Racemix mixture and resolution

Racemix mixture and resolutionMinggu ke-8Racemic ProductsIf optically inactive reagents combine to form a chiral molecule, a racemic mixture of enantiomers is formed.

Racemic MixtureRacemic mixture (d,l;): an equimolar mixture (50:50) of two enantiomersbecause a racemic mixture contains equal numbers of dextrorotatory and levorotatory molecules, its specific activity is zero.The mixture may have different b.p. and m.p. from the enantiomers!

33939393939

a sample that is optically inactive can beeither an achiral substance or a racemicmixtureOptical ActivitySome mixtures are neither optically pure (all one enantiomer) nor racemic (equal mixture of both enantiomers).

Optical purity:Ratio of the rotation of a mixture to the rotation of a pure enantiomer

o.p. = observed rotationx 100%rotation of pure enantiomerOptical ActivityExample: (-)-2-butanol has a specific rotation of - 13.5o while the specific rotation of (+)-2-butanol is +13.5o. Calculate the optical purity of a mixture containing (+) and (-)-2-butanol if the mixture has an observed rotation of 8.55o. Does the mixture contain more (+) or more (-)-2-butanol? o.p = -8.55o x 100% = 63.3% -13.5o Optical ActivityAnother method to express (or determine) the relative amounts of enantiomers present in a mixture is enantiomeric excess.Numerically identical to optical purity

e.e. = o.p. = excess of one over the other x 100% entire mixture

Optical ActivityExample: Calculate the e.e of a mixture containing 25% (+)-2-butanol and 75% (-)-2-butanol if the specific rotation of (+)-2-butanol is 13.5o.

Optical ActivityExample: Calculate the relative proportions of (+)-2-butanol and (-)-2-butanol required to give a specific rotation of +0.45o.o.p. = +0.45o x 100% = 3.3%+13.5o

So: d - l = 3.3 d + l = 100Add both equations: 2d = 103.3d = 51.65% = 52%l = 48.35% = 48%Enantiomeric excessWe can use the observed optical rotation to determine the relative amounts of R and S enantiomers in a mixture. The optical purity of a mixture is referred to as the enantiomeric excess (ee), with 100% ee referring to a pure enantiomer and 0% ee referring to a racemic mixtureEnantiomeric excess

The enantiomeric excess (ee) is given by:

[a]D(observed) [R] [S] [a]D (pure) [R] + [S]=Using 2-chloro-1-phenylethanol as an example, what would be the enantiomeric excess if the sample we made had an observed optical rotation of -35.-35/-50 = 0.70 = ([R] [S])/([R] + [S]) = (x-(1-x))/1 = 2x 1 = 0.70x = 0.85 Therefore, [R] = 85%, [S] = 15% and the ee = 70%Calculate % CompositionThe specific rotation of (S)-2-iodobutane is +15.90. Determine the % composition of a mixture of (R)- and (S)-2-iodobutane if the specific rotation of the mixture is -3.18.

Resolution of EnantiomersReact a racemic mixture with a chiral compound to form diastereomers, which can be separated.=>

Stereochemistry and Reactivity(Study of stereochemistry change)Minggu ke-9162Stereochemistry and ReactivityMost reactions of alkenes generate a chiral center

Alcohol is prepared as a racemic mixture Why?17Racemic Mixture FormsAddition of Hg(II) gives rise to two cationsAddition of water gives rise to both enantiomers

18Reactions with Chiral SubstratesReaction goes through chiral carbocationProvides some stereochemical preferenceDo not observe a 50:50 mixtureProducts are diastereomeric

19The Synthesis of Chiral MoleculesMost chemical reactions which produce chiral molecules produce them in racemic form20

General RuleReactions of chiral substrates with:An achiral reactant gives unequal amounts of diastereomersA chiral reactant gives a chiral product

Reactions of achiral substrates withAn achiral reactant gives an achiral product22ProchiralityA molecule that is achiral but that can become chiral by a single alteration is a prochiral molecule

24Prochiral Distinctions: FacesPlanar faces that can become tetrahedral are different from the top or bottomA center at the planar face at a carbon atom is designated re if the three groups in priority sequence are clockwise, and si if they are counterclockwise

