Dynamic Stereochemistry


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Useful For Post Graduate Students of Pharmacy to study dynamic approaches of stereochemistry

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Dynamic Stereochemistry

  1. 1.
  2. 2. <ul><li>Introduction </li></ul><ul><li>Selection of substrates </li></ul><ul><li>Quantitative correlation between conformation and reactivity </li></ul><ul><li>Conformation, reactivity, and mechanism : Cyclic system </li></ul><ul><li>Conformation, reactivity, and mechanism: acyclic systems </li></ul><ul><li>Conformational atropisomers and reactivity </li></ul><ul><li>Formation and reactions of enols and enolates </li></ul><ul><li>Reduction of cyclohexanones </li></ul><ul><li>Reference </li></ul>
  3. 3. <ul><li>Concerned with stereochemical studies </li></ul><ul><li>of any rate process </li></ul><ul><li>involving bond-breaking and bond-making </li></ul><ul><li>or interconversion of conformers </li></ul><ul><li>It correlates the stereochemistry of </li></ul><ul><li>starting material and products </li></ul><ul><li>in terms of transition states </li></ul>
  4. 4. <ul><li>Substrate used for study of conformation-reactivity correlation </li></ul><ul><li>divided into three categories- </li></ul>
  5. 5. <ul><li>Reacting groups are locked into two different orientations e.g.equitorial and axial </li></ul><ul><li>provide a direct relationship between conformation and reactivity </li></ul><ul><li>Ex: trans-2 α - decalol and trans -2 β -decalol </li></ul><ul><li>OH group is equitorial and axial respectively </li></ul><ul><li>(trans-2  -decalol) (trans-2  -decalol) </li></ul>
  6. 6. <ul><li>Example- 2,3,4-triphenylbutyric acid </li></ul><ul><li>The compound exists in threo and erythro: </li></ul><ul><li>(Threo) (tetralone) </li></ul><ul><li>(Erythro) (indanone) </li></ul><ul><li>Ring-closure of threo and erythro isomers of 2,3,4- </li></ul><ul><li>triphenylbutyric acid </li></ul>The relative specific reaction rates of the two diastereomers depends on the corresponding rates and their populations in the equillibrium mixture of each diastereomer
  7. 7. <ul><li>ni = mole fraction of i-th confomer </li></ul><ul><li>Ki = specific reaction rate </li></ul><ul><li>Example :4-methylcyclohexanone </li></ul><ul><li>( 2-isooctyl nitrite) </li></ul><ul><li>Conversion of 4-methylcyclohexanone </li></ul><ul><li>into optically active 2-oxyimino derivative </li></ul>The overall specific reaction rate (k) of a substrate in mobile equillibrium depends both on the ground state population of conformer and on their specific reaction rate as given in the equation- k = ∑ ni ki i
  8. 8. <ul><li>Curtin-Hammett principle correlates: </li></ul><ul><li>The product distribution with the transition state energies, </li></ul><ul><li>-for two different reaction pathways </li></ul><ul><li>-by two different conformers </li></ul><ul><li>of a substrate </li></ul><ul><li>-giving non-equilibrating products </li></ul><ul><li>Winstein-Eliel rate equations correlates: The overall observed specific reaction rate(k) of a substrate with </li></ul><ul><li>-specific reaction rate of individual conformers </li></ul><ul><li>-irrespective of whether the products are equilibrating or non-equilibrating </li></ul><ul><li>S </li></ul><ul><li>k ae </li></ul><ul><li>A E </li></ul><ul><li>k a k ea k e </li></ul><ul><li>P A P E </li></ul><ul><li>P </li></ul><ul><li>K = = </li></ul><ul><li>and ke , ka << kae , kea </li></ul>
  9. 9. <ul><li>E2 elimination of cyclohexyl tosylate - </li></ul><ul><li>equatorial conformer cannot have the tosyl group antiperiplanar with an adjacent hydrogen </li></ul><ul><li>So, unable to react </li></ul><ul><li>Ex: trans-4- t -butylcyclohexyl tosylate lacks reactivity </li></ul><ul><li>cis isomer reacts with specific rate </li></ul><ul><li>7.1 X 10 -3 mol-1sec-1 at 75˚ </li></ul><ul><li>Specific rate constant of cyclohexyl tosylate </li></ul><ul><li>2.4 X 10 -3 mol-1sec-1 at 75˚ </li></ul><ul><li>Hence, K=(7.1-2.4)/2.4=2.0 </li></ul>
