Download OC 2 (FS 2013) Lecture 4 Prof. Bode 1 Carbenes and Nitrenes 1

OC 2 (FS 2013)
Lecture 4
Prof. Bode
Carbenes and Nitrenes
1
Introduction
1.1
Review of carbon valencies and hybridization
H
H
H
H
H
Methane
CH3
3
sp
H
H
Methyl anion
CH4
sp
H
H
H
H
H
−
H
Methyl radical
Methyl cation
CH3
CH3
3
sp

2
sp
+
2
Rule of thumb: electron deficiency normally goes in p orbitals, negative charge in s orbitals.
2
Carbenes
2.1
Definition
“Carbenes are neutral, highly reactive species containing a divalent carbon atom with an electron sextet”
2.2
Possible hybridizations of methyl carbene
H
H
H
H
Structure
2.3
2.3.1
2
H
sp
2
H
Hybridization
sp
sp
Geometry
Bent
Bent
Linear (not observed)
State
Singlet
Triplet
Triplet
Comparison between triplet and singlet carbenes
Spin state
p
p
sp2
sp2
σ
σ
triplet carbene
These two spin systems
can be distinguished by
EPR
singlet carbene
In most cases lower
in energy (Hund's rule)
2.3.2
Geometry
From X-ray structures (see also subchapter 5.6.1) we know that both singlet and triplet states are bent.
Bond angle
Triplet carbene
Singlet carbene
130-150°
100-110°
1
OC 2 (FS 2013)
2.4
Lecture 4
Prof. Bode
Reactivity differences of singlet vs triplet carbenes
Generation of triplet carbenes
H2C N N
hν
Different reactivities
-N2
Me
hν
H2C
H2C
H2CN2 +
relaxation
Me
+
Me
triplet
singlet
Me
hν
Me
cis-olefin
Me
trans
triplet carbenes
react like biradicals
(stepwise)
cis
Generation of singlet carbenes
CHBr3
3
3.1
CHBr3
Br2C
-KBr
-tBuOH
Me
Generation of Carbenes
1,1 elimination
base
R
X
R
R
X
R
R
Diazo compounds
R2C
N N
R2C
4.1
Me
only cis, stereospecific reaction
cis-olefin
R
4
singlet carbenes
react in concerted way
KOtBu
+
singlet
H
3.2
Me
Me
KOtBu
a) Δ
b) h ν
c) metal catalyst
N N
R
R
+
N2
Carbenoids (metal stabilized carbenes)
Generation
Fischer route
O
O
C C
R1 Li
O C M C O
C C
O
O
M = Cr, Mo, W
R1
(OC)5M
OLi
R2X
R1
(OC)5M
-LiCl
OR2
Me
stable complex
O
From diazocompounds
Rh
O
O
O
Rh2(OAc)4
H
+ EtO
-N2
Me
H
EtO
Rh
N2
4.2
O
Rh
O
Rh
OO O
Me
Rh2(OAc)4
Properties
Improved thermodynamic and kinetic stability with respect to the non-stabilized carbenes.
Fischer carbenes
- low oxidation state metals;
- middle and late transition metals Fe(0), Mo(0), Cr(0), W(0);
- π-acceptor metal ligands;
- π-donor substituents on methylene group (-OR or -NR2).
H
H
singlet
M d-orbitals
Shrock carbenes
- high oxidation states metals;
- early transition metals Ti(IV), Ta(V);
- non π-acceptor ligands non π-donor substituents.
