Professor David L. Van Vranken
Chemistry 201: Organic Reaction Mechanisms I
Topic 14: Alkali Organometallics
X
X Li OR 2
E+
Read:
F. A. Carey & R. J. Sundberg Advanced Organic Chemistry, Part A: Structure and
Mechanisms. 5th Ed. Ch. 6
M. Schlosser, Ed. Organometallics in Synthesis: A Manual Wiley, 1994. "Chapter 1.
Organoalkali Reagents"
Misconception
■ Consider these two resonance forms:
covalent
M
M+
R 3C
-
..
R 3C
ionic
■ Electronegativity determines ionic character & basicity
Electronegativity:
2.2
R-M Covalent character:
H
(Ionic character) Basicity:
1.3
> Mg
0.98
>
Li
0.93
Na
>
0.82
>
0.82
K
>
Rb
R-MgBr < R-Li < R-Na < R-K
R MgBr
R Li
R
Na
R
K
0.79
>
Cs
<
R-Cs
R
■ Avoid ionizing R-M bonds; just use the bond as the base/nucleophile.
like this
H 3C
Li
..
H 3C
not this
Li +
O
■ COMPLETE FICTION: Li, Na, K, Mg, Ca, etc. want no electrons
They want 8 valence electrons!
Here’s what H3CLi does in hexane.
H 3C
+
Li
Li
Li
-
Li
+
H 3C
CH3
Li
H C
HH
HH
C H
+
Li
HH
C H
H 3C
Li
-
H H
-2
+2
H C
Li
+2
Li
CH3
-2
+2
Li
H C
H H
+2
C H
H
Li H
-2
Lewis structure
Formal charges: Li 2-, C 2+
3 bonds to each Li
6 bonds to each C
Cs
Aggregation of Alkali Organometallics
■ Alkyllithiums aggegrate to form tetramers, hexamers, etc. to help lithium satisfy the octet. Sterics often
prevents Li from achieving an octet. Bulkier alkyl groups lead to less aggregation. Using dative bond
representations reduces the complexity of these structures.
H H
-2
+2
H C
Li
+2
Li
CH3
-2
+2
C H
H
Li H
Li
+2
H H
H C
Li
Li
CH3
H C
H H
Li
H C
H H
-2
Lewis structure
C H
H
Li H
dative bonds
crystal structures of (MeLi)n
■ Metal alkoxides also aggregate
t-BuOK
t-Bu
-2
K
t-Bu
+2
+2
O
K
OLi
-2
+2
O
t-Bu
O
K
K
-2
=
+2
O
t-Bu
■ You don’t have to draw these aggregrates; but never be afraid to form additional bonds to alkali metals.
Dos and Don’ts for Drawing Mechanisms with Organoalkali Species in Chem 201
■ Draw arrow-pushing mechanisms that avoid ionizing anions and cationic metals
H 3C
MgBr
H 3C
+MgBr
..
Don't do this:
O
Do this:
H 3C
MgBr
O
Don't do this:
Do this:
t-BuO
t-BuO
t-BuO
..
K
t-BuO
..
O
-
t-BuO
-
K
H
H
H
R
K
R
K
H
+K
t-BuO
H
I'll accept..
+
MgBr
..
Don't do this:
H 3C
R
+ K
t-BuO
H
:R
-
+ K
t-BuO
H
:R
-
R
+K
- :
R
R
K
+ t-BuO
H
+K
t-BuO
H
K R
t-BuO
H
K R
:R
-
t-BuO
H
Metal Hydrides
Na-H
■ Na—H = cubic lattice
K-H
(Arrow pushers: pretend M—H is a monomer)
Dyck, W.; Jex, H. J. of Physics C 1981, 14, 4193
■ Example: metal hydride basicity
Na–H
+ H–OR
+
MH
+ H H
Li-H
NaH
KH
OM
O
M H
+ H H
Na–OR
H 2C
R
Ph
krel
1
1,000
1,000,000
■ Basicity (vs nucleophilicity) increases from RMg to RK.
O
H
H
H
M
π∗ OM
Ph-M
Ph
Ph M
CH3
Ph
Ph
Ph
Ph
MgBr
Li
Na
K
Grovenstein, E. JACS 1959, 4842
Ph
97
14
4
0
Ph
σ∗ OM
CH 2
Ph
0
75
60
67
more negative charge
= more basic
Synthesis of Organometallics
■ We don’t have arrow pushing representations for electron transfers, nor good Lewis representations
for the radical anion intermediates.
+ 2Na
Cl
Na+ e-
R Cl
NaCl +
•
–
Na+
-NaCl
■ Rates depend on R-X:
Na
R Cl
M
R•
RI > RBr > RCl
n-BuM
E2
+
SN 2
Wurtz coupling
Formation of R-Na requires special conditions:
(finely dispersed Na, high speed stirrer, vortical fluid motion, special glass, -10 °C)
■ Always make R–Li from R––Cl but not R –– I. Here’s why…
n-BuX
X
Cl
Br
I
+
n-BuLi
t1/2
40 h
30 min
< 5 min
Et 2O
σ*C-Cl
= EMO
σC-Cl
Why don’t we make n-BuNa?
