Wikipedia

User:Benjah-bmm27/degree/4/SPT

< User:Benjah-bmm27‎ | degree‎ | 4

Main group organometallic reagents in organic synthesis, SPT edit

References edit

  • Clayden, J. M. (2002). Organolithiums: Selectivity for Synthesis. Pergamon. ISBN 978-0080432625. {{cite book}}: Unknown parameter |city= ignored (|location= suggested) (help)
  • Yamamoto, H.; Oshima, K., eds. (2004). Main Group Metals in Organic Synthesis. Wiley. ISBN 978-3527305087. {{cite book}}: Unknown parameter |city= ignored (|location= suggested) (help)
  • Knochel, P.; Jones, P., eds. (1999). Organozinc Reagents: A Practical Approach. Oxford University Press. ISBN 978-0198501213.
  • Taylor, R. J. K., ed. (1994). Organocopper Reagents: A Practical Approach. Oxford University Press. ISBN 978-0198557586.
  • Krause, N., ed. (2002). Modern Organocopper Chemistry. Wiley. ISBN 978-3527297733. {{cite book}}: Unknown parameter |city= ignored (|location= suggested) (help)
  • Carey, F. A.; Sundberg, R. J., eds. (2007). Advanced Organic Chemistry Part B: Reactions and Synthesis. Springer. ISBN 978-0387683546. {{cite book}}: Unknown parameter |city= ignored (|location= suggested) (help)

Stereospecific and stereoselective reactions edit

General reminder:

  • Stereospecific Reaction: A reaction in which the stereochemistry of the reactant completely determines the stereochemistry of the product without any other option.
  • Stereoselective Reaction: A reaction in which there is a choice of pathway, but the product stereoisomer is formed due to its reaction pathway being more favourable than the others available.

Concise explanation from http://www.chem.ox.ac.uk/vrchemistry/nor/notes/stereo.htm

Preparation edit

Insertion edit

In the insertion (reduction) method of preparing a main group organometallic reagent, a metallic main group element M reacts with an organohalide RX. The term reduction refers to the fact that the oxidation state of carbon in the organohalide decreases by two units. For example, MeCl → MeLi can be thought of as carbon(+1) → carbon(−1), or [H3C+ Cl−] → [H3C− Li+]. In reality, MeCl and MeLi are much more covalent than this ionic formulation, but it highlights the change in formal oxidation state.

  • Halogen remains in the −1 oxidation state throughout
  • Oxidation state of carbon decreases by two units
  • Oxidation state of metal increases by two units (or two metals atoms are both oxidised by one unit): M → M2+ + 2e− or two lots of M → M+ + e−
  • For a Group 1 metal: RX + 2M0 → RMI + MIX
  • For a Group 2 metal: RX + M0 → RMIIX

The insertion reaction can be conducted on a large scale and is best for organobromides and organoiodides. Organochlorides usually require activation with zinc.

Metal-halogen exchange edit

  • RX + R′M → RM + R′X
  • Extremely fast - fast than deprotonation
  • The reaction works if RM is less basic than R′M, i.e. the organometallic with the lowest pKaH is formed
  • For example, BuLi + PhBr → PhLi + BuBr
    • This works because the pKaH of PhLi (40) is less than that of BuLi (50)
    • In other words, the pKa of PhH (40) is less than that of BuH (50), i.e. benzene is more acidic than butane
  • Consider PhI + tBuLi in Et2O and MeOH
    • If deprotonation were faster than metal-halogen exchange, would observe route 1: tBuLi + MeOH → tBuH + LiOMe
    • If metal-halogen exchange were faster than deprotonation, would observe route 2: tBuLi + PhI → tBuI + PhLi, then PhLi + MeOH → PhH + LiOMe
    • PhH is the observed product, implying route 2 takes places, and metal-halogen exchange is faster than deprotonation

Transmetallation edit

In transmetallation, an organic group from an organometallic species is transferred to a different metal.

