by van der Waals forces van der Waals forces: Group of intermolecular attractive forces As molecules are brought closer and closer, van der Waals attractive forces areovercome by repulsive forces between electron clouds of adjacent atoms Energy minimum - Point where attractive and repulsive forces are balanced Nonbonded interatomic and intermolecular distances at minima can be measuredby x-ray crystallography, and each atom and group of atoms can be assigned avan der Waals radius van der Waals radius: Minimum distance of approach to an atom that doesnot cause nonbonded interaction strain28
Haloalkanes - Trends in Boiling Points Constitutional isomers with branched chains have lower boiling pointsthan their unbranched-chain isomers Have a more spherical shape and decreased surface area, leading tosmaller van der Waals forces between their moleculesBr1-Bromobutanebp 100 CBr2-Bromo-2-methylpropanebp 72 CCH 3 CH 3bp -89 CCH3 Brbp 4 C For an alkane and a haloalkane of comparable size and shape, thehaloalkane has a higher boiling point Polarizability: Measure of the ease of distortion of the distribution of electrondensity about an atom in response to interaction with other molecules and ions Fluorine has a very low polarizability, whereas iodine has a very high polarizability Larger the halogen, the greater its polarizability29
Boiling points of fluoroalkanes are comparable to those ofhydrocarbons of similar molecular weight and shapeCH 3CH3 CHCH32-MethylpropaneMW 58.1, bp -1 CFCH3 CHCH32-FluoropropaneMW 62.1, bp -11 CFHexane(MW 86.2, bp 69 C)1-Fluoropentane(MW 90.1, bp 63 C) Low boiling points of fluoroalkanes are the result of the small size offluorine, the tightness with which its electrons are held, and theirparticularly low polarizability30
Haloalkanes - Density Liquid haloalkanes are more dense than hydrocarbons of comparablemolecular weight A halogen has a greater mass-to-volume ratio than a methyl or methylene group All liquid bromoalkanes and iodoalkanes are more dense than water Liquid chloroalkanes are less dense than water Substitution of chlorine for hydrogen increases the density of di- andpolychloroalkanes in comparison to water31
Density of Polyhalomethanes32
Haloalkanes - Bond Lengths and Strengths Bond dissociation enthalpy - Measure of bond strength Amount of energy required to break a bond homolytically into two radicals in the gasphase at 25 C Radical (free radical): Any chemical species that contains one or more unpairedelectrons Homolytic bond cleavage: Cleavage of a bond so that each fragment retains oneelectron, producing radicals Heterolytic bond cleavage: Cleavage of a bond so that one fragment retains bothelectrons and the other has none Fishhook arrows are used to indicate: Change in position of single electrons Homolytic mechanism As the size of the halogen atomincreases, the C—X bond lengthincreases and its strength decreases C—F bonds are stronger thanC—H bonds C—Cl, C—Br, and C—I bonds areweaker than C—H bonds33
Test Yourself Dipole moments of CH3—X are 1.85, 1.87, 1.81, and 1.62 D for F,Cl, Br, and I, respectively What is the best explanation of the small differences in dipole moments?1. The electronegativity of halogens in alkyl halides is nearly constant2. The inductive effects are counterbalanced by hyperconjugation3. The electronegativity effects are counterbalanced by bond strengths4. Lone-electron pairs are more delocalized on smaller halogens5. The charge-separation and bond-lengths trends have opposite effects34
Preparation of Haloalkanes by Halogenationof Alkanes35
Halogenation of Alkanes Haloalkanes can be prepared by: Addition of HX and X2 to alkenes Replacement of the —OH group ofalcohols by halogen Simpler low-molecular-weight haloalkanesare prepared by the halogenation ofalkanes by Cl2 or Br2 If a mixture of methane and chlorine is keptin the dark at room temperature, nochange occurs If the mixture is heated or exposed to visibleor ultraviolet light, reaction begins at oncewith the evolution of heat This is a substitution reaction Substitution reaction: An atom or groupof atoms is replaced by another atom orgroup of atoms36
If chloromethane is allowed to react with more chlorine, a mixture ofchloromethanes is formed37