■ Kronos behaviour (children swallowed by creator)
Cl
•
–
E2
+ SN 2
t1/2
>100 h
40 h
3h
in C6H 6...
Why rel. order?
Step 1 =
e- into σ* orb
E
σ*C-Cl
σ*C—Br
σ*C——I
Preparation of Alkyllithiums by Reductive Lithiation
■ Reductive lithiation of thiophenyl ethers.
Li + naphthalene = LiNp, but it is a pain to remove one
equivalent of naphthalene after the reaction is over. Dimethylaminonaphthylamine is readily removed
with an acid wash.
Li+
O
NMe 2
.. -.
-78 °C
SPh
O
Li
"LDMAN"
■ LiNp efficiently adds an electron to the pi* antibonding orbital of PhS groups. Rates of reductive
lithiation correlate with the ease of radical formation.
Li +
e-
many, many
res. structs.
radical
S+
Li
. ..
.
-
Li +
e-
rate of reductive lithiation:
SPh
SPh
SPh
R
Cohen, T. J. Am. Chem. Soc. 1984, 106, 1130.
Preparation of Alkyllithiums by Exchange Reactions
■ Metal/halogen exchange
Rates depend on R-X:
n-Bu—Li
+
RI > RBr > RCl
X—Ph
n-Bu—X
+
With R-I, instantaneous at -80 °C
Mechanisms: Newcomb, M. TL, 1989, 26, 1183
R-I, low temp - iodate; R-Br, high temp = e- transfer
Li—Ph
-70 °C
Rates: I >> Me 3Sn > Me 3Sn
Kanda, T J. Phys. Org. Chem. 1996, 9, 29.
80 : 1
■ Sn-Li exchange (same with lithium-iodide exchange)
R
MeO
SnMe3
n-BuLi
Et 2O
Me
Bu
–
R
Sn
Me
Me
MeO
Li+
stann-ate
R
Li
Bu—SnMe 3
Mechanism = stann"ate"
MeO
Sn: MacDonald, T. J. Am. Chem. Soc. 1988, 110, 842.
I: Farnham, W. B. J. Am. Chem. Soc, 1986, 108, 2449.
■ Sn-Li exchange proceeds with retention at carbon
Reich, H J. Am. Chem. Soc. 1992, 114, 6577-9.
Metal-Halogen Exchange Driven by Thermodynamics
■ Metal-halogen exchange is faster than SN2 (at low temp.)
R Li
+ Ph
I
-70 °C
Compound
R I
+ Ph Li
Keq
R Li
Li
0.004
Li
1
R
Li
n-BuLi ~
s-BuLi ~
I
-
R'
Li+
I
R'
10
Li
7,500
Li
10,000,000
R
I
Li
R'
way faster than S N2
Li >10,000,000
R Li
R'
I
Applequist, D.E.; O'Brien, D. F. “Equilibria in Halogen-Lithium Interconversions” J. Am. Chem. Soc., 1963, 85, 743-748.
Formation of Organometallics by Metalation
■ Recall:
pKa'
50
H 3C CH 2Li
Basicity:
41
H 2C CHLi
>
>>
10 9
24
HC CLi
10 17
<
36
R 2NLi
10 12
■ Direct metalation (deprotonation) of benzene is too slow to be useful
Li
slow!
Li +
H
+
...also with BuLi
■ Alkynes can be directly metalated
R C C H
+
fast
Et-MgBr
+
R C C MgBr
Et-H
■ Recall: deprotonation of alkyne C-H is relatively fast
Cl
NaOEt
H
OEt
EtOH
H
Ph
Cl
C
C
EtO -
C
..
..
C-
(w/ t-BuOK)
Shiner, V. J.; Humphrey, J. S., Jr. J. Am. Chem. Soc. 1967, 89, 622.
See also… Sonogashira couplings
C
C
Ph
Directed Ortho Metalation
■ Chelation of R-Li speeds up metalation and stabilizes Ar-Li
OH
OCONEt 2
Me
OH
Me
?
NaOH
CH3I
NEt 2
O
O
H
‡
NEt 2
O
n-BuLi
THF
-78 °C,1 h
NEt 2
O+
Li H
O
O+
Li + C 4H10
■ Relative directing power; (you keep the chelate in the aryllithium)
NEt 2
O
O
Li
O
t-Bu
O
S
O
Li
>
N
LiO
Li
Me
N
Li
N
>
O
Li
OMe
Li
V. Snieckus
“Directed ortho metalation. Tertiary amide and O-carbamate directors in synthetic strategies for polysubstituted aromatics”
Chem. Rev. 1990, 90, 879.