  • Tin-lithium exchange is a common example
  • R1SnBu3 + R2Li → Li+ [R1R2SnBu3]− → R1Li + R2SnBu3
  • The best leaving group, R1, departs from [R1R2SnBu3]− as "R1−"
  • RSnBu3 are bench-stable. Addition of BuLi generates Li[RSnBu4], which then decomposes to RLi + SnBu4. These products are easily separated by chromatography, so RSnBu3 are bench-stable stores of RLi.
  • Example: PhSnBu3 + BuLi →→ SnBu4 + PhLi

 

Deprotonation edit

R-H + R′-M → R-M + R′-H

  • Deprotonation of terminal alkynes by BuLi is common: R−C≡C-H + BuLi → R−C≡C-Li + BuH
  • Requires the basicity of R′-M to be greater than that of R-M, i.e. R-H must be more acidic than R′-H
  • pKaH BuLi, RMgX ~ 50
  • pKaH R2N-M ~ 35

Lithium edit

Organolithiums are common organic reagents. They are a source of "R−" and are very reactive towards electrophiles E+. They are often used to make other organometallic species by transmetallation.

Aggregation edit

 
Tetrahedron and cubane representations of tetrameric organolithium clusters
  • Organolithiums are oligomeric in solution - they form unreactive aggregates
    • BuLi is a tetramer in solution: (BuLi)4
    • tBuLi exists as a dimer in solution, (tBuLi)2 — this makes it easier to break up and thus more reactive


  • Organolithium aggregates can be made more reactive by breaking them up with additives
Additives for disaggregating organolithium clusters
  • The additives are ligands that complete lithium's coordination sphere

 

Preparation edit

Insertion/Reduction edit

  • R/Ar-Cl --[Li0]→ R/Ar-Li
  • Works best with chlorides rather than bromides or iodides
    • Rate of reaction is proportional to the stability of the radical R•
    • The mechanism of reduction is single-electron transfer

Alkyl chlorides edit

  • The rate-determining step (RDS) is the first step and involves a single electron from metallic lithium entering the C-Cl σ* orbital of tBuCl, breaking the C-Cl bond as a Cl-Li bond forms. The driving force for the reaction is the precipitation of insoluble LiCl.
  • In the much faster second step, a tert-butyl radical tBu• combines with a neutral lithium atom Li• to form tBuLi

 

Aryl chlorides edit

  • With aryl chlorides, the first step is reversible as the electron is entering a π* orbital
  • Instead of concerted electron transfer and C-Cl bond fission as shown above, a radical anion intermediate is formed
  • The radical anion slowly decomposes (RDS) to an aryl radical Ar• and LiCl
  • Ar• and another Li• then combine to form the aryllithium ArLi

 

Arene-mediated reductive lithiation edit

  • R/Ar-Cl + Li reactions don't work very well in practice, so an arene such as naphthalene is added as an electron shuttle

Naphthalene edit

  • A lithium atom donates its valence electron to naphthalene, generating a radical anion
  • The radical anion rapidly reduces the R/Ar-Cl to R/Ar•
  • R/Ar• reacts with another lithium atom to form R/Ar-Li
  • Problems: (i) R/Ar• can attack naphthalene, forming by-products and lowering yield, and (ii) naphthalene and its by-products can be difficult to separate from the desired product

 

DBB edit

  • 4,4′-di-tert-butylbiphenyl (DBB) gives higher yields and is more recoverable than naphthalene
    • Electron transfer can occur between species up to 7–9 Å, whereas bond formation requires less than 2 Å separation
    • The bulky tert-butyl groups of DBB separate it enough from other molecules to avoid forming bonds (and thus by-products), but allow sufficiently close approach for electron transfer

 

Lithium-halogen exchange edit

Mechanism of transmetallation edit

Tin-lithium exchange edit

Deprotonation edit

Superbases edit

Enantioselective deprotonations edit

Reaction of organolithiums with electrophiles edit

Carbonyls edit

Orbital considerations edit

Lithiated carbamates edit

Rearrangements edit

Shapiro reaction edit

Bamford–Stevens reaction edit

Brook rearrangement edit

Wittig rearrangements edit

Magnesium edit

Grignard reagents edit

  • Discovered by Victor Grignard in 1900, for which he won the 1912 Nobel Prize in Chemistry
  • They have a more covalent metal-carbon bond than organolithiums, and are less pyrophoric
  • A wide range of Grignard reagents are commercially available

Schlenk equilibrium edit

In ether solution, dissociation of Grignard reagents occurs:

2 R–Mg–X ⇌ R–Mg–R + X–Mg–X

Organomagnesium iodides, RMgI, exist primarily as R–Mg–R in THF.

