Transition Metals in Synthesis Flashcards
What enhances sigma donation from alkene pi system to M in organometallic bonding
electron donating groups on alkene (push) and electron poor metal (pull)
What enhances pi donation from metal to alkene pi* system
electron withdrawing group on alkene (pull) and electron rich metal (pull)
Characteristics of carbenes
Neutral, electron deficient, very reactive
Description of a Schrock carbene
Electrophilic M, nucleophilic C, M=high oxidation state early TM e.g. Ti(IV)
Description of a Fischer carbene
Nucleophilic M, electrophilic C, electron donating group on C, M= low ox state middle or late TM eg Fe(0)
What are the properties of Ru catalysts
Somewhere in between Fischer and Schrock
What does catalyst initiation involve
Activation by loss of one ligand; vacant coordination site on M required for catalysis
Advantages of using a chelating aryl carbene catalyst
off-cycle cat stabilised therefore large TO, possible catalyst recovery with column chromatography, relatively insensitive to oxygen
How do N-heterocyclic carbene (NHC) ligands interact
They are singlet carbenes. They are strong sigma donors, poor pi acceptors (p orbital not available for pi backdonation due to resonance from 2 Ns)
What biases the equilibrium in RCM
Entropy (1 molecule becoming 2)
Why do substrates with 1,1-disubstituted alkene sites react slowly
Steric clash at 1,1-disubstituted end due to the bulky Ru centre leads to slow 2+2
What happens if there is one 1,1-disubstituted end and one electron rich end
Only one accessible alkene required for cyclisation; one electron rich alkene required for initiation and then second 2+2 is easy as it is intramolecular
Why are substrates with basic amines not compatible with [Ru] catalysed RCM, and how would you overcome this
Amine is a good donor ligand due to the lp on N and blocks the site for catalyst initiation on [Ru]. Protect the amine (Boc, rip off with TFA)
How can temporary tethers help
Control alkene geometry
What is the driving force of ring opening RCM
Thermodynamics: relief of starting material ring strain
Describe conditions for RCM
G2 (5%), DCM, reflux
Describe conditions for ring opening RCM
G1 (3%) benzene (45%)
Describe the approach of avoiding a problem with 1,1-disubstituted alkenes
Relay approach: initiate on electron rich chain; second 2+2 easy as intramolecular
Why is RCM often run at high dilution
favours RCM vs CM and gives higher yields
How do you bias the system in cross metathesis
Using an excess of one alkene favours the cross product
Describe conditions for CM
GHII (5%), DCM, RT
Why does CM favour the cross product
Catalyst equilibrates most reactive alkene (mono-homodimer) until it meets next most reactive alkene to generate product which is inert to metathesis and provides a thermodynamic sink
In ene-yne metathesis where does initiation occur?
The alkene, NOT alkyne
Give conditions for ring closing ene-yne metathesis
GHII 1% RT DCM
What is the driving force for ene-yne methathesis
Thermodynamics: conjugated product
What is the Mori Modification
Use of ethylene atmosphere increases the rate of reaction and yield; ethylene cycle creates unhindered carbene (fast metathesis) while normal cycle creates hindered carbene (slow metathesis)
Considerations to make in intermolecular ene-yne metathesis
In formation of 4mr (includes [Ru]), two R groups will be on opposite corners to prevent strain. Also, CM (2 alkenes) is possible but reversible; the alkene is often used in excess
Describe conditions for particularly effective ene-yne metathesis
Ethylene as the alkene. G2 (5%), 1 atm, PhMe, 80*C; ethylene means that there are no regioselectivity considerations
What is alkyne metathesis useful for
Ring closing reactions, macrocyclisation
What catalyst do you use for alkyne metathesis
Metal alkylidene based on W or Mo; active form formed in situ [Mo] —(DCM)—> [Mo] (triple bond)–H
Carbenes are.. (2)
neutral and electron deficient
In Schrock carbenes what is the nature of the metal?
High oxidation state early TMs eg Ti(IV)
Label electrophile and nucleophile in Schrock carbenes
Electrophilic metal
Nucleophilic carbon
In Fischer carbenes what is the nature of the metal?
