Chapter 22 Pericyclic Reactions Bioorganic Chemistry Spring 2006 Chapter 22 Pericyclic Reactions a pericyclic reaction: formation/breaking of two or more bonds through a concerted cyclic transition-state (generally non-polar) BioorgChem-Chap22 Chapter 22

Pericyclic Reactions Highly stereospecific: concerted bond formation Bioorganic Chemistry Spring 2006 Pericyclic Reactions Highly stereospecific: concerted bond formation cycloaddition reactions: Diels-Alder reactions electrocyclic reactions: conjugated polyenes;  957 sigmatropic & other concerted rearrangements p MOs of conjugated molecules:  960, 962-3 No. of MOs = No. of component AOs similar E difference relative to an isolated p orbital E of an MO increases as the No. of node increases nodes are symmetrically placed in an MO BioorgChem-Chap22 Chapter 22

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(antibonding) (bonding) BioorgChem-Chap22

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Cycloaddition Reactions (I) Bioorganic Chemistry Spring 2006 Cycloaddition Reactions (I) Intermolecular pericyclic reactions giving a ring No. of pi orbitals involved: [m+n] cycloaddition;  975 Theories of orbital (MO) interactions favorable bonding interactions: stabilization of the total energy of the electrons → lower E of HOMO of product favorable interaction between a HOMO and a LUMO larger stabilization between similar energy levels theories: FMO (frontier MO) theory by K. Fukui & orbital correlation analysis by R. B. Woodward and R. Hoffmann BioorgChem-Chap22 Chapter 22

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larger stabilization between orbitals of similar energy levels BioorgChem-Chap22

frontier molecular orbital (FMO) theory by Fukui orbital correlation method by Woodward & Hoffmann [4p+2p] p4* A LUMO antisymmetric (A) p* LUMO p3* S p2 A HOMO symmetric (S) p HOMO p1 S BioorgChem-Chap22

Cycloaddition Reactions (II) Bioorganic Chemistry Spring 2006 Cycloaddition Reactions (II) [4+2] cycloaddition: thermally allowed;  977 top facile reactions with substituents of opposite polarity ‘normal electron demand’ & ‘inverse electron demand’ [2+2] cycloaddition: thermally forbidden;  976 top photochemically allowed: change of the ‘HOMO’:  977 mid. odd e--pairs: thermal, even e--pairs: photochemical Diels-Alder reactions: [4+2] cycloaddition powerful tool for substituted cyclohexenes:  978 dienophiles (reactive) + dienes (reactive: s-cis) BioorgChem-Chap22 Chapter 22

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Change of the Energy Level by a Substituent (I) “normal electron demand” p4* LUMO p3* LUMO p* p2 HOMO p1 p HOMO BioorgChem-Chap22

Change of the Energy Level by a Substituent (II) “inverse electron demand” LUMO p* p4* LUMO p3* p HOMO p2 HOMO p1 BioorgChem-Chap22

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Prohibited (Forbidden) Interactions [2p+2p] LUMO LUMO p* A A S p S HOMO HOMO BioorgChem-Chap22

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[2ps + 2ps] HOMO (SOMO) LUMO p* p HOMO BioorgChem-Chap22

high E BioorgChem-Chap22

Reactive Dienophiles BioorgChem-Chap22

Reactive Dienes (I) 10 times faster BioorgChem-Chap22

Reactive Dienes (II) retro-Diels-Alder reaction ‘do not react’ BioorgChem-Chap22

Cycloaddition Reactions (III) Bioorganic Chemistry Spring 2006 Cycloaddition Reactions (III) Stereoselectivities in cycloaddition reactions syn (cis) addition: stereospecific with the SMs endo addition: dienophiles with pi bonds;  980 secondary p-p orbital interaction between the two p bonds Regioselectivity: ‘ortho-like’/‘para-like’ products C-1/C-2 substituents: mediocre selectivity;  982 Other important Diels-Alder reactions aromatics as dienes/alkynes as dienophiles:  982-3 intramolecular/hetero Diels-Alder reaction:  983 BioorgChem-Chap22 Chapter 22