Prochiral distinctions, paired atoms or groupsAn sp3 carbon with two groups that are the same is a prochirality centerThe two identical groups are distinguished by considering either and seeing if it was increased in priority in comparison with the otherIf the center becomes R the group is pro-R and pro-S if the center becomes S

Designationpro-R: replaced atom leads to R configuration

pro-S: replaced atom leads to S configuration27

Terminologies Associated with Stereochemistry pro-R-hydrogenpro-S-hydrogenEnantiotopic hydrogens have the same chemicalreactivity and cannot be distinguished by achiral agents,but they are not chemically equivalent toward chiral reagents

Diastereotopic atomA pair of like atoms (or group of atom) that are not symmetry- equivalent, where substitution of one by a different group (i.e. desymmetrization) leads to a diastereomer of molecule obtained by like substitution of the other atom (or group of atoms).Diastreotopic atoms = different reactivity, different electronic enviroment different NMR

Diastereotopic hydrogens do not have the same reactivity with achiral reagents

Diastereotopic hydrogens do not have the same reactivity with achiral reagentsBiological ChemistryMany biological reactions involve prochiral centers

Chiral centers are extremely important in biological processes and drug development32Biological ChemistryEnzymes yield a single enantiomerEnzymes are chiral and induce chirality33A regioselective reaction: preferential formation of oneconstitutional isomer

A stereoselective reaction: preferential formation of a stereoisomer

A stereospecific reaction: each stereoisomeric reactant produces a different stereoisomeric product or a different set of productsAll stereospecific reactions are stereoselectiveNot all stereoselective reactions are stereospecific

Many reactions convert achiral reactants to chiral products.If all of the components of the starting state (reactants, catalysts, solvents, etc.) are achiral, any chiral products that will be formed are racemic mixtures."Optically inactive starting materials can't give optically active products." In order for a substance to be optically active, it must be chiral and one enantiomer must be present in greater amounts than the other.362Addition ReactionsElectrophilic addition (alkenes group)Nucleophilic addition (carbonyl group)

38Figure Number:

Title: Table 5.2Stereochemistry of Alkene Addition Reactions

Caption:

Notes: Addition Reactions

Addition of HBr

Addition of HBr to a Chiral AlkeneChiral intermediate is not attacked equally from top and bottom because of steric reasons. Therefore, a mixture of product is formed in unequal amounts.Addition of HBr to a Chiral Alkene

Addition of Br2Cis

Racemic mixtureAchiral bromonium ion

Addition of Br2Trans

Symmetry plane, therefore mesoModels are superimposible

Addition of Br2

RegioselectivityIf Br2 is added to propene there is no regioselectivity issue.

If Br2 is added in the presence of excess alternative nucleophile, such as CH3OH, regioselectivity may become important.

46Regioselectivity - 2

Consider, again, the cyclic bromonium ion and the resonance structures.

Weaker bondMore positive chargeStronger bondExpect the nucleophile to attack here. Remember inversion occurs.47

Syn-addition

Reaction Involving KMnO4

Addition of Carbonyl groups

diastereotopiccenterCrams Rule:(empirical)

when carbonyl is flanked by the S and M groups, the preferred attack is on the side with the smallest substituent

enantiomersC(+)C(-)2R(+)C(+)R(+)C(-)R(+)diastereomersC(+)R(+)C(-)R(+)R(+)R(+)C(+)C(-)Strategy11

54

Approaches to Pure Enantiomers Few SamplesLarge ScaleMany SamplesSmall ScaleChromatographicResolution of Enantiomers

Non-polar molecules have no affinity for the polar nature of the silicate groups on silica gel and can be washed right through the column with a relatively non-polar solventPolar molecules can form non-covalent attachments to the silicate groups, but can be washed through the column later with a more polar solvent

Hydrogen bondingColumn ChromatographyChiral ChromatographyChiral Recognition: Ability of chiral stationary phase, CSP, to interact differently with each enantiomer to form transient-diastereomeric complexes; requires a minimum of 3 interactions through:

H-bonding- interactionsDipole stackingInclusion complexingSteric bulk

Five general types of CSPs used in chromatography:Polymer-based carbohydratesPirkle or brush-type phasesCyclodextrinsChirobiotic phases Protein-based