Low oxidation steate late TMs eg Fe(0)
Label electrophile and nucleophile in Fischer carbenes
Nucleophilic metal, electrophilic carbon
Metallocarbenoids are…
because…
extremely reactive and non-isolable because they have a resonant structure where there is a carbocation next to an electron withdrawing group which is very reactive
Singlet free carbenes correspond to
& describe
Fischer carbenes
They have an empty p orbital and 2 electrons in sp2
They have strong carbon –> metal sigma bonding and weak metal to carbon C=E+ donation
Triplet free carbenes correspond to
& describe
Schrock carbenes
They have one electron in the p and sp2 orbitals and show covalent behaviour
They have strong carbon-metal sigma bonding and weak metal-p pi bonding
How do we generate metallocarbenoids?
From diazocompounds
Diazo + MLn –> lose N2, get metallocarbenoid
What is the most reactive type of diazo compound and why?
Acceptor is more reactive than acceptor/acceptor and acceptor/donor because there is increased conjugation in the a/a or a/d variants and therefore you need a more active catalyst to use them
Why is there a different pathway to prepare mono and disubstituted diazo compounds
The N anion prefers to attack the aldehyde rather than get protonated but the aldehyde is not present for disubstituted compounds
Describe the “Lantern” catalyst and how it works
Rh2(OAc)4
4 bridging acetates between the two Rh’s, up down out and back
16e per Rh
Forms metallocarbenoids by electron transfer between Rh centres
Acetates anchor them together
Explain the stereoselectivity of carbenoid catalysed cyclopropanation
Carbenoid approaches less hindered allene face i.e. look out for a bulky group
The carbocation then forms on the more substituted carbon
What reagent (catalyst) rpomotes asymmetric cyclopropanation
Rh2(s-DOSP)4
hexane, RT
What is the outcome of Cu(I) or Rh2(OAc)4 and diazo and a double bond?
cyclopropanation
works on alkenes, allenes, arenes(!!!)
How do metallocarbenoids react with OH bonds (alcohols, water)
formal insertion of metallocarbenoid into the O-H bond to give alkylated products
the enolate protonation is enantiodetermining
What happens with an N-H bond reacts with a metallocarbenoid
formal insertion into N-H bond
amines, anilines, carbamates, amides, aromatic amines, any N basically
What 3 types of bonds can both Cu(1) and Rh2(OAc)4 metallocarbenoid insert into
OH, NH, SH
Can be intermolecular or intramolecular
What catalyst do you need to insert into an unactivated CH bond
Rh(II)
How do you determine the CH bond reactivity for reaction with Rh(II)
CH bond reactivity correlates to ability to stabilise positive transition state: consider carbocations
1 < 2 < 3< allylic < benzylic < etherial ~ alpha amino (protecting group dependent)
While CH functionalisation with metallocarbenoids is often paralleled to classical strategies, what are the 3 advantages it has?
- asymmetry
- diastereoselectivity
- more synthetically accessible starting materials
How do you use a metallocarbenoid to generate an ylide
reaction with heteroatoms
oxygen attacks carbocation once metal is coordinated then metal leaves so C- O+ ylide is left
have to trap in situ as the carbonyl ylide is very reactive
What happens in a Cu(I) or Rh(II) catalysed rearrangement reaction
C- O+ ylide is formed and then if there is an R group attached to the oxygen it will jump onto the negative carbon
What is required for oxidative coupling
A free coordination site
Describe the stereospecifity of migratory insertion
Addition of R1 and M(n+2) across a double bond is ALWAYS syn
What is required for migratory insertion
A vacant coordination site
What is required, of two R groups, for reductive elimination with the two R groups leaving as a dimer
They must be cis at the metal centre
Describe the uses and reagents for Voldhart Co-trimerisation
3 alkynes, CpCo(CO)2 OR CpRh(CO)2 OR CpIR(CO)2, heat
It is a powerful method for the synthesis of substituted benzenes
What is the main problem for Voldhart Co-trimerisation and why are intermolecular reactions not useful
Selectivity is problematic for fully intermolecular reactions; there are so many possible products of the first step –> statistical mixture of homo and hetero dimeric regioisomers after coupling in non-biased systems
Subsequent alkyne insertion suffers analogous problems
In a fully intramolecular Voldhart Co-trimerisation where does the Co(I) initially coordinate?