References edit

Preparation of Grignard reagents edit

Insertion/reduction edit

R–X + Mg0 ⇌ R–Mg–X

Groups that react with Grignard reagents inhibit Grignard formation completely edit

Mechanism of Grignard reagent formation edit

  • Single electron transfer, as for organolithiums (see above)

Transmetallation and magnesium-halogen exchange edit

  • Although standard Grignard formation does not occur well below 0 °C, magnesium-halogen exchange is rapid
  • At these low temperatures, Grignard reagents do not react with many functional groups, including esters
  • They do still react with aldehydes and ketones, however
  • It is therefore possible to prepare Grignards bearing ester groups (which would react with themselves at higher temperatures) by Mg-X exchange
  • The usual reagent is iPrMgCl, which has bulky isopropyl groups
  • It is added to aryl bromides or chlorides at, say, −20 °C or −35 °C
  • The arylmagnesium halide formed by magnesium-halogen exchange
  • It can then react with an aldehyde or ketone

Knochel reactions in synthesis edit

Reactions of Grignards with electrophiles edit

Carbonyls edit

Differences in reactivity between RLi and RMgX edit

Copper edit

Overview edit

1,4-Addition of RCu to enones edit

Reaction of RCu with RX edit

Carbocupration edit

1,4-Addition edit

  • Reaction of R2CuLi with certain chiral enones leads to 92:8 of one diastereomer (the thermodynamic product)
  • Adding Me3SiCl to the reaction mixture gives > 99:1 of the other diastereomer (the kinetic product)
    • These results suggest the cuprate addition is reversible unless trimethylsilyl chloride is present to trap the enolate intermediate

Mechanisms edit

Kinetics edit

  • 1,4-addition is first order in (Me2CuLi)2 – two equivalents of Me2CuLi
  • Proceeds somewhat like a Grignard reaction
  • The rate determining step is reductive elimination of the enolate product from the CuIII intermediate
  • Krauss, S. R.; Smith, S. G. (1981). J. Am. Chem. Soc. 103: 141–148. doi:10.1021/ja00391a026. {{cite journal}}: Missing or empty |title= (help)

R2CuLi cluster edit

  • Readable account: Carey and Sundberg, Part B, chapter 8
  • Hardcore account: Nakamura; et al. (1997). J. Am. Chem. Soc. 119: 4900–4910. doi:10.1021/ja964209h. {{cite journal}}: Explicit use of et al. in: |author= (help); Missing or empty |title= (help)
    • All sorts of complicated equilibria and intermediate structures
    • A nightmare to remember for the exam! Are we really expected to memorise this?

Asymmetric 1,4-addition edit

Conjugate reduction of enones edit

 
Crystal structure of Stryker's reagent

Stryker's reagent edit

  • Need a soft source of H− to favour addition at the 4 position
  • Ph3P + CuCl --[1. tBuONa, 2. H2]→ [(Ph3P)CuH]6 — Stryker's reagent, a red crystalline solid, 50-65 %
  • React with enone in benzene at room temperature for 28 h
  • Acts as "H-Cu", irreversible addition of hydride, under kinetic control

Asymmetric enone reduction edit

  • Use (S)-p-tol-BINAP instead of Ph3P as a ligand for Cu, [{(S)-p-tol-BINAP}CuH]
  • Use polymethylhydrosiloxane (PMHS), (SiHMeO)n, as a very stable source of hydride
  • React with enone in toluene at room temperature for 22 h
  • Can even tolerate aldehydes — selective 1,4-addition, c.f. NaBH4/LiBH4

Zinc edit

Overview edit

  • Organozinc reagents are highly tolerant of functional groups - the least reactive R-M
  • Undergo facile transmetallation
  • Highly reactive with H2O and O2
  • Need a Lewis base (LB) to activate organozincs — they're unreactive when linear but reactive when bent by coordination of an LB

Addition to enones edit

Addition to aldehydes edit

Asymmetric addition to aldehydes edit

Simmons-Smith reaction edit

Mechanism edit

  • Syn addition of CH2 to the alkene
  • Zn inserts into a C-I bond, forming I-Zn-CH2I, which acts like the carbene :CH2, being both electrophilic and nucleophilic at C
  • Five-centred transition state
    • Two C-Zn bonds form, C=C, C-I and C-Zn bonds break

Alcohol-directed Simmons-Smith edit

  • Cyclic allylic and homoallylic alcohols have an OH group fixed above one side of the C=C bond
  • This OH group coordinates to Zn in IZnCH2I, directing addition of CH2 to the same face of the alkene
  • If the OH group is further away than homoallylic, no directing effect is observed and a racemic mixture of products is formed