2
H
H
triplet
M d-orbitals
Me
O
OC 2 (FS 2013)
4.3
Examples
Cl
Cl
Lecture 4
PCy3
W(CO)5
Ru
PCy3
Me
OMe
Ti
Me
NEt2
Ph
H2
C
CH2
Ta
Ph
Grubbs' complex
5
Fe(CO)4
Prof. Bode
Fischer carbenes
Al
Me
Cl
CH2 + AlMe2Cl
Ti
Me
Shrock carbenes
Reactions of Carbenes and Carbenoids
5.1
Cyclopropanation
CR2
+
5.1.1
R R
C
Intermolecular
Pd(OAc)2 (1 mol%)
N
CH2N2
+
Me
N
Me
Et2O
CO2Me
CO2Me
96%
5.1.2
Intramolecular
S
O
O
Rh2(OAc)4
N2
CH2Cl2
rt, 15 h
S
91%
5.1.3
Simmons-Smith
OTMS
OTMS
Et2Zn (1.5 equiv)
CH2I2 (1.5 equiv)
Et2O
0 °C to reflux, 4 h
Mechanism
ZnEt2
C4H10
+
CH2I2
IZnCH2I
(carbenoid)
H2C
+
5.2
I
IZn
R1
R1
R1
R2
R3
R4
R2
R3
R2
R3
R4
R4
C–H insertion
O
N2
O
O
Rh2(OAc)4
O
CHCl3
rt, 1 h
Mechanism
R1
H
R2
R3
+
M
C
M
R1
R5
C
R2
R4
R3
3
H
R5
R4
R1 R5 R4
R2
R3
H
+
ZnI2
OC 2 (FS 2013)
5.3
Dimerization
Lecture 4
Prof. Bode
Pd(PPh3)4 (10 mol%)
Et3N (1.1 equiv)
MeO
Cr(CO)5
Ph
Ph
MeO
THF
rt, 1.5 h
Ph
OMe
53% (E/Z = 2/1)
Mechanism
R1
R1
R2
R1
R2
(OC)5Cr
Pd
R1
R2
R1
R1
Pd
Pd
R2
R2
R2
R1
Cr(CO)5
R2
5.4
O–H & N-H insertion
N–H insertion
Cu bronze
O
+
N2
Ph
H N
O
EtOH
45 °C
(excess)
N
Ph
80%
O–H insertion
H OCH3
+
N2
Ph
5.5
O
Cu bronze
O
OCH3
Ph
50 °C
55%
(solvent)
Ylide Formation
N2
MeO2C
Rh2(OAc)4
+
rt, 24 h
S
CO2Me
reflux, 2 h
S
MeO2C
(solvent)
CO2Me
S
CO2Me
CO2Me
Ylide, 95%
70%
Mechanism
S
H
S
MeOOC
5.6
COOMe
MeOOC
COOMe
COOMe
S
S
H
COOMe
COOMe
COOMe
Wolff Rearrangement
O
benzene
Ph
Ph
N2
O
Reminder:
C
O
reflux
Ph
α-diazoketones
Nu
C
Ph
R
ketenes
R
O
O
R2
N
N
R1
O
R2
N
N
–N2
O
C
R2
R1
4
Nu
R
Nucleophiles: amines, alcohols...
Mechanism
R1
O
R
R1
R2
OC 2 (FS 2013)
5.6.1 Arndt-Eistert β-amino acid synthesis
Boc
1. iBuOCOCl
Et3N/Et2O, –15 °C
O
H
N
Lecture 4
OH
Boc
2. CH2N2
0 °C
R
Prof. Bode
1. PhCO2Ag
Et3N/MeOH, rt
O
H
N
N2
Boc
H
N
2. Base
MeOH/H2O, rt
R
OH
R
O
β-amino acids
α-amino acids
Mechanism
R'
O
H
N
N
N
O
H
N
R'
N
N
R
R'
H
C
H
N
Me
O
O
H
R'
O
Me
H
N
R'
R
HO
H+ transfer
H
N
OH-
OMe
R'
R'
OMe
H
N
R
R
5.7.1
R
R
O
5.7
R'
–N2
O
H
N
R
H
N
OH
R
O
O
Alkyne synthesis
Corey-Fuchs reaction
H
O
Br
PPh3 (3.0 equiv)
CBr4 (1.5 equiv)
H
1. nBuLi (4 equiv)
THF, –78 °C, 30 min
H
CH2Cl2
0 °C, 30 min
MeO
Br
2. aq. NH4Cl
MeO
MeO
Alkyne
Aldehyde
90% from aldehyde
O
Mechanism
Br
Ph3P
Br
C+
Br
Ph3P CBr2
PPh3
Br
Ph3P CBr2
Br
R
O
H
PPh3
CBr2
R
Ph3P CBr2
ylide
O
CBr2
R
Li
H
H
R
R
R
nBuLi
O PPh3
Br
Br
carbene
R
R
H
H3O+
R
Li
nBuLi
R
PPh3
H
Br
R
Br
Br
nBuLi
Br
Little is known about the reaction mechanism from the dibromoolefin to the alkyne, one of the accepted
mechanisms proceeds via a carbene intermediate.