  10. 10. <ul><li>a) Elimination in N,N-dimethyl-s-butylamine oxide : </li></ul><ul><li>N,N-Dimethyl-s-butyl amine oxide along with 1-butene a mixture of cis- and trans- 2-butene in a ratio of 1:2 </li></ul><ul><li>cis-2- butene less stable due to an eclipsing interaction between the two methyl groups </li></ul>
  11. 11. <ul><li>b) Quaternisation of Tropanes: </li></ul><ul><li>Tropanes are more sterically hindered on the side of the piperidine ring than on pyrrolidine ring </li></ul><ul><li>Conformer ‘b’ is less stable than ‘a’ </li></ul><ul><li>(a) (b) </li></ul><ul><li>Methylation of tropane </li></ul>
  12. 12. <ul><li>Difference in the reactivity between two stereoisomer or conformers depends on the transition states through </li></ul><ul><li>Two factors determining the stability of the transition state: a steric factor and a stereoelectronic factor </li></ul>
  13. 13. <ul><li>Stereoelectronic factor has little relevance </li></ul><ul><li>Steric and other factors operate </li></ul><ul><li>An equatorial substituent is less hindered than an axial one and so is more reactive </li></ul><ul><li>The steric requirements of the group thus becomes markedly greater in the transition state than in the ground state </li></ul><ul><li>The difference in the free energies of the axial and equatorial isomer is enhanced in the transition state than in the ground state </li></ul><ul><li>Axial isomer reacts at a slower rate than the equatorial isomer </li></ul>
  14. 14. <ul><li>(steric hindrance) (steric assistance) </li></ul>
  15. 15. <ul><li>Difference in the rates of a reaction for an equatorial and axial isomer is diminished as the site of crowding moves away from the ring </li></ul><ul><li>Substituents at an axial group at C-3, affect the relative rates of the equatorial and axial isomers </li></ul><ul><li>Difference in the ground state free energies of an axial and equatorial isomer is greater than that in transition state. </li></ul><ul><li>Axial isomer with its higher ground state energy would react at a faster rate- steric assistance or steric acceleration. </li></ul>
  16. 16. <ul><li>a) S N 1 reaction- </li></ul><ul><li>Nucleophilic reactions follow a unified ion - pair mechanism, it form the two extremes </li></ul><ul><li>RX and a solvent, a common carbocation is formed from both the axial and equatorial isomers </li></ul><ul><li>solvolysis of 4- t- butylcyclohexyl tosylates </li></ul><ul><li>Transition state of an SN1 reaction (cyclohexyl system) </li></ul>
  17. 17. <ul><li>Transition state involve a pentaco-ordinated carbon atom </li></ul><ul><li>Leaving group (X) and the incoming group (Y) are partially bonded </li></ul><ul><li>In 4- t- butylcyclohexyl bromides(X= Br), cis isomer reacts ≈ 60 times faster than trans isomer </li></ul><ul><li>Transition states of an SN2 reaction </li></ul><ul><li>(cyclohexyl system) </li></ul>
  18. 18. <ul><li>Nucleophile attacks the reacting centre from the same side of the leaving group with retention of configuration </li></ul><ul><li>Amine-nitrous acid reaction </li></ul><ul><li>NH2 is replaced by OH </li></ul><ul><li>Equatorial amines usually give equatorial alcohols </li></ul><ul><li>Stereochemistry of amine-nitrous acid reaction </li></ul>
  19. 19. <ul><li>An allylic substrate, eg. R-CH=CH-CH2-X undergoes substitution reaction with allylic rearrangement through an SN2̍ mechanism </li></ul><ul><li>Incoming nucleophile approaches γ-C from the side syn to the leaving group </li></ul><ul><li>6-alkyl-2-cyclohexenyl mesitoates react with piperidine stereospecifically </li></ul><ul><li>Cis isomer gives the cis and trans isomer and then trans cyclohexene </li></ul><ul><li>Stereochemistry of SN2' reaction </li></ul>
