http://www.courses.fas.harvard.edu/~chem206/ Me Me Me CH2O BF3?OEt2 N OMe MeO Me NH2 OHC CHO Me3Si CO2R CH2Cl2 Me Me Me OBF4 N Rc Rd Ra Rb Me Me Me OBF4 Me Me Me O H N N MeO MeO Me H CO2R Chem 206D. A. Evans Matthew D. Shair Friday, December 6, 2002 Reading Assignment for this Lecture: Other Relevant Background Reading Carbocations: Stability, Structure, & Rearrangements Carey & Sundberg, Advanced Organic Chemistry, 4th Ed. Part A Chapter 5, "Nucleophilic Substitution", 263-350 . Saunders, M. and H. A. Jimenez-Vazquez (1991). “Recent studies of carbocations.” Chem. Rev. 91: 375. Chemistry 206 Advanced Organic Chemistry Lecture Number 31 Introduction to Carbonium Ions–2 a73 Allyl- & Vinylsilanes: The β-Silicon Effect a73 Carbonium Ion Rearrangements Walling, C. (1983). “An Innocent Bystander Looks at the 2-Norbornyl Cation.” Acc. Chem. Res. 16: 448. (handout) Birladeanu (2000). “The Story of the Wagner-Meerwein Rearrangement.” J. Chem. Ed. 77: 858. (handout) Lambert, (1999). “The β effect of silicon and related manifestations of σ conjugation.” Acc. Chem. Res. 32, 183-190. (handout) Question 13. Final Exam, 1999. During Corey's synthesis of Aspidophytine (JACS, 1999, 121, 6771), the pivotal intermediate 3 was assembled by the union of 1 and 2 under the specified conditions. Provide a mechanism for this single-pot transformation. + 1) mix at roomtemp, 5 min 2) 2 equiv.TFAA, 0 °C + 3) excess NaBH 3CN 1 2 3 Here is a typical carbonium ion question that you should be able to handle by the end of the course. Write out a mechanism for the following transformation. A. Srikrishna, Chem Commun 1994, 2259 60% yield Ph Cl H OH OPh CH3 Z RR X B A C D B A Z RR B A C D B X– A B A C D RR B Z A Z RR A X OH MsO OH TBSO H H B Me3Si H R2 R1 Z RR Et2AlCl A Ph CH3 Cl OHH OPh NIS B AgBF4 Et2O I H R2 R1 TBSO H O OH H RR A Ph CH3 C OH O Ph Z B Chem 206Carbocation Rearrangements-1 Carbocation [1,2] Sigmatropic Rearrangements 2-electron Huckel transition state 1,2 Sigmatropic shifts are the most commonly encountered cationic rearrangements. When either an alkyl substituent or a hydride is involved, the term Wagner-Meerwein shift is employed to identify this class of rearrangments. Stereoelectronic requirement for migration.... bridging T.S. retention of stereochemistry In the most stable ground state conformation, if the relationship between the migrating group (Z) and the leaving group (X) is gauche, usually retention is observed in the migration terminus. Long-lived Carbocations: X departs before Z moves. These observations can be ascribed to the principle of least motion: "...those elementary reactions will be favored that involve the least change in atomic position and electronic configuration." In the most stable ground state conformation, if the relationship between the migrating group (Z) and the leaving group (X) is anti, usually inversion is observed in the migration terminus. O. S. Tee JACS 1969, 91, 7144 Principle of least motion in action: InversionMigration attends ionization R. Bach J. Am. Chem. Soc. 1979, 101, 3118 CH2Cl2, -78?C S. L. Schreiber et al Tetrahedron Lett. 1989, 30, 3765. If migration accompanies ionization, the migration terminus will be inverted. Overlap between the σ C-C (migration origin) and the σ* C-X (migration terminus) will be maximized in an antiperiplanar arrangement. M. Shair, D. Evans Birladeanu (2000). “The Story of the Wagner-Meerwein Rearrangement.” J. Chem. Ed. 77: 858. (handout) CH2NH2 OH OH Me Me H HMe OH Me Me H H Me Me Me HO H Me Me Me H+ H2SO4 Me Me Me Me