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Transcript
Applications of Phosphorus, Sulfur, Silicon and Boron Chemistry: Stereo- and Regioselective Synthesis and Reactions of Alkenes Semester 1 Dr Andrew Boa, T: 01482 465022, E: [email protected] Contents Overview 1. SYNTHESIS OF ALKENES : A QUESTION OF REGIO- AND STEREOCONTROL 2. SYN ELIMINATIONS - AMINE OXIDE, SULFOXIDE AND SELENOXIDE ELIMINATIONS; CHUGAEV REACTION 3. PETERSON OLEFINATION 4. HORNER-WITTIG REACTION 5. WITTIG REACTION - UNSTABILIZED AND STABILIZED YLIDS 6. SCHLOSSER MODIFICATION OF THE WITTIG REACTION 7. ARBUZOV REACTION 8. HORNER-WADSWORTH-EMMONS REACTION 9. SWERN OXIDATION AND RELATED PROCESSES 10. JULIA AND MODIFIED JULIA OLEFINATION 11. HYDROBORATION OF ALKENES AND ALKYNES 12. OXIDATION OF ALKYL AND ALKENYLBORANES 13. PROTONOLYSIS OF ALKYL AND ALKENYLBORANES 14. HALOGENATION OF ALKYLBORANES 15. AMINATION OF ALKYLBORANES 16. FURTHER REACTIONS OF ALKENYLBORANES – CIS ALKENES 17. FURTHER REACTIONS OF ALKENYLBORANES – TRANS ALKENES 18. SILYL ETHERS: HYDROXYL PROTECTING GROUPS Suggested reading Organic Chemistry, J. Clayden, N. Greeves, S. Warren and P. Wothers, Oxford University Press. 1st Edition: Chapters 31, 46 and 47; 2nd Edition: Chapter 27 and sections of Chapters 11 and 26 (and 17 good for revision). Organic Synthesis: the Roles of Boron and Silicon, S.E. Thomas, (Oxford Primer No. 1) Organosulfur Chemistry, G.H. Whitham, (Oxford Primer No. 33) Learning outcomes: At the end of the course you should be able to: 1. Formulate the P, S or Si product formed from a given set of reagents (as covered in the course), e.g. synthesis of phosphonates, phosphonium salts, ylids etc. 2. Identify the alkene-forming reaction type for a given set of reagents, e.g. “Peterson olefination” or “Wittig: stabilized ylid” 3. Work out the structure of the alkene product(s) arising from given reagents (see LO2) 4. 5. 6. Predict the stereochemistry of the (major) alkene product (see LO3) Rationalize your deductions using a mechanistic argument (see LO3 and 4) Formulate the alkyl- or alkenylborane product arising from reaction of borane, or a borane derivative, with an alkene or alkyne. 7. Formulate the product arising from oxidation, protonolysis, halogenation or amination of an alkyl- or alkenylborane. 8. Formulate the cis or trans alkene product arising from reaction of alkenylboranes via a boronate intermediate. 9. Predict the stereochemistry of the product(s) arising from reactions covered (see LO6, 7 and 8) using reaction mechanisms to explain the stereochemical outcome of the transformations. 10. Show how silyl ethers can be used as hydroxyl protecting groups in organic chemistry. These notes, self-study workbook problems with answers, and sample past exam paper questions (some with solutions) are available for download at: http://www.hull.ac.uk/php/chsanb/teaching.html Summary of key points It is important to recognize the structure and names of the new functional groups, in particular xanthate, phosphine oxide, phosphine, phosphonium salt, phosphite, phosphonate, sulfoxide and sulfone. By doing so you will be able to spot names and structures and link this quickly to the subsequent chemistry which will be studied. Your notes Summary of key points It is really helpful use a molecular modelling kit to visualise the molecules in the Newman projection and for comparison to flat 2D representations on paper (cf. 06520 Y2 S1 “Stereochemistry” course). Do not get too “hung up” by correctly the identifying the threo and erythro isomers. Just looking at the structure properly (with or without your model kit) will allow you to work out the answer. Your notes Summary of key points In due course you will need to be sure you fully understand the difference in meaning of the terms ending “-specific” and “-selective” (e.g. stereoselective vs. stereospecific). Your notes Summary of key points E1 mechanism is two steps, stepwise reaction, cation formation followed by loss of proton. E2 is a one step, concerted reaction, occurring via the lowest energy anti periplanar conformation. Both of these have been studied before (cf. 06513 Y1 S2 “Substitution and Elimination” course). Your notes Summary of key points The Ei elimination is a one-step, stereospecific concerted process, and occurs via less stable syn periplanar conformation. In fact it is a concerted process, as covered in Dr Eames course in this same module. Your notes Summary of key points The Chugaev reaction is a thermal syn (Ei) elimination involving a xanthate group. Your notes Summary of key points Sulfoxides and selenoxides can be made by the oxidation of the corresponding sulfide/selenide. The later can be made by SN2 processes (cf. Y1 S2 06513) or enolate chemistry (cf. 06522 Y2 S2 “Bifunctional Chemistry”). Your notes Summary of key points Thermal elimination of sulfoxides and selenoxides are syn–eliminations. Selenoxides with a βhydrogen are thermally unstable and readily undergo this process, sometimes as soon as they are formed. Your notes Summary of key points The Peterson olefination involves making an alkene by elimination of a β-trialkylsilyl alcohol. Do not get confused with silyl ethers (slides 26/7) where the O is bonded directly to the Si. (NB olefin is an old fashioned word for alkene, and so an olefination is a reaction making an alkene). Your notes Summary of key points The synthesis of β-silyl alcohols is the first step of the Peterson reaction. This is basically chemistry of the carbonyl group (cf. 06512 Y1 S2 “Carbonyl Chemistry”) involving addition of a carbon-based nucleophile (organo- magnesium or lithium reagent) to a ketone or aldehyde. Your notes Summary of key points For the Peterson elimination step, acidic conditions gives rise to an anti periplanar elimination, and basic conditions a syn periplanar elimination. The alkene isomer formed [(E) or (Z)] depends on the starting material isomer AND the conditions employed. You will not be expected to know how to make a particular (single) isomer of a hydroxysilane. Your notes Summary of key points A single diastereoisomer of the starting β-hydroxysilane gives a single isomer of the alkene, and the other diastereoisomer will always give the other alkene isomer as product. Thus the elimination step is stereospecific. The synthesis of the β-hydroxysilane is diastereoselective (mixtures of isomers may be formed, whether it be 50:50 or 99:1) and so this step controls the (E)/(Z) ratio of the alkene unless the isomers of the β-hydroxysilane are separated. Your notes Summary of key points The key concepts of the Horner-Wittig reaction are very similar to the Peterson reaction under base conditions. You will not be expected to know how to make a particular (single) isomer of a βhydroxyphosphine oxide, but may be asked to discuss this in very general terms. Your notes Summary of key points The ‘trick’ to getting a pure alkene isomer is by choosing the best method to make the desired βhydroxy phosphine oxide isomer and, very probably, separation of minor isomers before elimination. Your notes Summary of key points A phosphonium salt gives rise to an ylid upon treatment with a suitable base. These react with aldehydes to form alkenes. The driving force of the reaction is the formation of the strong P=O bond (phosphine oxide) in the by-product. Your notes Summary of key points The (E):(Z) ratio of the alkene depends on the R group of the phosphorus ylid and to a lesser extent) the conditions. The ylid may be described as stabilised or unstabilised (with a few in a few cases being described as semi stabilised). Your notes Summary of key points The Wittig reaction with an unstabilized ylid (presence of CH2 group next to the C=PPh3, i.e. no conjugation) leads to the (Z) alkene major isomer via irreversible formation of four-membered oxaphosphetane intermediate. Your notes Summary of key points Reaction of ylids with ketones leads to lower stereoselectivity (and lower yields). Your notes Summary of key points The Wittig reaction with a stabilized ylid (conjugation of C=P with unsaturation in R) leads to the (E) alkene as the major product. Your notes Summary of key points The threo betaine gives rise to the (E) alkene (and the erythro betaine the (Z) alkene), but these do not equilibrate via