  20. 20. <ul><li>Formation of epoxide (oxiranes) from vicinal bromohydrines </li></ul><ul><li>Nucleophile approaches oxirane carbon from the rear side of the oxide linkage </li></ul><ul><li>C-1 of ‘b’ is antiparellel and at C-2 is parallel </li></ul><ul><li>Leads to chair-like transition state </li></ul><ul><li>Gives the diaxial product </li></ul><ul><li>Parallel approach </li></ul><ul><li>Leads to twist-boat transition state </li></ul><ul><li>Gives diequitorial product </li></ul><ul><li>Chair like transition </li></ul><ul><li>state is favoured </li></ul><ul><li>over twist-boat </li></ul><ul><li>Stereochemistry of epoxide ring opening </li></ul>
  21. 21. <ul><li>a) Electrophilic addition. </li></ul><ul><li>Br + adds to the double bond forms cyclic intermediate, e.g., bromonium ion. </li></ul><ul><li>A nucleophile opens up the ring from the side opposite to the electrophile </li></ul><ul><li>Results in trans diaxial product </li></ul><ul><li>Ex: Conversion of 2-cholestene into 2β,3α-dibromocholestane and 2β-hydroxy,3α-bromocholestane </li></ul><ul><li>Stereochemistry of addition reaction </li></ul>
  22. 22. <ul><li>Addition to an isolated double bond is very rare </li></ul><ul><li>As π system of the double bond is electron-rich </li></ul><ul><li>But in enone systems-double bond is polarized by the presence </li></ul><ul><li>of an electron withdrawing carbonyl group </li></ul><ul><li>Thus 1,4-addition of nucleophiles is facile </li></ul><ul><li>(e.g, Michael reaction) </li></ul>Stereochemistry of 1,4-addition
  23. 23. <ul><li>Addition of reagents takes place through a cyclic intermediate or transition state </li></ul><ul><li>Ex: Selective oxidation of a cyclic olefin to cis-l,2-glycol with osmium tetroxide </li></ul><ul><li>-Addition of the components of hydrogen peroxide to a double bond </li></ul><ul><li>-Proceeds through five-membered cyclic intermediates </li></ul><ul><li>cis-Hydroxylation (osmylation) </li></ul>
  24. 24. <ul><li>Three types of elimination reactions - </li></ul><ul><li>1) E2 elimination (ionic) </li></ul><ul><li>2) cis elimination (pyrolytic) </li></ul><ul><li>3) 1,4-elimination leading to molecular </li></ul><ul><li>fragmentation </li></ul>
  25. 25. <ul><li>Broad spectrum of mechanisms with E1cB and E1 </li></ul><ul><li>In E1cB - </li></ul><ul><li>C-H bond is broken in the H-C-C-X fragment Elimination of X- from carbanion. </li></ul><ul><li>In E1 – </li></ul><ul><li>C-X bond dissociates give a carbonium ion </li></ul><ul><li>Eliminates a β-proton </li></ul><ul><li>In intermediate mechanisms </li></ul><ul><li>H and X are eliminated with a varying degree of concertedness </li></ul><ul><li>This is E2 (elimination, bimolecular) </li></ul><ul><li>Stereoelectronic factor requires : </li></ul><ul><li>Two leaving groups, e.g., H and X must be either antiperiplanar or synperiplanar and the elimination </li></ul><ul><li>is accordingly designated anti or syn </li></ul>
  26. 26. <ul><li>(A) (A’) </li></ul><ul><li>3-Menthene (B) (C) 2-Menthene (B’) </li></ul><ul><li>E2 elimination of menthyl neomenthyl chloride </li></ul>
  27. 27. <ul><li>In cyclohexane system, axial-equatorial alignment of the eliminating groups </li></ul><ul><li>Methyl xanthate esters (Chugaev reaction) derived from menthol and neomenthol. These isomers give pre­ponderantly 3-menthene and 2-menthene respectively </li></ul>
  28. 28. <ul><li>In 3-Aminoalcohol derivatives, the p orbital of N with a lone pair is antiperiplanar to 3-2 bond and is antiperiplanar to the leaving group </li></ul><ul><li>Undergo a concerted 1,4-elimination leading to the fragmentation* of the molecule </li></ul><ul><li>The epimeric structure cannot be so converted into the amino olefin, shows that the stereoelectronic </li></ul><ul><li>requirements in the reaction (known as Grob fragmentation ) are very stringent </li></ul>