CSPBiphenyl derivative60

The silica gel is functionalized with a chiral substituent derived from amino acidsR-entantiomerWhen a racemic mixture of R and S enantiomers is passed through this chiral column, the R enantiomer has less affinity for the stationary phase and will elute before the S entaniomer, allowing for separation of the entantiomersChiral Column ChromatographyClassification of Chiral Stationary Phases (CSP)Polymer-based CarbohydratesChiral polysaccharide derivatives, i.e. amylose and cellulose, coated on a silica supportEnantiomers form H-bonds with carbamate links between side chains and polysaccharide backboneSteric restrictions at polysaccharide backbone may prevent access of one of enantiomers to H-bonding siteCan be used with normal phase HPLC, SFC, RP-HPLCLimitations: Not compatible with a wide range of solvents other than alcoholsAvailable columns:i.e. Chiralpak AD, AD-RH, AS, AS-RH, and Chiralcel OD, OD-RH, OJ, OJ-RH, etc. from Chiral Technologies, Inc.Chiralpak IA and IBsame chiral selectors as AD and OD, respectively, but these are immobilized on the silica; more robust and has much greater solvent compatibilities62Classification of Chiral Stationary Phases (CSP)Pirkle or Brush-type Phases: (Donor-Acceptor)Small chiral molecules bonded to silicaMore specific applications; strong 3-point interactions through 3 classes:-donor phases-acceptor phasesMixed donor-acceptor phasesBinding sites are -basic or -acidic aromatic rings (- interactions), acidic and basic sites (H-bonding), and steric interactionSeparation occurs through preferential binding of one enantiomer to CSPMostly used with normal phase HPLC, SFC. May get less resolution with RP-HPLC; compatible with a broad range of solventsLimitations: only works with aromatic compoundsAvailable columns:Whelk-O 1, Whelk-O 2, ULMO, DACH-DNB (mixed phases), -Burke 2, -Gem 1 (-acceptor phases), Naphthylleucine (-donor phases), from Regis Technologies, Inc.Phenomenex Chirex phases63Cyclodextrin CSPsAlpha, beta and gamma-cyclodextrins bond to silica and form chiral cavities3-point interactions by: Opening of cyclodextrin cavity contains hydroxyls for H-bonding with polar groups of analyte Hydrophobic portion of analyte fits into non-polar cavity (inclusion complexes)One enantiomer will be able to better fit in the cavity than the otherUsed in RP-HPLC and polar organic modeLimitations: analyte must have hydrophobic or aromatic group to fit into cavityClassification of Chiral Stationary Phases (CSP)Available columns:Cyclobond (-, -, and -cyclodextrins) from Astec, Inc.ORpak CDA (), ORpak CDB (), ORpak CDC () from JM Sciences64Classification of Chiral Stationary Phases (CSP)Chirobiotic PhasesMacrocyclic glycopeptides linked to silica Contain a large number of chiral centers together with cavities for analytes to enter and interactPotential interactions:- complexes, H-bonding, ionic interactionsInclusion complexation, steric interactions Capable of running in RP-HPLC, normal phase, polar organic, and polar ionic modesAvailable columns:Chirobiotic V and V2 (Vancomycin), Chirobiotic T and T2 (Teicoplanin), Chirobiotic R (Ristocetin A) from Astec65Protein-based CSPsNatural proteins bonded to a silica matrixProteins contain large numbers of chiral centers and interact strongly with small chiral analytes through:Hydrophobic and electrostatic interactions, H-bondingLimitations: Requires aqueous based conditions in RP-HPLC Analyte must have ionizable groups such as amine or acid. Not suited for preparative applications due to low sample capacityClassification of Chiral Stationary Phases (CSP)Available columns:Chiral AGP (-glycoprotein) from ChromTechHSA (human serum albumin) from ChromTechBSA (bovine serum albumin) from Regis Technologies66General use column with no solubility issues Polymer-based phases Specific applications; solubility issuesPirkle-typeChirobiotic phasesSFC onlyPolymer-based, Pirkle-type, ChirobioticBiological Samples Protein-based phases

Selecting a CSP67Relating Configurations through Reactions in which No Bonds to the Stereogenic Carbon are BrokenA reaction which takes place in a way that no bonds to the stereogenic carbon are broken is said to proceed with retention of configurationIdentification of enantiomer structures