5
OC 2 (FS 2013)
5.7.2
Lecture 4
Prof. Bode
Seyferth-Gilbert Homologation
H
O
O
O
+
H
K2CO3 (2 equiv)
P(OMe)2
Me
MeOH
rt, 8 h
N2
Cl
Cl
Ohira-Bestmann reagent
97%
Mechanism
O
O
MeO
O
O
P(OMe)2
P(OMe)2
Me
N2
O
R1
R2
6
O
P(OMe)2
R2
O
R1 2
R
N2
R1
O
P(OMe)2
N2
N
R2
R1
R1
R1
N
C
N2
R1
C
N
N
C
–N2
R2
R2
R2
N-heterocyclic carbenes
6.1
History
The first applications of thiazolydenes in umpolung organocatalysis were reported as early as 1943 (J.
Pharm. Soc. Jpn. 1943, 63, 296) and metal complexes of NHCs were already reported in the late 60’s.
However, it is only in the last two decades (milestone: 1991, Arduengo, first X-ray structure of a carbene)
that NHCs have become ubiquitous both as ligands in organometallic chemistry and as organocatalysts.
Cl
N
N
NaH
N
N
THF
H
stable carbene
(Arduengo 1991)
6.2
NHCs are singlet carbenes
For NHCs the singlet state is lower in energy than the triplet state, the reason being
π-donation into the p-
orbital of carbon from the heteroatoms adjacent to the carbene.
6.3
Examples of the most frequent NHCs and their nomenclature
R N
N R
Imidazolynidene
R N
R
R
Pyrrolidinylidene
R N
N R
Imidazolydene
R N
R
N R
Benzimidazolydene
N
R N
N R
Triazolydene
S
Thiazolidene
R can be modified to fine-tune the chemical behavior of the NHC (R = alkyl or aryl).
6.4
Properties
NHC are electron rich and particularly stable carbenes. The stability arises both from:
-
shielding effect by sterically demanding substituents (minor effect);
6
R
Tetrahydropyrimidiylidene
N
R N
N
OC 2 (FS 2013)
Lecture 4
Prof. Bode
- electronic stabilization (mesomeric interaction of the lone pairs of electrons on the nitrogen atoms
2
with the empty p orbital of the sp hybridized carbene).
X
base
N R
R N
N R
R N
H
azolium salt
R
ylide
N
N R
carbene
Acidic proton: the pKa value of the 2-position of imidazolium salts ranges from 16 to 23 (in DMSO).
6.5
Synthesis (generation)
X
N R
R N
H
X
base
N R
R N
most
common
route
N R
R N
Hg(TMS)2
K0
S
- KS
N R
R N
Cl
- Hg
- TMSCl
- TMSX
Free NHC
Δ
- HY
-CO2
Δ
N R
R N
R N
H Y
Y= C6H5, CF3, CCl3 ...
6.6
O
N R
O
Use as ligands
NHC-complexes are known for almost every transition metal, but the most important for organic chemist are:
Metal
Ru
Class
Example
Metathesis
EtOOC COOEt
Catalyst
Mes N
Cl
EtOOC COOEt
Grubbs II catalyst
reactions
Cl
N Mes
Ru
PCy3 Ph
CH2Cl2, 40 °C
Grubbs II
R
Buchwald-Hartwig coupling with hindered substrates
Cl
NH2
Pd
Cross-coupling
iPr
iPr
Me
Pd-PEPPSI
+
reactions
N
R
R
R
Cl Pd Cl
iPr
Me
Me
N
H
N
N
KOtBu, DME, 24 h, rt
Me iPr
90 %
Cl
Pd-PEPPSI
NHC behave like phosphines when they are coordinated to metals (electron donating properties) but they
have more influence on the coordination sphere of the metal (sterics).