  29. 29. <ul><li>Chromic acid oxidation of a secondary alcohol to a ketone is undergo two steps: </li></ul><ul><li>(i)Rapid formation of a chromate ester followed by its rate-determining decomposition into the ketone, a chromite ion, and a proton as shown: </li></ul><ul><li>R 2 CHOH + HCrO 4 + H = R 2 CH-O-CrO 2 -OH+H 2 O </li></ul><ul><li>R 2 CH-O-CrO 2 -OH= R 2 C=O+HCrO 3 - + H + </li></ul><ul><li>In substituted cyclohexanols and in steroidal alcohols, axial alcohols are oxidised at a faster rate than equatorial ones by a factor of 3 to 6 </li></ul>Relative rates of Chromic acid oxidation of cyclohexanols
  30. 30. <ul><li>If a substrate of an S N reaction contains a nucleophilic group, </li></ul><ul><li>The leaving group is removed through an intramolecular S N 2 mechanism </li></ul><ul><li>Gives a cyclic intermediate </li></ul><ul><li>The latter then reacts with the external nucleophile by another S N 2 process and the internal nucleophile returns to its original position*, the net result being a nucleophilic substitution </li></ul><ul><li>This is called neighbouring group participation </li></ul>
  31. 31. <ul><li>Two distinctive features: </li></ul><ul><li>(i) an enhancement of rate (at least by a factor of 10, usually much more) which is known as anchimeric (synartetic) assistance and </li></ul><ul><li>(ii) retention of configuration at the reacting carbon if it happens to be a chiral centre (this is a result of two consecutive inversions). </li></ul>
  32. 32. <ul><li>Example of neighbouring group participation in a cyclic system- </li></ul><ul><li>Acelolysis of 2-acetoxycyclohexyl tosylate, </li></ul><ul><li>-cis and the trans isomers gives </li></ul><ul><li>trans -l,2-diacetoxycyclohexane </li></ul><ul><li>Former by direct S N 2 reaction and the latter through neighbouring group participation </li></ul>
  33. 33. <ul><li>A pair of π-electrons of a double bond helps in removing a leaving group </li></ul><ul><li>The anti tosylate reacts 10 11 times faster than norbornyl tosylate which proves removal of the tosyl group (the rate determining step) </li></ul><ul><li>Gives strong anchimeric assistance by the double bond </li></ul><ul><li>carbonium ion react only from the right hand side giving an acetate with retained configuration </li></ul>
  34. 34. <ul><li>Molecular rearrangement leads to ring contraction and ring expansion </li></ul><ul><li>Requirements are : </li></ul><ul><li>-Presence of a carbon atom (Cα) with a leaving group (the migration terminus), </li></ul><ul><li>-a migrating group at Cβ (the migration origin), </li></ul><ul><li>-preferably an electron-donating substituent at C β </li></ul><ul><li>The migrating group and the leaving group must be antiperiplanar </li></ul>
  35. 35. <ul><li>Deamination with nitrous acid gives rise to a very reactive carbocation </li></ul><ul><li>cis -2-amino-cyclohexanol exists in two conformations </li></ul>
  36. 36. <ul><li>In the trans isomer, the conformer has the NH 2 group anti to the 1-6 bond & results in ring contraction </li></ul><ul><li>Deamination of trans -2-amino-cyclohexanol </li></ul>
  37. 37. <ul><li>The two epimeric tricyclic chloronitriles (A) and (B) provide an example of a concerted ring expansion and ring contraction </li></ul>
  38. 38. <ul><li>Deamination of syn - and anti -2-bornenyl-7-carbinyl amines (A) and (B) appears to give the same rearranged carbocation shown as ion pairs (a) and (b) </li></ul><ul><li>Double rearrangementmemory effect </li></ul>