H+ CH2 O MeMe Me Me OH H Me Me Me Me Me MeMe Me H OH MeMe Me Me OTs HMe Ph MeH OTs MeH Ph MeH RR X: R R Y Cl SO2ClF HF-SbF5 TsO– TsO– Me Me HH R R RR X Me H MeH Y- RR X: R R Nuc OAc HMe Ph MeH OAc MeH Ph MeH Ph MeH H Me AcO Ph HMe H Me AcO Chem 206Carbocation Rearrangements-2 Carbocation [1,2] Sigmatropic Rearrangements Wagner-Meerwein Rearrangements: Application in Total Synthesis α-caryophyllene alcoholE. J. Corey J. Am. Chem. Soc. 1964, 86, 1652. Pinacol rearrangement (vicinal diol): Driving force is the gen. of C=O Deamination " NO+ " Demjanov-rearrangement (Driving force: relief of ring strain) equiv to Synthesis of (±)-Isocomene: Pirrung, JACS 1979, 7130; 1981, 82. (±)-Isocumene Carbocations: Neighboring Group Participation Nuc: a73 Groups with accessable electron density (heteroatoms, arenes) and the correct stereoelectronic orientation (anti-periplanar) can "assist" in the ionization of a leaving group. M. Shair, D. Evans The Cram Phenonium Ion Experiments: Cram, JACS 1949, 71, 3865 L-Threo L-Threo D-Threo 98% chemical fidelity L-Erythro 98% chemical fidelity L-Erythro L-Erythro tetrahedral carbon in C13 NMR (68.8 ppm) Physical Evidence for Neighboring Group Participation Phenonium ion G. Olah JACS 1976, 98, 6784. See Lowry & Richardson, pp 434-439 for discussion of this controversy Cl Me H AcOH Me H OTsH KOAc AcO- HOAc OAcH AcO Me H Me MeOAc Chem 206Carbocation Rearrangements-3 Introduction Saturated = inversion a73 Solvolysis of 3-β-cholesteryl chloride with acetate ion proceeds with complete retention Additionally, the β-Cl solvolyzed at an enhanced rate vs. the α-Cl. Under certain conditions, the cholesteryl i-acetate is obtained. C. Shoppee J. Chem. Soc. 1946, 1147S. Winstein J. Am. Chem. Soc. 1954, 76, 18 "Nonclassical" carbonium Ions cholesteryl i-acetate End-on Overlap retention a73 These results have been attributed to an end-on overlap between the filled p orbital of the double bond and the vacant p orbital of the cation in a σ-type of interaction. This type of stabilization (a 3 center-2 electron bond) results in what are referred to as "nonclassical carbonium ions". Full retention & 1011 times faster hydrolysis than saturated system end-on overlap The Norbornenyl Example Physical Evidence of Nonclassical Carbonium Ion a73 In the norbonenyl system, both p orbitals of the double bond can stabilize the vacant p orbital in an end-on orientation. M. Shair, D. Evans 1.467 ? + 1.855 ? 1.503 ? 1.495 ? T. Laube, JACS 1989, 111, 9224 Me Me Me H OBs H HOAc H H OAc H HOAc Me Me Me H OBs H H H+ MeMe O Me Me H Me Me Me F OH Me Me SO3H H2SO4 2 SbF5 OH2 Me Me Me Me Me Me H Me MeMe O SO3H [F5Sb–F–SbF5]– OH Me Me Chem 206Carbocation Rearrangements-4 "Nonclassical" carbonium Ions: The Facts!The 2-Norbornyl Cation 1350 How do we explain the rate difference and stereochemical result? σ C-C p C+ Stabilization of the 2-norbornyl cation is provided by interaction with the C1-C6 bonding σ orbital in an end-on orientation relative ratesof solvolysis Resonance representationof norbornyl cation Winstein: The delocalized structure is the lowest energy structure Brown: Delocalized structure is the transiltion state separating localized ions "An Innocent Bystander Looks at the 2-Norbornyl Cation" Walling, C. Acc. Chem. Res. 1983, 16, 448. + T. Laube, Angew. Chem. Int. Ed. 1987, 26, 560 Functionalization of Camphor M. Shair, D. Evans 1.467 ? 1.442 ? 