Cross-coupling reactions
Heck
Negishi
Stille
NHC-Pd
Buchwald-Hartwig
Sonogashira
R
Suzuki-Miyaura
Kumada
N
N
R
M
R groups pointing at
the metal "coordination
sphere"
7
R
R
P
R
M
R groups pointing away from
the "coordination sphere"
OC 2 (FS 2013)
6.7
Use as catalysts
Lecture 4
Prof. Bode
See redox neutral chapter.
7
Nitrenes
7.1
Structure & hybridization
Nitrenes are nitrogen analogues of carbenes. The nitrogen atom possesses only six valence electrons; in
nitrenes the triplet state is lower in energy than the singlet state.
R N
7.2
7.2.1
R N
Generation
From 1,1-elemination
H
N
R
base
X
R
N
N
X
R
nitrene
7.2.2
From azides
N
N
R
N N
R
7.3
7.3.1
N
N N
a) heat
b) light
+
N2
R
Hoffman-type rearrangements
Hoffman rearrangement
O
F
NH2
NaOH, Br2
NH2
THF, 70 °C
N
F
N
Mechanism
O
R
Br
O
Base
H
Br
O
H
R
N
H
R
NH
O
Base
O
R
N
N
Br
R
N
C
H2O or
O
R
ROH
H
N
R
Br
Base
O
H
–CO2
O
R
nitrene
NH2
isocyanate
7.3.2
Curtius rearrangement
O
O
N
H
O
O
Toluene
N3
N
H
O
65 °C, 10 min
Acyl azide
N
C
O
Isocyanate
Mechanism
O
R
O
N
N
O
N
N
N
R
–N2
N
8
R
N
N
R
N
C
O
OC 2 (FS 2013)
7.3.3 Lossen rearrangement
Lecture 4
Prof. Bode
O
N
H
N
Δ
O
C
O
O
Mechanism
O
R
N
R
N
R
N
C
O
O
H
7.4
O
–R'OOH
R'
O
Beckmann rearrangement
N
OH
aq. H2SO4
NH
rt, 4 d
O
63%
Mechanism
N
R1
7.4.1
OH
N
H
R2
R1
OH2
R1
N R2
R2
H2O
R2
N
R1
- H2O
R2
tautom.
OH
R1
R1 C N R2
Mechanistic analogy to Baeyer-Villiger reaction
O
Ar
O
m-CPBA
R1
7.4.2
H
O
R2
O
O O
R1
R1
R2
R2
O
Industrial nylon synthesis
N
OH
O
aq. H2SO4, Δ
base (cat.)
NH
Beckmann
Rearrangement
H
N
Ring-Opening
Polymerization
O
(CH2)5
n
Nylon 6
7.4.3
Metal catalyzed C–H insertion
[(cod)Ir(OMe)]2
(2 mol%)
Ph
F3C
Ph
N3
N
H
F3C
benzene
rt, 15 h
93%
Mechanism
Ph
F3C
N
N
Ph
N
F3C
N
Ph
F3C
N
N
Ph
[Ir]
–N2
N
[Ir]
–[Ir]
H
Ph
F3C
[Ir]
9
N
F3C
N
H
H
NH
O
OC 2 (FS 2013)
8
Biological counterparts
Lecture 4
Prof. Bode
Carbenes play a central role in a number of biological processes. One of the most important examples is
Vitamin B1 (Thiamine pyrophosphate), a coenzyme involved in many metabolic pathways. For instance, the
enzyme pyruvate decarboxylase is assisted by TPP in catalyzing the transformation of pyruvate into
acetaldehyde: a key step in the anaerobic fermentation… Think about it next time you’ll have a drink!
CO2
H OH
HO
HO
H
H
Glucose
OH
OH
O
Glycolysis
HO
H
TPP, Mg2+
O
Me
NAD+
EtOH
pyruvate decarboxylase
O
Pyruvate
Me
H
Acetaldehyde
NH2
N
Me
NADH + H+
O
Me
N
O OH OH
P O
OH
P
O
O
TPP = thiamine pyrophosphate
N
S
10
alcohol dehydrogenase