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E D G + W - BioorgChem-Chap22

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inverse electron demand BioorgChem-Chap22

Other Cycloaddition Reactions Bioorganic Chemistry Spring 2006 Other Cycloaddition Reactions [2+2] cycloaddition under photo irradiation cyclobutane rings: strained, hard to make;  984 Paterno-Büchi reaction: oxetanes;  985 thermal [2+2] cycloaddition: cis-cyclobutanones ketenes [LUMO] + alkenes [HOMO] Other cycloadditions: [8+2];  985 BioorgChem-Chap22 Chapter 22

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[2ps+2pa] BioorgChem-Chap22

Electrocyclic Reactions Bioorganic Chemistry Spring 2006 Electrocyclic Reactions Intramolecular pericyclic reactions:  965 top acyclic conjugated polyenes cyclic alkenes [4n] e-: conrotation thermally allowed;  966 top disrotation: photochemically allowed;  966 bottom [4n+2] e-: disrotation thermally allowed;  967 top conrotation: photochemically allowed;  967 bottom practice: allowed? or forbidden?  967-970 thermal reactions: equilibrium-controlled;  970-972 photochemical reactions: irreversible;  970 bottom Dewar benzene: an isomer of benzene;  973-974 BioorgChem-Chap22 Chapter 22

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trans-cyclobutene (E,E)-diene cis-cyclobutene BioorgChem-Chap22

cis-cyclohexene (E,Z,E)-triene trans-cyclohexene BioorgChem-Chap22

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[71 kcal/mole less stable] BioorgChem-Chap22

[1962] [1963] BioorgChem-Chap22

Sigmatropic Rearrangements Bioorganic Chemistry Spring 2006 Sigmatropic Rearrangements Intramolecular migration of a sigma bond:  986 along a pi system with rearrangement of the pi bond [m,n] sigmatropic: No. of atoms broken;  986-987 feasibility: HOMOs of two radicals;  988 middle allowed only when both terminal overlaps are bonding odd e--pairs: thermal, even e--pairs: photochemical;  988-9 [1,3]/[1,5] sigmatropic rearrangements:  990 [3,3]: Cope/Claisen rearrangements:  991-992 stereoselectivity: chair-type TS mechanism vitamin D3 from 7-dehydrocholesterol:  993-994 BioorgChem-Chap22 Chapter 22

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t1/2 = 1 h at 20 oC BioorgChem-Chap22

Cope rearrangement: equilibrium-controlled stable at -20 oC BioorgChem-Chap22

Claisen rearrangement (I): Product favored BioorgChem-Chap22

Claisen rearrangement (II): Product favored BioorgChem-Chap22

Cope rearrangement: chair TS (I) BioorgChem-Chap22

Cope rearrangement: chair TS (II) BioorgChem-Chap22

Cope rearrangement: chair TS (III) BioorgChem-Chap22

Cope rearrangement: chair TS (IV) BioorgChem-Chap22

[1,7] sigmatropic rearrangement thermally allowed BioorgChem-Chap22

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Other Concerted Rearrangements Bioorganic Chemistry Spring 2006 Other Concerted Rearrangements Pinacol rearrangement: 1,2-alkyl shift;  995 [1,2] sigmatropic shift to a carbocation: mechanism Beckmann rearrangement: 1,2-shift;  996 R anti to OH of an oxime: caprolactam;  997 Hofmann rearrangement: amide with X2;  997 one less carbon homologation: RCO2H → RNH2 Curtius rearrangement: RCON3;  999 Baeyer-Villiger rearrangement:  998 ketones to esters / cyclic ketones to w-hydroxyesters BioorgChem-Chap22 Chapter 22

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caprolactam raw material for nylon 6 BioorgChem-Chap22

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