Relative configuration: the relationship between comparable stereogenic centers in two different molecules(R)-1-Bromo-2-butanol and (S)-2-butanol have the same relative configuration

Absolute configuration: the actual 3-dimensional orientation of the atoms in a chiral moleculeCan be determined by x-ray crystallography Reactions of Nucleophilic Substitutions and EliminationsMinggu ke-11 & 1272Alkyl Halides React with Nucleophiles and BasesAlkyl halides are polarized at the carbon-halide bond, making the carbon electrophilicNucleophiles will replace the halide in C-X bonds of many alkyl halides(reaction as Lewis base)Nucleophiles that are also Brnsted bases can produce elimination

73The Discovery of the Walden InversionIn 1896, Walden showed that (-)-malic acid could be converted to (+)-malic acid by a series of chemical steps with achiral reagentsThis established that optical rotation was directly related to chirality and that it changes with chemical alterationReaction of (-)-malic acid with PCl5 gives (+)-chlorosuccinic acidFurther reaction with wet silver oxide gives (+)-malic acidThe reaction series starting with (+) malic acid gives (-) acid74Reactions of the Walden Inversion

75Significance of the Walden InversionThe reactions alter the configuration at the chirality centerThe reactions involve substitution at that centerTherefore, nucleophilic substitution can invert the configuration at a chirality centerThe presence of carboxyl groups in malic acid led to some dispute as to the nature of the reactions in Waldens cycle76Stereochemistry of Nucleophilic SubstitutionIn the 1920s and 1930s Kenyon and Phillips carried out a series of experiments to find out how inversion occurs and determine the precise mechanism of nucleophilic substitution reactions.Instead of halides they used tosylates (OTos) which are better leaving groups than halides.77Only the second and fifth steps are reactions at carbon. So inversion certainly occurs in these substitution steps

78Kinetics of Nucleophilic SubstitutionRate is change in concentration with timeDepends on concentration(s), temperature, inherent nature of reaction (activation energy)A rate law describes relationship between the concentration of reactants and rate of conversion to products determined by experiment.A rate constant (k) is the proportionality factor between concentration and rate

Example: for S P an experiment might findRate = k [S] (first order)79Reaction KineticsThe study of rates of reactions is called kineticsRates decrease as concentrations decrease but the rate constant does notThe rate law depends on the mechanismThe order of a reaction is sum of the exponents of the concentrations in the rate law the example below is second orderExperiments show that for the reaction

OH- + CH3Br CH3OH + Br-

Rate = k[OH-][CH3Br]80The SN2 ReactionOne type of nucleophilic substitution reaction has the following characteristics:Reaction occurs with inversion at reacting centerFollows second order reaction kinetics rate = k [Nu:-][RX]81

The SN2 Reaction82 SN2 Transition StateThe transition state of an SN2 reaction has a planar arrangement of the carbon atom and the remaining three groups.

83Characteristics of the SN2 ReactionSensitive to steric effectsMethyl halides are most reactivePrimary are next most reactiveSecondary might reactTertiary are unreactive by this pathNo reaction at C=C (vinyl halides)84Reactant and Transition-state Energy Levels

Higher reactant energy level (red curve) = faster reaction (smaller G).Higher transition-state energy level (red curve) = slower reaction (larger G).85Steric Effects on SN2 Reactions

The carbon atom in (a) bromomethane is readily accessibleresulting in a fast SN2 reaction. The carbon atoms in (b) bromoethane (primary), (c) 2-bromopropane (secondary), and (d) 2-bromo-2-methylpropane (tertiary) are successively more hindered, resulting in successively slower SN2 reactions. 86Steric Hindrance Raises Transition State EnergySteric effects destabilize transition statesSevere steric effects can also destabilize ground state

Very hindered87Order of Reactivity in SN2The more alkyl groups connected to the reacting carbon, the slower the reaction

88The NucleophileNeutral or negatively charged Lewis baseReaction increases coordination at nucleophileNeutral nucleophile acquires positive chargeAnionic nucleophile becomes neutralSee Table 11-1 for an illustrative list

89

90Relative Reactivity of NucleophilesDepends on reaction and conditions More basic nucleophiles react faster (for similar structures. See Table 11-2)Better nucleophiles are lower in a column of the periodic tableAnions are usually more reactive than neutrals