Least hindered alkyne; the monosubstituted one
Define the selectivity of migratory insertion of nitriles,
R-M(n+2) + HCN
R –> C
M –> N
Carbonylation is a type of migratory insertion which (3)
- requires a vacant site
- is very fast
- is reversible and the equilibrium is influenced by concentration of CO (pressure)
What is the Pauson-Khand reaction
alkyne + CO + alkene + Co2(CO)8 (36e, sat) ---> cyclic pentenone powerful synthesis reaction is stoichiometric in Co CO comes from the catalyst other TMs can be used
Give 1 possible difficulty of the Pauson-Khand reaction
Regioselectivity can be a problem if there is small steric difference between R groups
What is the selectivity of the alkene coordination to Co
Alkene coordinates less hindered face of Co
Due to sterics, the R group on the alkene coordinates away from the R groups from the alkyne
What are the reagents and conditions for the Pauson-Khand reaction
Co2(CO)8 (stoich.)
PhMe
100*C, 18hours
What are the reagents for Voldhart Co-trimerisation
CpCo(CO)2 (~40%)
PhMe
110*C
What would you do to try to prevent competitive Voldhart Co-trimerisation if you were trying to perform a Pauson-Khand reaction
start with the pre-formed Co-alkyne complex
What are the reagents and conditions for Rh catalysed Pauson-Khand
[RhCl(CO)2]2 5%
CO (1 atm)
xylene
Room temperature
What are the reagents for Rh catalysed Voldhart like trimerisation
[RhCl(cod)2]2 5%
BINAP 10% (binap displaces cod)
THF
60*C
What happens in terms of electrons/orbitals in pi-allyl formation with Pd
Pd puts a pair of electrons into the sigma* orbital of C-X
What is the Pd precatalyst used for allylic substitution
Pd tetrakis (PPh3)4Pd 18e, becomes L2Pd(0)
OR
Pd2(dba)3.X X=solvent of recrystallisation
also becomes L2Pd(0)
What is the Tsuji-Trost reaction
Pd-catalysed substitution of an allylic leaving group
In the Tsuji-Trost reaction, which product is favoured in linear systems?
The linear product and the branched one is not generally formed
What catalysts can you use to form the branched Tsuji-Trost product of a linear system
Mo or Ir
What is the requirement of the chiral ligand that we use to carry out asymmetric Tsuji-Trost
It must be able to reach around to the opposite side of the allyl fragment so that the nucleophile “feels” the chirality
What ligand is used for asymmetric Tsuji-Trost
Trost modular ligand
its the one with the walls and flaps
Pd ligates two phosphines
Different enantiomers available of the N-C-C-N part of the molecule and it is this chirality that determines the relative orientation of the phenyl groups: chirality of diamine transferred to conformation of phenyl groups
How can we favour the branched product
Switching to electronic control
Primary carbocationic resonance form is strongly disfavoured
Can increase M-allyl carbocationic character by
- moving to 3rd row TM (easier to accomodate additional negative charge)
- using electron deficient phosphine ligands
What are the reagents for Ir catalysed allylic substitution
[Ir(cod)Cl]2 2%
PR3 (8%) THF Room temperature
nucleophile
How does the Ir catalysed allylic substitution work
Ir(I) / Ir(III) cycle operative
What increases the efficiency of the Ir-catalysed allylic substitution
electronegative groups on P ligand increase the electron withdrawing nature of ligand and decrease sigma donation and increase pi backbonding
6% 24:76 PPh3
44% 53:47 P(OiPr)3
89% 96:4 P(OPh)3
What is the criteria for an asymmetric Ir catalysed allylic substitution
The ligand must either
- favour formation of 1 Ir-pi-allyl over the other by biasing the equilibrium (thermodynamic control)
- favour attack of nucleophile onto Ir-pi-allyl over the other (kinetic control, equilibrium independent)
