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Carbocations

terminology: historically, R3C⊕ was referred to as a “carbonium ion” but:

C

vs C

carbonium carbenium (hypervalent) (hypovalent) 5 bonds to C -rare 3 bonds to C -commonplace

moot point until the advent of super acids (George Olah, Nobel ‘96)

ex:

CH4

FSO3H - SbF5

SO2 (l)

"super acid"

CH5 SbF6 CH3

- H2

(also HF - SbF5)

methanonium

ion extremely non-nucleophilic,non-basic counterion

(see Olah, JACS 1972, 94, 808; CHEMTECH 1971, 1, 566)

structure:

R''R

R'C

empty p orbital

sp2 hybridized

quite standard sp2 hybridizationH

CHH

H

H

3 - center, 2e- bondplanar structure

note: it lacks an octet ⇒ unstable

What about ?

H

H H

H H

empty sp2 orbital (very unstable)

-can’t rehybridize to give empty p orbital

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contrast this with benzenonium ion:

H

H H

H H

H

H

H

H

H

H

and benzyl cation:

H

H H

H H

H

H

stability:

+18 +27 +38 kcal general trend: 3o > 2o > 1o > CH3

(due to hyperconjugation of β C-H bonds)

special case: R3Si

CH2 very stable (hyperconjugation of C - Si)

extra stability:

> >

~ (CH3)3C

(resonance)

R'

R overlap of empty p orbital with cyclopropyl

p orbital

special case:

tropylium ion - very stable

Br Br

(Doering, JACS 1954, 76, 3203)

α - heteroatom: Y R

O

(CH3)3C> > Y = Cl < OR < NR2 < SR

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Why this order?

consider resonance: Y Y

so, order is dictated by a balance of electronegativity & π bond energy

Why is Y C so stable when Y is more electronegative than C?

⇒ Y C is hypervalent, not hypovalent ⇒ has a full octet

unstable cations:

bridgehead carbocations (can’t planarize)

, RC C -sp2, sp carbocations (can’t empty a p orbital)

hypovalent heteroatoms ( R O ,RN

R , etc.)

“Non - Classical” Carbocations

used to describe carbocations stabilized by 3-center, 2e- interactions

ex:

1 2

3

question: what is the structure of the cation? 1 2 or 3?

The answer to this question has been debated for 35 years

players: Winstein (3) vs. Brown (1 2)

We will discuss this question more later on ...

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Methods of Generation of Carbocations

1) Ionization by heterolytic bond cleavage

C Y LA C Y LA+

Y = Cl, Br, I, OR, SR

LA depends on Y

Y LA

Cl, Br, I Ag+, FeX3, AlX3, SnX4 (F with SbF5)

OR TiCl4, TMS-OTf, TMS-I, BF3, R2AlCl; H+, Li+, Sc3+, Yb3+, Eu2+

SR Hg++, Cu+

Example:

O OCH3 BF3•OEt2O O

2) Addition of an electrophile to a multiple bond

alkenes: E

E

E+ = H+, X+, RSe+, RS+, R3C+, Pt+

Y Y

EE

Y

E

Y E+

O TiCl4, Sn(OTf)2, BF3, TMS-OTf, Et2AlCl, H+

S HgCl2, Hg(BF4)2

NR BF3, TiCl4, Yb(OTf)3, Sc(OTf)3

Example:

BF3•OEt2

O OBF3

OBF3

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3) Hydride abstraction (very exotic)

FSO3H - SbF5

SO2 (l)

H2R3C H CR3 + + SbF6

HOlah, JACS 1967, 89, 4739

Reactions of Carbocations

1) Nucleophilic attack

R3C⊕ + :Nuc → R3C-⊕Nuc

:Nuc = ROH, RSH, X-, alkene (produces new carbocation), Ar

note: this is the opposite of ionization (#1 of previous section)

2) β - elimination

H

Y

H

Y

also:

SiR3

Nuc:

SnR3

Nuc:

note: this is the opposite of generation method #2

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3) Rearrangements

H H

“1,2 hydride shift” - favors more stable cation (VERY fast reaction)

CH3 H3C

Wagner - Meerwein shift (less fast, but still fast)

Wagner-Meerwein rearrangement is an equilibrium reaction;

ex:

HH

H

H

H H

OH OH2 H

H2SO4 - H2O

+ +

B:

B:

(note: this is not a good thing if you’re trying to synthesize something!)

Carbanions

C M

occurs as a complex with M⊕, either ionic or covalent

M⊕ = Li⊕, Na⊕, K⊕, ⊕MgIX, ⊕CuI, ⊕ZnIIX, ⊕CeIIICl2, ⊕CrIICl, Al3+

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structure:

CR

3R1

R2

CR

3R

1R

2

sp3 orbital

sp3 hybridized

-rapid epimerization of stereogenic

carbanions, except when R1 = OR

(Still, JACS 1978, 100, 1481 & JACS 1980, 102, 1201)

C

sp2 does not easily invert

C CR

sp

stability:

3o < 2o < 1o < allylic, benzylic

sp3 < sp2 < sp

[note: these trends are exactly opposite those of carbocations]

R3SiC < R2NC < RSC <<O

CR C<

O

S

O

R C

(enolate)

generation of carbanions

1) reduction of σ bonds

R X R MMo

M X

R M

+

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ex:

R Br R MgBr

Mgo

Et2O Grignard Reaction

Cl BaClBa

o

Yamamoto, JACS 1994, 117, 6130

other bonds (besides R-X) can be reduced:

O SPh O LiLi

"lithium naphthalide" - single electron reductant

Accts. Chem. Res. 1989, 22, 152

O OO O O O

R LiLiSPh

H HLi

H

R R

THF, - 78o

axial

-780 to -20o

(stable at -78o) (>99:1)

-inverse anomeric effect

Rychnovsky, JACS 1992, 57, 4336

2) Metallation (deprotonation)

-very basic reagents can deprotonate C-H

-like any acid / base chemistry, it’s an equilibrium dictated by pKa

so, we use n-BuLi, s-BuLi, t-BuLi, PhLi

ex:

OMe OMe

Li

tBuLi

THF, 0o

JOC 1979, 44, 2004

Why that product? sp2 C next to O most acidic (pKa ≈ 30) Keq ≈10(50-30) ≈ 1020

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also:

KOtBu

BuLiTHF

"LICKOR"

"Schlosser base"

z isomer is favoredLi

Schlosser, JACS 1978, 100, 3258

structure of LICKOR base: Venturello, Tetrahedron 1996, 52, 7053

note that many hydrocarbons can’t be easily deprotonated due to kinetics

another special case:

NEt2 OO Et2N

Lin-BuLi

TMEDA

THF, -78o

“ortho metallation” (stabilized by O-Li

bond)

also:

OH O

Li

Lis-BuLi

THF JOC 1977, 42, 1823

O OOMe OMe

Lis-BuLi

JOC 1979, 44, 4463

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3) Transmetallation

R1 M1 R2 M2 R1 M2 R2 M1+ +

equilibrium favors putting more electropositive M on more acidic R

ex:

ZnBr Li

tBuLi tBuZnBr+ +

corrollary:

R Li R MgBr + LiBr

MgBr2

(consider Br as R2)

R Li R ZnBr + LiBr

ZnBr2

R Li R CeCl2 + LiCl

CeCl3

(very synthetically useful)

R Li R2 CuLi + LiI

CuI

(very synthetically useful)

this follows electropositivity: Li⊕, Na⊕, K⊕ > MgII⊕, CaII⊕ > ZnII⊕ > CuI⊕ > PdII⊕

(ionic) (covalent)

“hard” “soft”

related exchange reactions:

R SnBu3 R Li + Bu4Sn

BuLi

stable, chromatographable works if R is more acidic than butane (pKa ≈ 46)

also, metal - halogen exchange:

R1X R2

Li R1Li R2

X+ +

-110o to -30

o

X = Br, I -equilibrium governed by basicity of R1, R2

(favors less basic R-Li)

-very fast reaction! (competes with proton transfer)

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mechanism:

R1 X R2 Li+(+ e-)

R1 X + R2

- X

R1 R2+ R1 R2

R2 X+(+ e-)

R1Li -sequential single electron transfers

evidence is the formation of R1-R2 as a minor side-product (so-called Wurtz coupling)

this can be made irreversible:

R ItBuLi (2eq)

R Li +

H

I

Li

elimination

RLi LiI+ +

Seebach, TL 1976, 4839

Characteristic Reactions

1) acid / base chemistry

2) transmetallation / metal-halogen exchange

3) nucleophilic addition

O

R' Y

O

RR'

YR M +

M

(works best when Y = H, OR, NR2, X; R = 1o, allylic, sp2, sp)

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4) nucleophilic substitution (uncommon)

R M R' X R R' M X++

-note that this is the Wurtz Coupling, a side reaction of Li / X exchange

most common when M = CuI,, but probably isn’t SN1 or SN2

Ylides - a special class of carbanions

R2C YRn

H

R2C YR2

base

When a carbon α- to a positively charged heteroatom is deprotonated, it forms an ylide

(“yl” = ⊕; “ide” = )

-very stable carbanions

ex:

R2C PR3 R2C SR2 R2C NR3, ,

(less stable)

(note that R2C SO2R R2C PO3R R2C NO2, , can be viewed as ylides)

Enolates - another special class of carbanions

Obase

O

H

Abstraction of acidic α-proton produces resonance-stabilized carbanion => very useful

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Free Radicals - Species containing unpaired electron(s)

hybridization of carbon varies between sp3& sp2 depending on the substituents

( CH3 is

planar ) => 7 valence electrons (electron deficient like carbocations)

like carbanions, free radicals can be chiral, but invert too rapidly

stability:

look at C-H bond strengths (first handout)

1o < 2o < 3o < benzylic, allyl, acyl (similar to cation)

sp < sp2 < sp3

EWG CR2 CR3> EWG = OR, NR2, SO2R, CN,

O

CY

Why do electron - withdrawing substituents stabilize α-radicals?

through resonance, primarily:

RO R' RO R'

NC R

NC R

very stable radicals:

Ph3C N

O

O

stable & isolable

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unstable radicals:

RO R2N, ,

(note that RS is quite stable)

Methods of generation:

1) homolytic bond cleavages

R O O R R O

OOO! or h" - CO2

2R

N N

CN

CN

(AIBN)

! or h"

( - N2)2 CN

N N

O

O

O

O

X X +h!

(X = I, Br, Cl)

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2) photochemical excitation of π bonds

R R'

O

R R'

O

! = 300nm(n "*)

diradical - behaves much like 2 isolated radicals

h#

Characteristic reactions:

1) atom transfer

R + Y R' R Y R'+

equilibrium process favoring stable radical

ex:

Br Bu3SnH, AIBN (5%)

,

mechanism:

N N

CN

CN

!

( - N2) NC+ H SnBu3

H atomtransfer

very weak bond

NC-

SnBu3 +

Br

Br transfer

Bu3Sn Br

v. stable bond

-

HBu3Sn H

H atomtransfer

typically, H• & X• transfers are observed

(note: also a method of generating new radicals)

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2) Addition to π systems

R +R

the most common variant of this reaction is intramolecular:

Br

CH3Bu3SnH, AIBN (cat.)

PhH, h!

mechanism:

Br

CH3SnBu3 5 - exo trig

CH2H SnBu3

Bu3SnH

radical cyclization: Beckwith, Tetrahedron 1981, 37, 3073

review: Curran, Synthesis 1988, 417 & 489

- π system can also be

O N

R

R C N

radicals most easily detected by electron spin resonance (ESR)

- they appear as doublets

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Radical Anions & Cations

These species consist of neutral molecules that have gained (R. A.) or lost (R.C.) a single

electron.

ex:

Li

NH3 (l)Li

lithium naphthalide"dissolving metal"reduction

What is meant by the structure?

etc.

-an extra electron is delocalized throughout the π system

(unlike free radicals, no addition/loss of atoms during formation)

MO description:

e-

!"

!3

!"

!3 extra electron is placed in antibonding MO

likewise we can place an extra electron in σ* orbital:

O O OSPh SPh

- PhSLi

very common example:

O ONa

o

Na

sodium benzophenone ketyl (blue-purple)

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radical cations are somewhat more rare; most commonly encountered when single

electron oxidants are used (also in mass spectroscopy)

ex:

OR

OMe

OR

OMeCe

IV

CH3CN-H2O

para-methoxybenzyl (PMB) group

OR OR OR

etc.

MO description

- e-

!1"

!2

!1"

!2

vacant bonding orbital (“hole” in π2)

Radical cations also arise in the oxidations produced by DDQ

O OO

OO

O

O

Cl

Cl

NC

NC

(- e-)

very e- deficient

- H

(- e-)

- H

O

O

Cl

Cl

NC

NC

OH

OH

Cl

Cl

NC

NC

H

H+

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radical ions can also be distonic (Kenttamaa)

ex:

O O

vs.

-differing stabilities, reactivities

(these species are very important in mass spectrometry experiments)

Carbenes - neutral molecules lacking on octet

R1

C

R2 divalent carbon with two non-bonded electrons

⇒ VERY reactive & unstable

two different spin states:

!2

!1

!2

!1

vs.

singlet (J = 0) triplet (J = 1)

at first approximation, we can consider them as: R1

C

R2

R1

C

R2 triplet singlet

-behaves as isolated radicals -behaves as zwitterion

C

R1

R2

sp3

C

R1

R2

sp2

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structure:

much debate on structure of methylene (CH2)

CH H136o

triplet

CH H103o

singlet triplet - Wasserman, JACS 1970, 92, 7491

singlet - Herzberg, Nature 1959, 183, 1801

- same bent structure holds for most other carbenes

stability:

methylene (CH2) is a ground state triplet (by 8 - 10 kcal/mol)

-normally, carbenes are generated as singlets

carbenes are stabilized by resonance:

H2CHC COR

OHC X C H X C X< < < <

(X = Cl, Br)

a very stable carbene has been reported:

N

N

N

N

N

N

Arduengo, JACS 1991, 113, 361

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Methods of Generation

1) α - elimination

HC

R

X

R

base

slow

C

R

X

R

C

R R

ex:

HCCl3KOH

H2O

35o

CCl2 (dichlorocarbene)

also:

HCCl3MeLi

THF

-78o

CHCl (chlorocarbene)CHCl2-78o to 25o

In many cases, one can get a carbenoid instead:

CH2I2Zno

Zn(CH2I)2 Zn(CH2I)2

2

stable to α - elimination but behaves like a carbene

“Simmons - Smith” reagent

2) decomposition of diazo compounds

C N2

R1

R

R CR1

h! or "

- N2 (Δ gives singlet, hν gives excited state)

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mechanism:

C N

R1

RN N

R1

RNC

- N2

! - elim.

R CR1

also works with diazirines:

NR2C

N

h! or "

- N2

R CR

most important to synthetic chemists is the metal-catalyzed decomposition:

C N2R1

R Rh2(OAc)4

- N2

"R2C MLn"

stable, but reacts like carbene

see, e.g.: Doyle, JACS 1996, 118, 8837

Characteristic Reactions

1) Cyclopropanation

R CR1

+ R2C

singlet and triplet behave differently

:CH2

singletone isomer

triplet

:CH2mixture+

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singlet reacts in concerted fashion (no intermediate)

triplet reacts via diradical intermediate:

H

can rotate

can invert

Skell, JACS 1956, 78, 4496

more commonly:

CO2EtN2CHCO2Et

Rh2(OAc)4

Zn-Cu, CH2I2"Simmons-Smith reaction"

[via Zn(CH2I)2]

CHCl3, KOH

25°

[via CCl2]

Cl

Cl

2) C-H insertion

H

H:CH2

CH3

H

how? Maybe via 3-center, 2-electron transition state

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for preparative purposes:

O

N2

O

Rh2(OAc)4

THF

O

O

H

H

Doyle in Comprehensive Organometallic Chemistry II, (1995), Vol. 2, Ch. 5.2

(very powerful transformation – stereoselective functionalization of methylene group)

this can also be intramolecular:

Br Br

KOH

- 30o > 25

o

C-H

insertion

H Doering, Tetrahedron 1960, 11, 266

3) Rearrangements (like carbocations)

1,2 shift

Schechter, JACS 1960, 82, 1002

also:

R

N2

O

h!, "

or Rh2(OAc)4

(- N2)

R

O OC

R

(ketene)

ROH

R CO2R

this is known as the Wolff rearrangement (JACS 1961, 83, 492)

when the ketene is trapped by an alcohol, it’s the Arndt - Eisnert rxn

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The nitrogen equivalent (nitrenes) are also known:

N3 Nh! or "

very reactive

they behave similarly to carbenes, but are less stable and more reactive