the ylid. The presence of lithium ions affects the stereoselectivity of a reaction. Your notes Summary of key points Stabilized ylids form (E)-alkenes and unstabilized form (Z)-alkenes, but in the presence of Li+ ions increasing amounts of the amount of the other isomer may be formed. Your notes Summary of key points The Wittig reaction with Schlosser modification lead to an unstabilised ylid generating the (E) alkene as the major isomer via isomerisation of the betaine (NB betaine-Li ion complex not shown for clarity, but presence is inferred). Your notes Summary of key points Reduced yields and selectivity are seen when a tri-substituted alkene is being made (when a ketone is used). Making tetrasubstituted alkenes by any phosphorus based method is often low yielding. Your notes Summary of key points The Michaelis-Arbuzov reaction used to make phosphonates (phosphite + alkyl halides → phosphonate). Your notes Summary of key points The Horner-Wadsworth-Emmons (HWE) reaction uses a phosphonate instead of a phosphorus ylid (Wittig). One advantage of the HWE over the Wittig reaction is the formation of a water soluble phosphate salt as by-product (can be easily extracted). Your notes Summary of key points HWE olefinations with simple phosphonates (OEt or OMe) generate almost exclusively (E) alkenes. Other ‘R’ groups may generate a mixture of (E) and (Z) alkenes. Your notes Summary of key points The Swern oxidation is a mild, metal-free oxidation of alcohols to aldehydes/ketones. (Over)oxidation to the carboxylic acid is not observed. Your notes Summary of key points The most common reagents/conditions for this (type of) reaction are (COCl)2 (oxalyl chloride) and DMSO (dimethyl sulfoxide) at low T (see slide 14a). Your notes Summary of key points The Julia olefination uses a sulfone in a multi-step (separate flaks for each step) process. Your notes Summary of key points This method makes predominantly the (E) isomer of the alkene. Your notes Summary of key points The Julia-Kocienski olefination uses a heteraromatic sulfone which leads, via a Smiles rearrangement, directly to the alkene in one step (unlike the multistep Julia reaction). Your notes Summary of key points The alkene isomer ratio depends on the selectivity of the initial addition to the aldehyde and you will not be expected to predict or work out the alkene isomer ratio, other than the (E) isomer is generally the major isomer. Your notes 17a Boron and borane Boron is in group 13 of the periodic table and thus can form neutral compounds with 6-electrons in its outer shell. Borane, BH3, is such an example and due to the empty p-orbital these compounds can act as Lewis acids (cf. AlCl3) H B H H H H B H H B H H Due to its electron deficiency borane forms the dimer diborane (B2H6). Two-electron three-centre bonds (i.e bridging hydrogen atoms) are used to explain the bonding in this species. Borane is also commercially available in a variety of forms as a 'complex' with an electron pair donator - i.e. a Lewis base. The coordinate bond is formed between the vacant 2p oribtal of boron and the lone pair of a small molecule such as an ether - e.g. diethyl ether or THF (tetrahydrofuran). H H H H B H H B H H B H O O S Me Me BH3.OEt2 BH3.THF BH3.SMe2 Summary of key points Borane or diborane? In text books, papers (or exam questions!) this reagent may mentioned in either monomeric or dimeric form, but you can treat it as the same. Also, for the purposes of the “paper chemistry” in this course, borane complexed with another reagent (e.g. THF) can be considered as just another source of borane. Your notes Summary of key points Borane reacts with alkenes to form alkyl boranes. The more hindered an alkene the more likely it will undergo controlled mono- or dihydroboration reaction. In the presence of excess borane, the mono adduct can be assumed to be the major (only) product formed. Your notes Hydroboration of dienes 18a Borane can also react with dienes to form cyclic boron compounds. 