  39. 39. <ul><li>Acyclic molecules have relatively </li></ul><ul><li>free rotation around a C-C single bond </li></ul><ul><li>One or more conformations satisfy the </li></ul><ul><li>stereoelectronic requirements of a reaction </li></ul><ul><li>and results in more than one product </li></ul>
  40. 40. <ul><li>The difference in stereochemical behaviour of two diastereomeric substrates towards addition reactions is illustrated by bromination (anti addition) and bis- hydroxylation (syn addition) of maleic and fumaric acid </li></ul>
  41. 41. <ul><li>In acyclic system, anti elimination is preferred with good leaving groups such as Cl and Ots </li></ul><ul><li>-Syn elimination is preferred with bulky and poor leaving groups such as onium </li></ul><ul><li>-Syn elimination gives predominantly the trans olefins </li></ul><ul><li>Cis olefins are obtained through anti elimination </li></ul><ul><li>(syn-anti dichotomy) </li></ul>
  42. 42. <ul><li>The anti mode of E2 elimination in the system, eg., R-CHX-CH 2 R (X = Cl or Br) has been proved by dehydrobrotnination of deuterated 2-bromobutane </li></ul><ul><li>‘ cis – effect’ due to eclipsing of two Ph groups is shown </li></ul><ul><li>Dehydrochlorination of dichlorostilbenes </li></ul>
  43. 43. <ul><li>The syn elimination leads predominantly to the trans product while the anti elimination leads mainly to the cis product </li></ul><ul><li>The phenomenon known as syn-anti dichotomy </li></ul><ul><li>Competitive syn-anti elimination </li></ul>
  44. 44. <ul><li>The threo and erythro isomers of (1,2-diphenylpropyl) trimethylammonium salt react with t -butoxide in t -butanol to give trans -1-methylstilbene </li></ul><ul><li>β-H is first eliminated to give a carbanion undergo rapid isomerisation at α-C followed by elimination to the more stable trans -1-methylstilbene </li></ul><ul><li>Stereoconvergent elimination </li></ul>
  45. 45. <ul><li>Reorganisation of bonding takes place at three centres in a molecular rearrangement </li></ul><ul><li>-At the migrating group </li></ul><ul><li>-At the migration terminus </li></ul><ul><li>-At the migration origin </li></ul>
  46. 46. <ul><li>Retention of configuration in the </li></ul><ul><li>migrating group </li></ul><ul><li>(a) is a semi-pinacol rearrangement - chiral alkyl group migrates from one carbon to another </li></ul><ul><li>(b) is a Hofmann degradation - an atropisomeric biphenyl group migrates from a carbon atom to a nitrogen </li></ul><ul><li>(c) is a Baeyer-Villiger oxidation - chiral alkyl group migrates from a carbon atom to an oxygen atom </li></ul><ul><li>The configuration of the migrating group is retained </li></ul>
  47. 47. <ul><li>If the migration origin is chiral and remains so after rearrangement </li></ul><ul><li>If the migration and attachment of a new nucleophile at the migration origin are concerted </li></ul><ul><li>Inversion at the migration origin occur </li></ul><ul><li>Example-solvolysis of the tosylate of R-3- methyl-2-phenylbutan-1-ol </li></ul><ul><li>Inversion of configuration at migration origin </li></ul>
  48. 48. <ul><li>The migration group approaches from the side opposite to the leaving group </li></ul><ul><li>Leading to inversion of configuration </li></ul><ul><li>Migration terminus may be accompanied with varying degrees of retention: </li></ul><ul><li>(i) Forms very reactive carbocation, inversion, retention, or both may follow </li></ul><ul><li>(ii) The carbocation so formed is very stable, to form more than one transition state of relative stabilities </li></ul><ul><li>Determine the stereochemistry of the migration terminus </li></ul>
  49. 49. <ul><li>Atropisomerism is restricted rotation about one or nore single bonds </li></ul><ul><li>In diastereomeric form, functional group is located in the acyclic part </li></ul><ul><li>Considered as the counterparts of rigid and anancomeric cyclohexane systems </li></ul>
  50. 50.