91

92The Leaving GroupA good leaving group reduces the barrier to a reactionStable anions that are weak bases are usually excellent leaving groups and can delocalize charge

93Poor Leaving GroupsIf a group is very basic or very small, it is prevents reaction

94The SolventSolvents that can donate hydrogen bonds (-OH or NH) slow SN2 reactions by associating with reactantsEnergy is required to break interactions between reactant and solventPolar aprotic solvents (no NH, OH, SH) form weaker interactions with substrate and permit faster reaction

95The SN1 ReactionTertiary alkyl halides react rapidly in protic solvents by a mechanism that involves departure of the leaving group prior to addition of the nucleophileCalled an SN1 reaction occurs in two distinct steps while SN2 occurs with both events in same stepIf nucleophile is present in reasonable concentration (or it is the solvent), then ionization is the slowest step Previously we learned that tertiary alkyl halides react extremely slowly in SN2 reactions. But tert-butyl bromide reacts with water 1,000,000 times faster than methyl bromide.96

97SN1 Energy Diagram

Step through highest energy point is rate-limiting rate = k[RX]98Rate-Limiting StepThe overall rate of a reaction is controlled by the rate of the slowest stepThe rate depends on the concentration of the species and the rate constant of the stepThe highest energy transition state point on the diagram is that for the rate determining step (which is not always the highest barrier)This is the not the greatest difference but the absolute highest point (Figures the same step is rate-determining in both directions) 99Stereochemistry of SN1 ReactionThe planar intermediate should lead to loss of chiralityA free carbocation is achiralProduct should be racemic

100SN1 in RealityCarbocation is biased to react on side opposite leaving groupSuggests reaction occurs with carbocation loosely associated with leaving group during nucleophilic additionAlternative that SN2 is also occurring is unlikely

101Effects of Ion Pair FormationIf leaving group remains associated, then product has more inversion than retentionProduct is only partially racemic with more inversion than retentionAssociated carbocation and leaving group is an ion pair

102Characteristics of the SN1 ReactionTertiary alkyl halide is most reactive by this mechanismControlled by stability of carbocation

103Delocalized CarbocationsDelocalization of cationic charge enhances stabilityPrimary allyl is more stable than primary alkylPrimary benzyl is more stable than allyl

104Allylic and Benzylic HalidesAllylic and benzylic intermediates stabilized by delocalization of chargePrimary allylic and benzylic are also more reactive in the SN2 mechanism

105Effect of Leaving Group on SN1Critically dependent on leaving groupReactivity: the larger halides ions are better leaving groupsIn acid, OH of an alcohol is protonated and leaving group is H2O, which is still less reactive than halidep-Toluensulfonate (TosO-) is excellent leaving group

106Nucleophiles in SN1Since nucleophilic addition occurs after formation of carbocation, reaction rate is not affected normally affected by nature or concentration of nucleophile

107Solvent Is Critical in SN1Stabilizing carbocation also stabilizes associated transition state and controls rate

Solvation of a carbocation by water108Polar Solvents Promote IonizationPolar, protic and unreactive Lewis base solvents facilitate formation of R+ Solvent polarity is measured as dielectric polarization (P) Nonpolar solvents have low PPolar SOLVENT have high P values

109Effects of Solvent on EnergiesPolar solvent stabilizes transition state and intermediate more than reactant and product

110Alkyl Halides: EliminationElimination is an alternative pathway to substitutionOpposite of additionGenerates an alkeneCan compete with substitution and decrease yield, especially for SN1 processes

111Zaitsevs Rule for Elimination Reactions (1875)In the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates

112Mechanisms of Elimination ReactionsIngold nomenclature: E eliminationE1: X- leaves first to generate a carbocation a base abstracts a proton from the carbocationE2: Concerted (one step) transfer of a proton to a base and departure of leaving group113The E2 Reaction MechanismA proton is transferred to base as leaving group begins to departTransition state combines leaving of X and transfer of HProduct alkene forms stereospecifically

114E2 Reaction KineticsOne step rate law has base and alkyl halideTransition state bears no resemblance to reactant or productRate = k[R-X][B]Reaction goes faster with stronger base, better leaving group115Geometry of Elimination E2Antiperiplanar allows orbital overlap and minimizes steric interactions