9-borabicyclo[3.3.1]nonane BH3.THF 0 oC BH adds across 2nd C=C intermolecular BH2 intramolecular H B + BH 9-BBN cycloocta-1,5-diene heat H B 9-BBN BH 9-BBN is another commercially available important borane which will be encountered during the course. Mono alkyl boranes can also react with dienes to form trialkylboranes. Here the examples are reactions of thexylborane with acyclic dienes: BH2 B BH2 B Summary of key points Borane can also react with dienes to form cyclic boron compounds (as long as the ring size is reasonable). Your notes Regiochemistry of alkene hydroboration 18b The regiochemical outcome of the hydroboration reaction is that the boron adds preferentially to the least hindered carbon of the C=C bond. BH3.THF BH2 >>> 0 oC H BH2 H Addition of BH3.THF across simple alkenes is regioselective, but even more so if a more hindered alkyl borane is used. B 9- B N BN 9 -B B 99.9 : 0.1 BH 3 Cl B 98.9 : 1.1 Cl BH 3 H2 B H2 B Cl 60 : 40 94 : 6 Electronic factors also play a role in the regiochemical outcome of the reaction. As can be seen below, there is build up of positive charge on the more substituted carbon in the transition state. cf. Markovnikov addition of HX to alkenes + H H2B + - H H2 B Summary of key points The addition of a borane across an alkene is regioselective in which the boron atom adds preferentially to the least hindered carbon of the C=C bond. However there is also an “electronic factor”, which may be significant when the alkene has an electron withdrawing or donating group directly attached. If an alkyl borane is used, especially hindered ones, then the regioselectivity is often much greater. Your notes Stereochemistry of alkene hydroboration 19a The addition of a B-H across a carbon-carbon double (or triple) bond is a concerted process. The addition has been shown to be syn-stereospecific with the use of deuterated boranes or alkenes. BH3.THF BD3.THF H H BH2 H H H D BD2 D on same side as B D BD3.THF D BD2 BD2 H H H H half-chair conformation viewed side on D D B D D D H B H D H H Summary of key points The addition of a B-H across a carbon-carbon double (or triple) bond is a concerted, syn addition process. Your notes Hydroboration of alkenes: examples H BH2 Me H H BH2 + H BH2 H BH2 BH3.THF Me 19b H Me H H The addition is syn stereospecific, but the borane adds equally to each face. BH2 BH2 H H A racemic mixture is produced. BH3.THF + less hindered face CH3 H more hindered face H BH2 CH3 BH3.THF H > CH3 H H BH2 Addition to each face is different. Unequal amounts of diasteroisomers are produced. regioselective and diastereoselective addition Summary of key points The hydroboration is syn stereospecific. The borane and hydrogen always add to the same face of the alkene, so I f the alkene has two identical faces then this can lead to a racemic mixture. However, if the alkene faces are different [e.g. when the alkene contains nearby stereogenic (chiral) centres] then addition to one face of the alkene may be preferred (diastereoselectivity). Your notes Summary of key points Hydroboration of alkynes is a regioselective and stereospecific syn addition. Monohydroboration of terminal alkynes occurs smoothly only in presence of excess alkyne, and using borane leads to polymers (unhindered double addition to the triple bond). Your notes Reactions of alkylboranes 20b The carbon boron bond in alkylboranes may be cleaved in a variety of ways. Coupling the alkene hydroboration with further reaction provides a range of very useful functional groups interconversions. Oxidation R3 B Examples H2O2, NaOH BR2 3 x R-OH Me H2O2, NaOH retention of configuration OH Me Protonolysis R3 B CH3CO2H BR2 3 x R-H Me CH3CO2D retention D Me Halogenation R3 B NaOMe, X2 BR2 3 x R-X Me NaOMe, Br2 inversion Br Me Amination R3 B NH2Cl BR2 2 x R-NH2 Me NH2Cl retention NH2 Me Summary of key points There are many possible reactions of alkylboranes, and this just covers a few examples. There is no getting around having to learn the reagents to recognise these processes. Once this is done you will need to be able to note which proceed with retention of configuration and which with inversion of configuration. Your notes Reactions of alkylboranes - oxidation 21a The oxidation reaction of alkylboranes proceeds via formation of a boronate complex. Mechanism