Asymmetric Simmons-Smith edit

Boron edit

Hydroboration edit

Asymmetric hydroboration edit

  • Enantioselective syn addition of R2B–H across C=C of an alkene
  • Diisopinocampheylborane (Ipc2BH) + Z/cis-alkene → Ipc2B–alkyl, 87% ee

Rhodium-catalysed hydroboration edit

  • The topic of GCLJ's PhD with J. Brown. Hyashi also investigated.
  • R–CH=CH2 + HB(OR)2 (catecholborane) --[Rh(I)Ln]→ R–CH2–CH2–B(OR)2 (β) or R–CHMe–B(OR)2 (α)
  • RhI catalysts tend to give the branched α-product (Markovnikov addition)
  • Catalytic cycle involes four major steps:
    • Oxidative addition of H–B to Rh(I)Ln
    • Coordination of the alkene to Rh(III)
    • Hydride transfer to the alkene (hydrorhodation) – becomes alkyl–Rh (selectivity-determining step)
    • Reductive elimination of the boronic ester RB(OR)2

Oxidation of organoboranes edit

To alcohols edit

  • H2O2 and NaOH convert R3B to ROH
  • Retention of B–C stereochemistry due to orbital requirements of the mechanism
  • Mechanism:
    • HOO− and R3B form an ate-complex [R3B–OOH]−
    • A 1,2-metallate rearrangement (stereospecific, antiperiplanar step) sees an R-group migrate from B to O, expelling OH− in the process
    • A boronic ester R2B–O–R is the product
    • This is hydrolysed to the alcohol ROH by NaOH/H2O

To amines edit

  • H2N–OSO3H converts R3B to RNH2
  • Mechanism:
    • H2N–OSO3H and R3B form an ate-complex [R3B–NH–OSO3H]−
    • An R-group migrates from B to N, expelling OSO3H−, leaving R–NH–BR2
    • R–NH–BR2 is hydrolysed to RNH2 by H2O

Carbonyl reduction edit

  • RCO2H is reduced to RCH2OH by BH3
  • Very selective for carboxylic acids, even in the presence of aldehydes, ketones (which are more reactive), amides and esters
  • Mechanism:
    • The OH oxygen of RCO2H forms an ate complex with BH3, losing H+ to give RC(=O)–O–BH2
    • H–BH2 then adds across C=O, forming R–CH(OBH2)2
    • Some further (not given in lectures) step(s) occur to give the alcohol

1,2-Metallate rearrangement edit

  • H. Brown, D. Matteson, D. Hoppe. P. Kocienski, VKA
    • Addition of "R−" from R–M to (RO)2B–CR′2(LG) gives ate-complex [(RO)2BR–CR′2(LG)]−
    • R migrates from B to C, expelling LG in the process, generating RR′2C–B(OR)2 (the actual 1,2-metallate rearrangement step)
    • RR′2C–B(OR)2 can be oxidised to RR′2C–OH
  • The 1,2-metallate rearrangement step is stereospecific, requiring antiperiplanar R–B and C-LG bonds and involving inversion at carbon

Matteson edit

  • Add LiCHCl2 to R′–B(OR)2, where (OR)2 is actually a chiral bidentate "ligand" for B
  • Initial ate-complex formed is [R′–B(OR)2–CHCl2]−
  • Undergoes 1,2-met to R′–CHCl–B(OR)2 with loss of Cl−
  • Add a Grignard R″–MgX to R′–CHCl–B(OR)2, attack at B is faster than SN2 at C–Cl σ*, forming [R′–CHCl–B(OR)2–R″]−
  • Another 1,2-met: R″ migrates from B to C, expelling the second chloride, undergoing inversion at C, and forming R′R″HC–B(OR)2
  • R′R″HC–B(OR)2 is then oxidised to R′R″HC–OH or R′R″HC–NH2
  • Two inversions at carbon lead to overall retention at carbon, stereospecific reaction

VKA: lithiation-borylation edit

  • Enantioselective deprotonation (s-BuLi, (−)-sparteine) converts a carbamate to a lithiated carbamate
  • The lithiated carbamate forms an ate-complex with a pinacol-boronic ester RBpin
  • 1,2-met: R migrates from B to C, expelling OCb, forming a different pinacol-boronic ester
Retrieved from "https://en.wikipedia.org/w/index.php?title=User:Benjah-bmm27/degree/4/SPT&oldid=1192503351"