116Elimination reactionE2 reactions must go by an anti eliminationThis means that the hydrogen atom and halogen atom must be 180o (coplanar) with respect to each other!!Draw a Newman projection formula and place the H and X on opposite sides. 117E2 Stereochemistry Overlap of the developing orbital in the transition state requires periplanar geometry, anti arrangement

Allows orbital overlap118Predicting ProductE2 is stereospecificMeso-1,2-dibromo-1,2-diphenylethane with base gives cis 1,2-diphenylRR or SS 1,2-dibromo-1,2-diphenylethane gives trans 1,2-diphenyl

119Elimination From CyclohexanesAbstracted proton and leaving group should align trans-diaxial to be anti periplanar (app) in approaching transition stateEquatorial groups are not in proper alignment

120Stereochemistry of E2 Reaction

This is the cis isomer. The trans isomer does not react by an E2 reaction.121(S,S)-diastereomer

122

This one is formed!123(R,S)-diastereomer

124

This one is formed!125Kinetic Isotope EffectSubstitute deuterium for hydrogen at positionEffect on rate is kinetic isotope effect (kH/kD = deuterium isotope effect)Rate is reduced in E2 reactionHeavier isotope bond is slower to breakShows C-H bond is broken in or before rate-limiting step

126The E1 ReactionCompetes with SN1 and E2 at 3 centersV = k [RX]

127Stereochemistry of E1 ReactionsE1 is not stereospecific and there is no requirement for alignmentProduct has Zaitsev orientation because step that controls product is loss of proton after formation of carbocation

128Comparing E1 and E2Strong base is needed for E2 but not for E1E2 is stereospecifc, E1 is notE1 gives Zaitsev orientation

129Dehydration of Alcohols (acid assisted E1)Acid assisted reactions are always E1

130Mechanism of Dehydration

131

Rearrangements in dehydration reactions 132

Rearrangements in dehydration reactions133Bulky leaving groups -- Hofmann EliminationThis give the anti-Zaitsev product (least substituted product is formed)!

134

Orientation of elimination: regiochemistry/ Hofmanns Rule In bimolecular elimination reactions in the presence of either a bulky leaving group or a bulky base, the hydrogen that is lost will come from the LEAST highly-branched b-carbon.

Less branchedMore branched135Product from previous slide

136Elimination with bulky basesNon-bulky bases, such as hydroxide and ethoxide, give Zaitsev products.

Bulky bases, such as potassium tert-butoxide, give larger amounts of the least substituted alkene (Hoffmann) than with simple bases. 137Comparing Ordinary and Bulky Bases

1381-butene: watch out for competing reactions!

139The E1cb mechanism:

140Alpha-Elimination Reactions:These unusual reactions occur with one carbon compounds, only.Examples include chloroform and methylene chloride.Cyclopropane compounds are formed.141Dehalogenation:This reaction requires the two Brs to be anti.

142Preparation of Alkynes -- double dehydrohalogenation

143Summary of Reactivity: SN1, SN2, E1, E2Alkyl halides undergo different reactions in competition, depending on the reacting molecule and the conditionsBased on patterns, we can predict likely outcomes.144

145Pericyclic ReactionMinggu-ke-13Pericyclic Reactions What Are?Involves several simultaneous bond-making breaking process with a cyclic transition state involving delocalized electronsThe combination of steps is called a concerted process where intermediates are skippedPericyclic ReactionPericylic reactions is a type of concerted organic reaction which occurs through cyclic transition state in order to maintain electron flow. They are usually rearrangement reactions.Pericylic Reactions are listed below: Electrocylic Reactions Cycloadditions Sigmatropic ReactionsWoodward-Hoffman rules are set of rules in organic chemistry predicting the stereochemistry of pericyclic reactions based on orbital symmetry.