1.739 ?2.092 ? Ion Equilibrium Experiments: Field & Soloman, JACS 1976, 98, 1567 + + ?G° = -2.3 kcal/mol R3Si A SiMe3 Si H3Si H H CH2 R3Si SiMe3 H2C SiMe3 E R3Si E E E H3C H H CH2 B E E Me3Si SiMe2Ph Me3Si SiMe2Ph Me3C H SiMe3 OCOCF3 HH Me3C H H OCOCF3 SiMe3H H H Me3Si SiMe2Ph Me3C H Me OCOCF3 HH Me3C H H OCOCF3 MeH Me3Si SiMe2Ph Chem 206Allyl- & Vinylsilanes: The β-Silicon Effect Allyl– & Vinylsilanes react with electrophiles Mechanism - the simple picture: -Silicon stabilizes carbocation References: Lambert Acc. Chem. Res. 1999, 32, 183-190 Lambert, JACS 1990, 112, 8120; 1996, 118, 7867. Fleming, Organic Reactions 1989, 37, 54. Fleming, Chem. Rev., 1997, 2063. E E E Nu E Nu -Silicon Effect: the origin of regioselectivity σSi–C → pz empty σSiC pz Eσocc pz versus Calculation: A more stable than B by 38 kcal/mol. Jorgensen JACS 1985, 107, 1496. Proof for a stepwise mechanism provided the following protodesilylation experiment: both silanes yield the same product mixture. Hence, the reaction proceeds most likely via a common intermediate, a carbeniumion Magnitude of the -Silicon Effect 1 2 Solvolysis (CF3CH2OH) k1 k2 = 2.4 x 10 +12 3 4 Solvolysis (CF3CH2OH) k3 k4 = 4 x 10 +4 "These figures established the -effect as one of the kinetically strongest in organic chemistry": J. Lambert Data provide no distinction between open and bridged intermediates M. Shair, D. Evans "R3Si+" "R3Si+" (trapped by solution Nu) Me3Si Me CH2Cl2 R Me OH R Me OH TiCl4 R O HE R1R 2 H R R3 RH R3 E R1R 2 CH2Cl2 R Me OH Me3Si Me TiCl4R O H R3 Si H R E R1 R3 R 2 R1 HR Si E R2 R2R1 SiMe3 O XnM R2R1 SiMe3 H R H OR OXnM R R3 R2 R1 Si H RR3 R2 R1 H R Si R Ph HMe3Si R PhHF CH2Cl2 Ph t-BuH MeMe Ph Me3Si H t-BuCl, TiCl4 Chem 206Allyl- & Vinylsilanes: The β-Silicon Effect-2 General: Allylsilanes are more nucleophilic than alkenes HOMO is higher in energy due to negative hyperconjugation ( *) C–Si Houk, JACS 1982, 104, 7162. Electrophile Addition - Stereoelectronics if R = medium size to large and/or R1 ≠ H ? major product arises via this reactive conformation if R = small and R1 = H a reaction pathway via this reactive conformation could compete σCSi E E major (trans) minor (cis) + Nu - NuSiMe3 + Nu - NuSiMe3 The stereochemical consequences for the major product are: Examples: JACS 1982, 104, 4962.But Protodesilylation E:Z 88:12! Eschenmoser, Helv. Chim. Acta 1979, 62, 1922. + > 95:5 syn + ca. 65 : 35synHayashi, TL 1983, 2865. anti addition A1,3-strain minimized σC–Si σC–Si M. Shair, D. Evans σSi–C E pi pi* σSi–C pi a203 trans-alkene: a203 anti-addition of E+ with respect to SiR3 Carbonyl Addition of Allylsilanes: Open Transition States Me3Si– is not sufficiently Lewis acidic to activate C=O through pre-association; however(RO) 2MeSi– is Lewis acidic enough to activate C=O through pre-association. These allylsilanes add to RCHO througl closed transition states Antiperiplanar TS Synclinal TS Calculations by Houk et al. show that the relative energy differences between the antiperiplanar and and synclinal transition states are negligible. Both the antiperiplanar and synclinal models predict a syn selectivity for the newly formed stereogenic centers. Me3Si Ph Me3Si Ph Me3Si Me Me O MeH O MeH OCH3 H3CO n-C4H9 OCH3 H3CO n-C4H9 TiCl4 TiCl4 TiCl4 n-C4H9 OCH3 Me Me OH n-C3H7 Ph OH n-C3H7Ph n-C4H9 OCH3 Me Me (Pri)3Si MeO2C CO2Me Ar Me O TiCl 4 ZrCl4 CH2Cl2 Me3Si Me Me TiCl4 Me O Me3Si TiCl4 CH2Cl2 Me OTiCl4 SiMe3 Me O Me O Me3Si Me O EtAlCl2 CH2Cl2 Me O SiMe3 CH2Cl2 (Pri)3Si Ph(Pri)2Si CO2MeMe PhMe2Si Me H O Me OTiCl4 Si(iPr)3 CO2Me Ar MeO OZrCl4– SiR3 Me O (Pri)3Si CO2Me CHO MePhMe 2Si Me Ar CO2Me MeO2C SiR3 Me OTiCl4 Si(iPr) 3 CO2Me Ar MeO OZrCl4– SiR3 Chem 