  51. 51. <ul><li>Enols and enolates derived from ketones </li></ul><ul><li>These are basically nucleophilic </li></ul><ul><li>Few organic reactions such as protonation (or deuteration), halogenation, alkylation, acylation, and aldolisation(all are electrophilic addition to enolic and enolate double bond) are mediated through them </li></ul><ul><li>The stereochemistry of these reactions is best studied in cyclohexanone system. </li></ul>
  52. 52. <ul><li>Enolisation of unhindered cyclohexanones with base or acid involves the preferential abstraction of an α-axial proton and in reverse reaction, e.g., ketonisation of enols with proton or bromine </li></ul><ul><li>The electrophile occupies the axial position in the product </li></ul>
  53. 53. <ul><li>The reduction of substituted cyclohexanones gives a mixture of axial and equatorial alcohols, the stereochemistry of the products depending on various factors: </li></ul><ul><li>Nature of the reagents, </li></ul><ul><li>Nature of the substrates, </li></ul><ul><li>Reaction reagent </li></ul><ul><li>  Ex </li></ul>
  54. 54. <ul><li>Cyclohexanone is hydrogenated to acyclohexanol in presence of catalysts such as Pt and Ni in acidic or neutral medium </li></ul><ul><li>Catalyst absorbs the substrate from its less hindered side forming a 7 π -bonded intermediate and transfers hydrogen to that side </li></ul><ul><li>Rapid reduction with active catalysts (Ni or Pi) </li></ul>
  55. 55. <ul><li>Unhindered cyclohexanones on reduction with lithium aluminium hydride or sodium borohydride afford more stable equatorial alcohols </li></ul><ul><li>Hindered cyclohexanones give less stable axial alcohols </li></ul>
  56. 56. Ketone Stable alcohol Percentage Group A: 4-Methylcyclohexanone 3-Methylcyclohexanone 2-Methylcyclchexanoue 4- t -Butyltyclohcxanone Menthone 3-Cholestanone trans (e) Cis (e) trans (e) trans (e) trans (e) 3 – β - ol (e) 81 88 70 90 79 91 Group B: 3.3,5Trimethylcyclohexanone Camphor Norcamphor 11-Oxosteroids Cis (e) endo exo 11-a-ol (e) 45 (29) 10 11 22
  57. 57. <ul><li>(M-P-V) reduction is a classical reaction in which a hydride is transferred from aluminium isopropoxide (or any other secondary alkoxide) to a carbonyl carbon </li></ul><ul><li>The reverse reaction, i.e. oxidation of aluminium alkoxides with a ketone is known as Oppenauer oxidation </li></ul>
  58. 58. <ul><li>A few analogous reactions are known such as reduction with sterically hindered Grignard reagents which are kinetically controlled and are associated with high stereoselectivity </li></ul>Ketone Stable alcohol M.P.V equilibration Percentage Li – NH 3 4- 1- Butylcyclohexanone 4- Methylcyclohexanone 3- Methylcyclohexanone 2- Methylcyclohexanone 3.3,S-Trimethylcyclohexanone 2- Norbornanone (norcamphor) Camphor 79 70 - - 94 80 71 98-99 99 94-95 99 99 9-32 79-90
  59. 59. <ul><li>Saturated cyclic and acyclic ketones are reduced to alcohols by alkali and alkaline earth metals dissolved in lower alcohols (M + ROH) or better in liquid ammonia (M+NH3) </li></ul><ul><li>The latter reaction is known as Birch -reduction </li></ul>
  60. 60. <ul><li>The mechanism of Birch reduction (and reduction with alkali metals in alcohols) of a saturated ketone - </li></ul><ul><li>Reduction of α,β-unsaturated cyclohexenones </li></ul><ul><li>The stereochemical results for a few 3,4-disubstituted cyclohex-2-enones – </li></ul><ul><li>R = R' = Me 86% 14% </li></ul><ul><li>R = R' =Et 56% 44% </li></ul><ul><li>R = Ph , R' = Me 6% 94% </li></ul><ul><li>R = R' = Ph 2% 98% </li></ul>
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