R B boronate NaOH R H2O2 R R O NaOH + HO-OH HO O B R R R R B R O repeat B R O O 3x R OH NaOH O H2 O R OH R migrates with its electron pair. Thus the migratory aptitude, in general, follows the trend 1o > 2o > 3o HO O R O HO B R O O R The alkyl group migrates from B to O with retention of configuration. Example R HO R O B R O R OH O BR2 Me anti HO O BR2 H NaOH Me H O H BR2 H NaOH Me H2 O OH Me anti Summary of key points Oxidation of alkylboranes proceeds via formation of a boronate complex. As you will see, many reactions start this way when the electron poor boron is in the presence of MeO- or HO-.The alkyl group migrates from B to O with retention of configuration. Your notes Summary of key points Oxidation of alkenylboranes is just like that for alkylboranes, however you need to remember the enol tautomerisation to the more stable keto form at the end (cf. 06522 Y2 S2 “Bifunctional Chemistry”). Your notes Summary of key points Protonolysis of alkylboranes is a stereospecific process. The alkyl group migrates with its electron pair so there is no change in spatial orientation in going from the C-B to C-H structures. Your notes Summary of key points Protonolysis of alkenyboranes is also stereospecific, and so the combined hydroboration/protonolysis sequence is a useful way to make alkenes of fixed geometry. Your notes Reactions of alkylboranes - halogenation 23a Carbon-boron bonds are not usually cleaved as easily as seen in protonolysis. As found in the oxidation reaction, however activation of the C-B bond can be acheived by making a boronate complex. This can be seen in the halogenation reactions below. Example NaOMe BH3.THF BH2 X X = I, Br Br H2B X2 Mechanism OMe OMe BH2 BH2 Br OMe Br Stereochemical implications - this reaction proceeds with inversion of configuration at the C-B centre. OMe BH2 Br2 NaOMe H B H H H Br Br Br H inversion of configuration Summary of key points Activation of the C-B bond is achieved by making a boronate complex. The reaction proceeds with inversion of configuration at the C-B centre and so is different from the other reactions looked at. Your notes Summary of key points In amination of alkylboranes the activation of the C-B bond is achieved by forming a boronate-type complex. The reaction proceeds with retention of configuration in the intramolecular migration step. With trialkylboranes the reaction stops at the second amination so only 2 moles of amine can be made. Your notes Reactions of alkenylboranes - synthesis of (E)-alkenes 24a Hydroboration of 1-haloalk-1-ynes, followed by reaction with NaOMe followed by acetic acid gives rise to (E)-alkenes via a R-B to R-C migration. Overall Me X 1. R2BH 2. NaOMe 3. CH3CO2H Me H H R X = halogen migration occurs with retention of configuration in the R group but inversion of the alkenyl geometry trans alkene Mechanism Me Me X R2BH Me C C X syn addition X NaOMe H B R boronate formation B R R OMe H R OMe Me H3COOC MeO B R H H R trans alkene Io and 2o R groups migrate preferentially MeO R Me H B H R CH3 O O MeO CH3CO2H Me B H R R stereospecific protonolysis Summary of key points Hydroboration of 1-haloalk-1-ynes can be used to make (E)-alkenes. The reaction could be viewed as the boron being used to link together alkenyl and alkyl fragments in the trans configuration. Your notes Summary of key points The migratory aptitude (3°<2°<1°) of alkyl groups in boronate complexes means that when unsymmetrical boroalkanes are used control is possible and single products can be made. Thexylborane is a common starting boroalkane for this reason. Your notes Reactions of alkenylboranes - synthesis of (Z)-alkenes 25a Hydroboration of alk-1-ynes, followed by reaction with NaOH/I2 gives rise to (Z)-alkenes Overall Me H 1. R2BH 2. NaOH, I2 Me R H H Mechanism Me Me C C H H Me H OH B R H R H H HO HO B R B R OH B R R I2 iodonium species I R H B OH R HO anti elimination Me H I Me H H OH B Me R H R OH I H OH B R R migration with inversion of configuration at C Summary of key points Hydroboration of alkynes, followed by reaction with NaOH/I2 give rise to (Z)-alkenes. Your notes H H R boronate OH R Me NaOH R2BH syn addition Me side