Metalation of Strained Rings
■ Epoxides undergo two competing reactions with bases
■ Lithium amide bases convert epoxides to allylic alcohols. The base removes the proton
syn to the epoxide.
LiNR 2
O
O
OLi
H ..
NR 2
Li
Thummel, R.P.; Rickborn, B. J. Am. Chem. Soc., 1970, 92, 2064
■ Very aggressive bases deprotonate epoxides and generate lithium carbenoids.
H
Li
O
H
NEt 2
16%
H
OLi
70%
it's an
electrophile
empty p
OLi
Li
it's a filled σC-Li
nucleophile
H
O
R-Li
Li
O
H
+
H
Li
Ocarbenoid
Cope, A. C.; Lee, H.-H.; Petree, H. E. JACS 1958, 80, 2849.
Hodgson, D.M.; Bray, C.D.; Humphreys, P.G. Synlett 2006,1.
Aggregation of R-Li
■ Ether solvents coordinate to alkali metals. n-BuLi forms a tetramer in THF + some dimer
.
Br
Li
C
C Li
C Li
O
Li C
O
Li
O
C
Li
C
Li wants octet
Ph
THF
Li = Li•THF
C = n-Bu
H
~1%
OLi "
"
i-Pr2N–Li
Ar
OEt 2
OEt 2
Ph
+
Mg
OEt 2
wrong!
O
Bn-Br
Ar
THF, -78 °C
Mg
dative bonds to metals
don't draw charges
don't use for arrow pushing
■ Li enolates = 99% dimer in THF, but reacts via monomer.
O
– ..
..OEt 2
Br
Ar
25 °C
Ph
Streitwieser
JOC 1995, 4688
Ar
O
Li
Li
25 °C
O
Ar
SLOW
99%
■ C=O Addition: Me—Li / n-Bu—Li add as dimer!
+ - R
O Li
Li
R
C
+
O Li
C
R
R Li
IMPORTANT RULE:
Arrow Pushers: Pretend RM is monomer
M = Li, MgBr
O
+
M
R
But never forget aggregation
Kaufmann, E.; Schleyer, P. v. R.; Houk, K. N.; Wu, Y. D. JACS 1985, 107, 5560.
Nakamura, M.; Nakamura, E.; Koga, N; Morokuma, K. JACS 1993, 115, 110167.
M
O
R
Organocuprates
■ Organocopper, R-Cu is not very nucleophilic or basic
■ Cuprates, R2CuLi are ARE nucleophilic.
They do all the things you wished RLi could do: substn with R-X, opening epoxides, 1,4-addn., etc.
Require exquisite technique and involve complex mechanisms.
"Me 2CuLi" + LiI
2 MeLi + Cu-I
cuprate
" Li+ Me
"
LiI
Me Cu
actually, aggregated
1. nucleophilic C
2. low charge on C
i.e., SOFT
borate
H
-B
H
H
H
(Me 2CuLi = Gilman reagent)
aluminate
silicate
H
H
- Al
- Si Et
Et
H
H
Et
H
OR
other "-ate" complexes
not soft
The true structures are complex
X-ray struct.
PhCu • 1/2Me 2S
■ Cross-coupling
Br
Ph
Ph 2CuLi
Me 2S
Cu
Cu
Cu
Cu
SMe2
=
Et 2O
0 °C, 5 h
Ph 2CuLi•Et 2O
■ Cuprates favor SN2'
Cu
X
Me
Bu 2CuLi
X = Cl, OAc
Bu
Et 2O
Li
Li
Cu
OEt 2
=
1,4 - Addition by Organocuprates
■ 1,4-Addition
LiO Me
MeLi
O
O
Me 2CuLi
CuMe Li +
-
OLi
Cu–R
R
Me
O
OLi
R
Cu
R
Li
R
Cu
R
Canisius, J.; Gerold, A.; Krause, N. Angew. Chem. Int. Ed. 1999, 38, 1644.
■ TMS-Cl accelerates 1,4 addn.
+ Me 3SiCl
O
SiMe3
silyl enol ether
Me
Bu
99%
no rxn at -70 °C
w/o TMSCl
O
Bu 2CuLi
•LiI
Me
added last
-70 °C
< 1 sec
Nakamura, E.-I.; Kuwajima, I. JACS 1984, 3368
■ Cuprates add 1,4- to α,β-unsaturated aldehydes. All other organometallics would add to C=O.
O
+ Me 3SiCl
R 2CuLi
H
Me
O
SiMe3
H
Bu
Me
Zinc Homoenolates
■ Nucleophilic cyclopropane bonds
EtO
OSiMe3
ZnCl2
Et 2O
EtO
O O
Zn
OEt
EtO
..
OSiMe3
ZnCl2
Nakamura, E.-I.; Kuwajima, I. JACS 1986, 27,83
EtO
SiMe3
O+
ZnCl2
–