Regioselectivity High for bromination, but not as high for chlorinationTakes the order of 3 2 1 Approximately 1600:80:1 per hydrogen for brominationApproximately 5:4:1 for chlorination38
Exercise - Free-Radical Halogenation Name and draw structural formulas for all monobromination productsformed by treating 2-methylpropane with Br2 Predict the major product based on the regioselectivity of the reaction of Br2 withalkanes39
Mechanism of Halogenation of Alkanes40
Energetics Heat of any reaction (enthalpy change) can be calculated by comparingthe bond strengths in the reactants and productsDH 0 SBDEs(broken) - SBDEs(formed)CH 4 Cl2 CH 3Cl HClBDE, kJ/mol 439 247DH 0 - 96 kJ/mol ( - 23 kcal/mol)- 351 - 431 Bond Dissociation Enthalpies for Selected C—H Bonds41
Formation of Radicals - Examples Following reactions result in homolytic cleavage to give radicals42
Radical Chain Mechanism - Steps Chain initiation: Chain propagation: Chain length:43
Chain termination: Involves destruction of reactive intermediates44
Energetics of Chain Propagation Steps After the radical chain is initiated, the heat of reaction is derived entirelyfrom the heat of reaction of the individual chain propagation steps Sum of the heats of reaction for each propagation step is equal to theobserved heat of reaction45
Example - Enthalpy of Reactions Using the bond dissociation enthalpies, calculate ΔH0 for each propagationstep in the radical bromination of propane to give 2-bromopropane andHBr Here are the two chain propagation steps along with bond dissociationenthalpies for the bonds broken and the bonds formed The first chain propagation step is endothermic, the second is exothermic, and theoverall reaction is exothermic by 71 kJ (17 kcal)/mol46
Test Yourself Which of the following radicals is expected to be the least selective?1.2.3.4.5.HO F Cl Br I 47
Regioselectivity of Bromination vs Chlorination Regioselectivity in halogenation of alkanes caused by the relativestabilities of radicals (3 2 1 methyl) More stable radical products are formed with a lower activation energy To account for the greater regioselectivity of bromination (1600:80:1)compared with chlorination (5:4:1), Hammond’s postulate should beconsidered. Structure of the transition state is: More similar to the structure of reactants or products depends on the energy Provides a reasonable way of deducing something about the structure of atransition state by examining the structure of reactants and products andheats of reaction Applies equally well to the transition state for one-step reactions and toeach transition state in a multistep reaction48
Hammond’s Postulate49
Enthalpies of Reaction for Hydrogen Abstraction in2-Methylpropane50
Hammond’s Postulate - Relative Regioselectivities ofChlorination vs Bromination of Alkanes Abstraction of hydrogen by chlorine is exothermic Transition state is reached early in the course of the reaction, and itsstructure resembles the alkane and the chlorine atom There is little radical character on carbon in the transition state Regioselectivity is only slightly influenced by the relative stabilities ofradical intermediates Products are determined by whether a chlorine atom happens to collidewith a 1 , 2 , or 3 H Abstraction of hydrogen by bromine is endothermic There is significant radical character on carbon in the transition state Reasons for larger regioselectivity Later transition state and correspondingly larger difference in activation energies(ΔΔG‡) that causes a large difference in reaction rates51
Transition States and Energetics for Hydrogen Abstraction in theRadical Chlorination and Bromination of 2-Methylpropane (Isobutane)52
Stereochemistry of Radical Halogenation When radical halogenation produces a chiral center or takes place at ahydrogen on a chiral center, the product is an racemic mixture of R and Senantiomers In the case of sec-butyl radical, the carbon bearing the unpaired electron is sp2hybridized and the unpaired electron occupies the unhybridized 2p orbital53
Radical Bromination of Butane54
Test Yourself How many constitutional monochloride isomers will form in the radicalchain chlorination of 2,3-dimethylpentane?1.2.3.4.5.3456755