on view H Summary of key points Using dialkylboranes one R group is wasted. So if using symmetrical dialkylboranes it is best if the R groups are simple (e.g. cyclohexyl, R = Cy). Otherwise bromoboranes may be used as the bromine does not migrate. Your notes Silyl ethers: temporary hydroxyl protecting groups 26a Silicon is a versatile element in organic chemistry, as typified by the Peterson reaction seen before. One ubiquitous application is the use of silyl ethers for the temporary protection of hydroxyl (alcohol/ phenol) groups when the presence of a free alcohol may interfere with a chemical transformation. alcohol R1 OH silyl ether * R3SiCl R1 O Bu4NF R1 OH SiR3 protection deprotection This protection / deprotection chemistry takes advantage of the particularly strong Si-O and S-F bonds. The relevant bond dissociation energies are shown below. C Si 320 kJ / mol C C 335 kJ / mol C O Si 320 kJ / mol C F 450 kJ / mol Si Si 530 kJ / mol F 810 kJ / mol *R1 is now amenable to chemical transformation without interference by the OH group, for example: protected O R3Si unstablised ylids can act as bases R = SiR3 CH2=CHPh3 nucleophile R=H O R O CH2=CHPh3 basic ylid O O Summary of key points Silyl ethers can be used for temporary protection of hydroxyl (alcohol/phenol) groups. They can be added and removed in high yield and under mild conditions. Your notes Silyl ethers 26b The following silyl ethers are commonly used as protecting groups steric bulk stability Ph Si O R Si O R Si O R Si O R Ph ease of deprotection t trimethylsilyl Me3Si-OR TMS butyldimethylsilyl t BuMe2Si-OR TBDMS -or- TBS t butyldiphenylsilyl t BuPh2Si-OR triisopropylsilyl i Pr3Si-OR TBDPS TIPS Also encountered are triethylsilyl, TES, and dichlorosilanes which can be used for protecting 1,2-diols HO O O Si Si HO TfO OTf O O TfO = CF3SO2O (trifluoromethanesulfonate, or triflate) Summary of key points The most commonly used protecting groups are TMS, TBDMS (or TBS) and TBDPS. Increasing steric hindrance leads to greater stability of the silyl ether, this is counterbalanced by requiring more forcing conditions for the deprotection. Your notes Summary of key points Protection of alcohols as silyl ethers uses a silyl chloride and a base (commonly imidazole, which also acts as a catalyst). Deprotection of silyl ethers uses either acid, or fluoride ion (Bu4NF also known as TBAF) as the Si-F bond is very strong. Your notes Selective protection using silyl ethers 27b Silyl chlorides, especially bulky TBDPSCl, TIPSCl and TBDMSCl, can be used to selectively protect 1o alcohols in the presence of 2o or 3o alcohols. This can be illustrated in the following example, showing how polyfunctional molecules may be selectively manipulated with the correct protection strategy. OH O OH OH O OH ? 2o alcohol OH ? 1o alcohol OH OH OTMS TMS-Cl imidazole TBDMS-Cl imidazole TBDMSO OTMS TBDMSO O OTMS [O] TBAF e.g. Swern (but TMS quite labile) THF / H2O OH TBDMSO O 1 eq. TBAF [O] TBAF THF / H2O (lose more labile TMS) e.g. Swern THF / H2O O OH OH O Summary of key points Judicious choice of silyl ethers means that selective protection (and deprotection) may be achieved. Bulky silyl chlorides (TBDPSCl, TIPSCl and TBDMSCl) can be used to selectively protect 1° alcohols in the presence of 2° and 3° alcohols. Your notes 28a Reactions of alkylboranes - summary R1 BR2 R2 stereospecific Oxidation R1 R 2 regioselective Protonolysis syn addition OH R H R3 R1 H2O2, NaOH retention 3 R 2 BR2 CH3CO2D H R3 retention inversion Br R2 R3 D R2 R3 NH2Cl NaOMe, Br2 R1 R1 retention reactions involve formation of a boronate intermediate Halogenation R1 NH2 R2 R3 Amination 28b Reactions of alkenylboranes - summary R2 B H R1 R2 stereospecific via enol tautomer O R1 regioselective if R1< R2 cf. cis hydrogenation syn addition H2O2, NaOH R2B R2 H R1 CH3CO2H R2 if R1 = Hal 1. NaOMe 2.CH3CO2H H H R1 R2 if R1 = H NaOH, I2 R R 2 Only one R group migrates so using thexylborane prevents wastage. The 3o thexyl group migrates slower than a 1o or 2o R group. thexyl R B H R R2 The thexyl group is known to migrate in this reaction so there is no advantage in using unsymmetrical boranes.