206Allylsilanes: Reactions with ElectrophilesB. Breit, D. Evans Allylsilanes add to aldehydes and acetals under Lewis acid promotion regioselectivity: Allyl inversion + + Acetals can be used as well + + (80%) (83%) Felkin Selectivity also holds with this class of nucleophiles The Sakurai Reaction (Enone Conjugate Addition) 75% 17%Fleming, Org. Reactions 1989, 37, 127-133 Majetich, Tetrahedron 1987, 43, 5621 78% Reactions Proceedilng through Silicon-Migration ?? A. I. Meyers, J. Org. Chem. 1998, 63, 5517 diastereoselection: 97:385% yield diastereoselection: 96:468-70% yield BF3°OEt2 rt 8 h diastereoselection: >30:193% yield Panek, J. Org. Chem. 1993, 58, 2345 Can you work out the mechanism?? Si migration may be promoted by using hindered Si substituents R2R1 ElH SiMe3 N O O I R1 R2H SiMe3 El R1 Me3Si R2H R1 R2El SiMe3H El SiMe3 H R O Me Me SiMe3 Et Et ClCH(OMe)2 NH NH Me SiMe3 TsOH TiCl4 TiCl4 R2R1 SiMe 3H El R1 R2H I Et Et OMe OMe OHH R MeMe NH N Me Si CMe Me H H H C CMeMe H H H C Me3Si C H H H H Si C Me Me HH Me C Me3Si C H H H H Si CMe Me H H C CMeMe H H H H C Me3Si C H H H H Me Me3Si Me3Si Si C Me Me H H C C H H H H C C H H H H Chem 206Vinylsilanes: Reactions with ElectrophilesB. Breit, D. Evans Stereochemistry of Electrophile Addition to Vinylsilanes RETENTION ≡ + Nu- - NuSiMe3 ? Rotation in direction a favored (avoidance of eclipsing interactions, ? Principle of least motion a Vinyl/Allylsilanes in Organic Synthesis - Selected Examples Fleming, Org. Reactions 1989, 37, 54. a Fleming p 289 + - 78 °C (73%) (CH2O)n Fleming p 148 2. Carbonium ions to Si are less stabilized than carbonium ions to Si. C to silicon C to silicon C–Si hyperconjugation is less pronounced than the anaologous C–C hyperconjugation do to the impact of the longer C–Si bond lengths. 3. According to Lambert, silicon has a propensity to stabilize β carbonium ion via hyperconjugation (vertical stabilization) rather than bridging (nonvertical stabilization. C to silicon hyperconjugation more important than bridging 4. Silicon has a lower propensity to undergo Wagner-Meerwein like rearrangements than carbon. Summary Statements 1. Me3C+ is more stable than Me3Si+ in spite of the fact that Si is less electronegative than C. C–Si bond length: 1.87 ? C–C bond length: 1.54 ? C–Si hyperconjugation is less pronounced than the anaologous C–C hyperconjugation do to the impact of the longer C–Si bond lengths. R1 R2 O N OR2 R1 N R4 R3H N R1 R2 R4 R3 N N H H MeO2C OH H N Me N Me Hg H H X X– N H H CO2Me OHH R H H NaBH4 HgX2 X- N N H H MeO2C OH H H N R1 R2 R4 R3 N R1 HX N Me H Hg(0) X– NMe3Si Ph N O H TMS R Me Me N Ph Me3Si N H Ph SiMe3 H H N H Me RMe OH TFA TFA N H Ph HH SiMe3 NH Ph H N H Me RMeTMS OH Chem 206M. Shair, D. Evans Iminium Ions Common Methods of Generation: Stabilized Cations: Iminium-Ions 1 H+, -H2O H+, -ROH or Lewis Acid or Lewis Acid Stereoelectronic Effects on Nu Addition to Iminium Ions Hg(OAc)2/EDTA one diastereomer Stork et al. JACS 1972, 94, 5109. rds Oxidation of Amines Nu (favored) (E) (Z) Overman et al. TL 1984, 25, 5739. Only in the case of the (Z) vinylsilane is the emerging p orbital coplanar with C-Si bond. Full stabilization of the empty orbital cannot occur with the (E) vinylsilane.....hence the rate difference. rel rates: 7000/1 (Z) vinylsilane) (E) vinylsilane) PPTS, MeOH 80?C 71 % one double bond isomer Overman et al. JOC 1989, 54, 2591. pumiliotoxin A "Least Motion Argument" steps C=N Stereoelectronic Effects: Lecture 19 For additional related transformations see Aza-Cope Handout , Lecture 11