Test Yourself The selectivity of chlorine radical is 1.0:3.5:5.0 for 1 , 2 , and 3 hydrogens, respectively If only monochlorides form in the radical chlorination of 1,3dimethylcyclobutane, what is the expected yield of the tertiary chloride?1.2.3.4.5.1/61/51/41/31/256
Test Yourself Radical chain chlorination of (2R)-fluorobutane yields 2-chloro-3fluorobutane as one of the products Which is the best accounting for the stereochemistry of this product?1.2.3.4.5.Two enantiomers in equal amountsTwo diastereomers in different amountsTwo diastereomers in equal amountsFour stereoisomers in different amount eachFour stereoisomers with enantiomeric pairs in equal amounts butdiastereomeric pairs in unequal amounts57
Test Yourself Which mechanistic step decides the regiochemistry of the radical-chainchlorination of 2-methylpropane?1. Protonation step2. Hydrogen abstraction step3. Chlorine abstraction step4. Chloride addition step5. Initiation step58
Test Yourself The reaction shown below produces 5 different bromides Which of the compounds listed is one of the expected products?NBSCCl459
Allylic Halogenation60
Allylic Halogenation Allylic carbon: Carbon adjacent to a C-C double bond Allylic substitution: substitution at an allylic carbon When propene and a halogen are allowed to react at a hightemperature, substitution of a halogen occurs at the allylic C An allylic C—H bond is weaker than a vinylic C—H bond61
Allylic Halogenation - Radical Reaction It is possible to change the product(s) by changing the mechanism througha change in reaction conditions Under high temperatures, concentration of bromine radicals becomesmuch higher than at room temperature Accelerates the substitution reaction, which occurs by the radical halogenationmechanism62
Allylic Bromination Can be executed in the laboratory at or slightly above room temperatureby using the reagent N-bromosuccinimide (NBS) in dichloromethane63
Allylic Bromination of Propene Using NBS A radical chain mechanism Chain initiation Chain propagation64
Chain termination The Br2 necessary for chain propagation is formed by reaction of NBSand HBr65
Allyl Radical Hybrid of two equivalent contributing structures Position of the radical electron in the two contributing structures predicts that radicalreactivity will occur at carbons 1 and 3 but not at carbon 266
Molecular Orbital Model of Covalent Bonding in the Allyl Radical Combination of three 2p orbitals gives three p molecular orbitals67
Example - Allylic Bromination Account for the fact that allylic bromination of 1-octene by NBS gives theseproducts Explain the results:68
Test Yourself Which of the following is not the product of a radical chain-reaction of 2pentene with NBS?69
Test Yourself What is the best reagent to carry out the transformation SOBr70
Test Yourself Which of the following molecules would not yield the desired organolithiumreagent when treated with Li in yl bromide4-Bromobutyl methyl etherCyclohexylbromide71
Radical Autoxidation72
Radical Autoxidation Autoxidation: Oxidation requiring oxygen, O2, and no other oxidizingagent Occurs by a radical chain mechanism Autoxidation of the hydrocarbon chains of polyunsaturated fatty acid esters Polyunsaturated fatty acid esters have chains of 16 or 18 carbons containing1,4-diene functional groups Radical abstraction of a doubly allylic hydrogen of a 1,4-diene forms aparticularly stable radical Doubly allylic C—H is weaker than an allylic C—H bond, which is in turnweaker than a corresponding alkane C—H bond73
Radical Autoxidation Begins when a radical initiator, X , abstracts a doubly allylic hydrogen toform a radical Radical is delocalized through resonance with both double bonds74
Radical Autoxidation The doubly allylic radical reacts with O2, a diradical, to form a peroxy radical The peroxy radical reacts with the CH2 of another 1,4-diene fatty acidester to give a new radical, R , and a hydroperoxide The new radical reacts again with oxygen, causing a radical chainreaction in which hundreds of molecules of fatty acid ester areoxidized for each initiator radical75
Radical Autoxidation Some autoxidation products degrade to short-chain aldehydes andcarboxylic acids with unpleasant “rancid” smells Some are toxic and/or carcinogenic Oils lacking the 1,4-diene structure are less easily oxidized Many natural and unnatural compounds are referred to as radical inhibitors Radical inhibitor: Compound that selectively reacts with radicals to remove themfrom a chain reaction and terminate the chain Example - PhenolHow to deal with the unwanted autoxidation?76
Naturally Occurring Antioxidant - Vitamin E Reacts preferentially with the initialperoxy radical to give a resonancestabilized phenoxy radical, which isless reactive and survives toscavenge another peroxy radical Resulting peroxide is relativelystable Known as α-tocopherol (a phenol)77
Example - Radical Autoxidation What products would you expect from the following reaction? Indicate the major one and specify stereochemistry if relevant78
Radical Addition of HBr to Alkenes79
Radical Addition of HBr to Alkenes Addition of HBr to alkenes gives either Markovnikov addition or nonMarkovnikov addition depending on reaction conditions Markovnikov addition occurs when radicals are absent Anti-Markovnikov addition occurs when peroxides or other sources of radicals arepresent80
Similarity in Polar and Radical Mechanisms Regiochemistry of each reaction is dominated by the reactions thatproceed through the most stable reactive intermediates Reactive intermediates in both cases are tertiary81
Example - Free-Radical Addition of HX to an Alkene Predict the product of the following reaction:82
Test Yourself What is the product of the following sequence of reactions?II2LiCuIpentaneetherether83
Problem A major use of the compound cumene is in the industrial preparation ofphenol and acetone in the two-step synthesis shown below Write a radical chain mechanism for the reaction of cumene and oxygen toproduce cumene hydroperoxide84
Alkyl Halides, Alcohols 19. Nomenclature — Halides 20. 21 Halides Alcohols/Thiols Ethers/Sulfides Epoxides. Nomenclature - common name and IUPAC System Haloalkanes Treated as an alkyl group; fluoro-, chloro-, bromo-, and iodo-and list them in alphabetical order with other substituents
Chemistry ORU CH 210 Organic Chemistry I CHE 211 1,3 Chemistry OSU-OKC CH 210 Organic Chemistry I CHEM 2055 1,3,5 Chemistry OU CH 210 Organic Chemistry I CHEM 3064 1 Chemistry RCC CH 210 Organic Chemistry I CHEM 2115 1,3,5 Chemistry RSC CH 210 Organic Chemistry I CHEM 2103 1,3 Chemistry RSC CH 210 Organic Chemistry I CHEM 2112 1,3
Organic Synthesis What are the Essentials in Synthesis? 5 Since organic synthesis is applied organic chemistry, to stand a realistic chance of succeeding in any synthesis, the student ought to have a good knowledge-base of organic chemistry in the following areas: Protecting group chemistry Asymmetric synthesis
Textbook Essentials of Organic Chemistry by Dewick The following textbooks are also available in the chemistry library on reserve: Organic Chemistry: A Short Course by Hart, Craine, Hart and Hadid Introduction to Organic Chemistry by Brown and Poon Fundamentals of Organic Chemistry by McMurry Essential Organic Chemistry by Bru
Advanced Organic Chemistry/ Organic Synthesis – CH 621 Ultrasound Assisted Organic Synthesis (Sonochemistry) Bela Torok Department of Chemistry
Synthetic Organic Chemistry and Synthetic Inorganic Chemistry. The term Organic Synthesis is often used –may be incorrectly in strict terms– to mean the same as Synthetic Organic Chemistry Chemistry creates its subject. This creative ability, similar to that of art, essentially distinguishes Chemistry among the natural sciences. Berthelot .
been developed in modern organic synthesis. The use of similar methods may open new possibilities of organic electrochemical synthesis, although a simple combination of a polar organic solvent and an ionic supporting electrolyte has been commonly used in conventional organic electro-chemistry. In modern organic synthesis, low temperatures and anhy-
In Press Advanced Inorganic Chemistry Gurdeep Raj 06 270 Chromatography B.K. Sharma 06 Organic Chemistry 302 Advanced Organic Chemistry Aditi Singhal 08 279 Organic Chemistry Natural Products - Vol. I O. P. Agarwal 09 280 Organic Chemistry Natural Products - Vol. II O. P. Agarwal 09 281 Organic Chemistry Reactions & Reagents O. P. Agarwal 10
Technical Terms ! Organic Synthesis-means the same as synthetic organic chemistry ! Total Synthesis: The chemical synthesis of a molecule from a relatively simpler starting materials ! Semisynthesis: the synthesis of