Electrocyclic ReactionsThese are pericyclic processes that involves the cyclization of a conjugated polyeneOne bond is broken, the other bonds change position, a new bond is formed, and a cyclic compound resultsGives specific stereoisomeric outcomes related to the stereochemistry and orbitals of the reactants

Example: Electrocyclic Interconversions With Octatriene

Example: Electrocyclic Interconversions with Dimethylcyclobutene

Sigmatropic RearrangementsA s-bonded substituent atom or group migrates across a p electron system from one position to anotherA s bond is broken in the reactant, the p bonds move, and a new s bond is formed in the productSelection Rules for Sigmatropic ReactionsSigmatropic ReactionsSigmatropic reaction is a pericyclic reaction involves the migration of sigma bond from one site to another site in the same molecule.

over pi-bonded system governed by orbital symmetry concerted intramolecular rearrangement uncatalyzed classified due to moving substituent that is given [i,j], format i and j number of the atoms that each sigma bond moved. Generally; [1,n] and [n,m]mostly hydrogen shiftsfrom one end (1) to another end (n) [1,n] Sigmatropic Rearrangements

Stereochemistry of [1,n] Sigmatropic RARSupraH moves same face of the n-plane

[1,5] sigmatropic6 electrons(4n+2)

AntraH moves opposite of the n-planeStereochemistry of [1,n] Sigmatropic RAR

[1,7] sigmatropic8 electrons(4n)

Stereochemistry of [1,n] Sigmatropic RAR[i,j]ThermalExcited State (hv)[1,3] Antra Supra[1,5] Supra Antra[1,7] Antra Supra4n+2, supra, retention, Thermal, allowed

[1,2] 2-electron system (4n+2)[1,3] 4-electron system (4n)[1,5] 6-electron system (4n+2)[1,7] 8-electron system (4n)[n,m] Sigmatropic Rearrangements

sigma bond moves chairlike or boatlike transition state

Stereochemistry of [n,m] Sigmatropic RAR

Chairlike

[3,3] Sigmatropic6 electronsStereochemistry of [n,m] Sigmatropic RAR

Boatlike

10-electron system[2,3] 6-electron system (Wittig RAR)(Claisen RAR) [3,3] 6-electron system

Sigmatropic NotationNumbers in brackets refer to the two groups connected by the s bond and designate the positions in those groups to which migration occursIn a [1,5] sigmatropic rearrangement of a diene migration occurs to position 1 of the H group (the only possibility) and to position 5 of the pentadienyl groupIn a [3,3] Claisen rearrangement migration occurs to position 3 of the allyl group and also to position 3 of the vinylic etherExamples of Sigmatropic RearrangementsA [1,5] sigmatropic rearrangement involves three electron pairs (two bonds and one s bond)Orbital-symmetry rules predict a suprafacial reaction5-methylcyclopentadiene rapidly rearranges at room temperature

Cope rearrangement of 1,5-hexadieneClaisen rearrangement of an allyl aryl ether

Cycloaddition ReactionsDiels-Alder reactionCreates two new C-C bondsForms a cyclic molecule

Reactants are:Conjugated dieneAlkene (dienophile) - diene lovingMUST have electron-withdrawing group!!!

Cycloaddition ReactionsDienophilesEWG increases the reactivity by sucking electron density from the alkene

Remember: Conjugated Diene is Nucleophilic

Cycloaddition ReactionsMechanismSimilar to a 1,4-addition to butadiene

Reaction is concerted to form new bonds

4p2p[4+2] cycloadditionThe reaction is concerted - allof the orbitalsare aligned in a6-ring.DIELS-ALDER REACTIONHOMOLUMORpushWpullThe HOMO of the dienedonates elec-trons into the LUMO of the dienophile.(diene)(dienophile)12172173Stereospecificity of the Diels-Alder ReactionThe reaction is stereospecific, maintaining relative relationships from reactant to productThere is a one-to-one relationship between stereoisomeric reactants and products

Regiochemistry of the Diels-Alder ReactionReactants align to produce endo (rather than exo) productendo and exo indicate relative stereochemistry in bicyclic structuresSubstituent on one bridge is exo if it is anti (trans) to the larger of the other two bridges and endo if it is syn (cis) to the larger of the other two bridgesIf the two bridges are equal, the product with the substituent endo to the new double bond is formed.

Endo-Stereochemistry:

Conformations of Dienes in the Diels-Alder ReactionThe relative positions of the two double bonds in the diene are the cis or trans two each other about the single bond (being in a plane maximizes overlap)These conformations are called s-cis and s-trans (s stands for single bond)Dienes react in the s-cis conformation in the Diels-Alder reaction

Practice Problem:

Solution:

Problem:

Reaction Mechanism:

Solution: