Cations

Carey & Sundberg, Part A Chapter 5, "Nucleophilic Substitution", 263-350 .

F5Sb F SbF5–

1.467 Å

+1.855 Å

1.503 Å

1.495 Å

T. Laube, JACS 1989, 111, 9224

Me

Me

Ph Cl

C

Me

Me

Ph

+

AgSbF6

B.A., 1941, UCLAPh.D. 1944, UCLA

Instructor, Harvard, 1945-6

John D. Roberts was born in 1918, starting his career in 1922. He became Prof. at MIT and then Prof. at Caltech where he is still active. His work is centered on mechanisms of organic reactions.

John D. Roberts graduated from the University of California at Los Angeles where he had received A. B. (hons) degree in 1941 and the Ph. D. degree in 1944. In 1945-1946 he was a National Research Council Fellow and Instructor at Harvard. Later on, he went to MIT in 1946 as an Instructor. He had introduced the terms "nonclassical" carbocations and "benzyne" into organic chemistry. He had won numerous awards; he is a member of the National Academy of Sciences (1956) and the American Philosophical Society (1974). He received the Welch Award (1990, with W. E. Doering), the National Medal of Science (1990), and the ACS Arthur C. Cope Award (1994). Since 1939 his research has been concerned with the mechanisms of organic reactions and the chemistry of small-ring compounds. His current work involves applications of nuclear magnetic resonance spectroscopy to physical organic chemistry.

Roberts made major research and pedagogic contributions to mechanistic organic chemistry. He pioneered the use of 14C and other isotopic labels to follow molecular rearrangements as, for example, in the complex and subtle solvolysis of cyclopropylcarbinyl systems. He introduced the terms "nonclassical" carbocations and "benzyne" into organic chemistry, and used isotopic labeling to establish the intermediacy of each. Roberts was early to recognize NMR's potential, and used 1H NMR to study nitrogen inversion, long-range spin-spin coupling and conformational isomerism, and later 13C and 15N NMR to study other reactions, including the active sites of certain enzymes. Roberts' superb short books on "Nuclear Magnetic Resonance" (1959), "Spin-Spin Splitting in High Resolution NMR" (1961) and "Notes on Molecular Orbital Calculations" (1961) did much to popularize and clarify these subjects for organic chemists. His highly successful text "Basic Principles of Organic Chemistry" (1964), written with Marjorie Caserio, introduced spectroscopy early to undergraduates. Roberts received many awards, including the Roger Adams (1967) and Priestley (1987) Medals. An excellent photographer, Roberts graciously supplied several of the photographs for the MSU collection.

“One of the joys of being a professor is when an exceptional

student comes along and wants to work with you”.

J.D. Roberts, The Right Place at the Right Time. p. 63.

Carey & Sundberg, Part A Chapter 5

Carbocations

QuickTime™ and aTIFF (PackBits) decompressorare needed to see this picture.

The Adamantane Reference(MM-2)

T. Laube, Angew. Chem. Int. Ed. 1986, 25, 349

110 °

100.6 °

1.530 Å

1.608 Å

1.528 Å

1.431 Å

Me

Me

Me

H

Me

Me

Me

C+

+ [F5Sb–F–SbF5]–

Carbocations

Carbocation Subclasses

R3 R2

R1

⊕R–R3 = alkyl or aryl

R3 R2

O⊕

R–R3 = alkyl or aryl

R1

R3 R2

N⊕

R–R3 = alkyl or aryl

R R

Carbon-substituted Heteroatom–stabilized

Cationic Systems

Stability: Stabilization via alkyl substituents (hyperconjugation)

R

R

R

H

R

R

H

H

R

H

H

H

Order of carbocation stability: 3˚>2˚>1˚

>> > Due to increasing number of substituents capable of hyperconjugation

C C+H

314

276

249

231

287386

239

Hydride ion affinities

The relative stabilities of various carbocations can be measured in the gas phase by theiraffinity for hydride ion.

J. Beauchamp, J. Am. Chem. Soc. 1984, 106, 3917.

+ H

Note: As S-character increases, cation stability decreases due to more electronegative carbon.

+ HI

ΔHI increases → C(+) stability decreases

Hydride Affinity = –ΔG°

C C C C

CH3+

CH3CH2+

(CH3)2CH+

(CH3)3C+

H2C=CH+

PhCH2+

R R–H

Carbocation StabilityCarbocation Stability

Hydride abstraction from neutral precursors

R3C H + Lewis-Acid R3C H =

H H

H

RS

RS

H

H

R2N

R2N

H

Hetc.

Lewis-Acid: Ph3C BF4, BF3, PCl5

Removal of an energy-poor anion from a neutral precursor via Lewis Acids

R3C X + LA LA–X LA: Ag , AlCl3, SnCl4, SbCl5, SbF5, BF3, FeCl3, ZnCl2, PCl3, PCl5, POCl3 ...X: F, Cl, Br, I, OR

Acidic dehydratization of secondary and tertiary alcohols

R3C OH - H2O R: Aryl + other charge stabilizing substituentsX: SO4

2-, ClO4-, FSO3

-, CF3SO3-

From neutral precursors via heterolytic dissociation (solvolysis) - First step in SN1 or E1 reactions

solventAbility of X to function as a leaving group:-N2

+ > -OSO2R' > -OPO(OR')2 > -I ≥ -Br > Cl > OH2+ ...

Carbocation Generation

R3C

R3C +

+ R3C +H–X X

R3C X R3C + X

Addition of electrophiles to π-systems

R

R

R

R

H R

R

R

RH R R

H R

HR

H

Carbocation Generation

Vinyl & Phenyl Cations: Highly Unstable

Phenyl Cations

H3C CH2

276

H2C CH

287

+21HC C

386

+81

Hydride ion affinities (HI)

H2C CH

287

+11

298

Allyl & Benzyl Carbocations

Carbocation Stabilization via π-delocalization

Stabilization by Phenyl-groups

The Benzyl cation is as stable as a t-Butylcation. This is shown in the subsequent isodesmic equations:

Ph CH2

239

Hydride ion affinities (HI)231

Me3 C

Carbocation Stability

Br

Carbocation Stability

Carbocations

Preparation of a vinyl cation

no good nucleophiles prevent loss of H+

stabilizing -Si groups

Müller T., Juhasz, M., Reed, C. A., Angew. Chem. Int. Ed., 2004, 43, 1543-1546.

-Si stabilization(hyperconjugation)

NMR evidence

Only one 29Si signal Symmetric in solution

(confirms ring closure) =C+ is far downfield Si resonance is downfield No solvent effect

+

29.129.1

202.4

75.3

13C and 29Si NMR chemical shifts

IR spectrum

Typical Frequencies:

C=C 1660 cm-1

C≡C 2200 cm-1

Exp. C=C+ 1987 cm-1

Calculated: 1956 cm-1

CB11

H6Br

6-+

C=

C+

B-H

Crystal Structure

crystal packing

Selected distances/angles

C2 - C11: 1.220 ÅC2-C11-C12: 178.8 °Si1 – C2: 1.984 ÅSi3 – C2: 1.946 Å

Selected distances/angles

C2 - C11: 1.220 ÅC2-C11-C12: 178.8 °Si1 – C2: 1.984 ÅSi3 – C2: 1.946 Å

Müller T., Juhasz, M., Reed, C. A., Angew. Chem. Int. Ed., 2004, 43, 1543-1546.

Carbocation Stabilization via Cyclopropylgroups C

A rotational barrier of about 13.7 kcal/mol is observed

H

Me

Me

R. F. Childs, JACS 1986, 108, 1692

1.464 Å

1.409 Å

1.534 Å

1.541 Å

1.444 Å

24 °

1.302 Å

R

O1.222 Å

1.474 Å

1.517 Å

1.478 Å

X-ray Structures support this orientation

Cyclopropyl CationsCyclopropyl Cations

Solvolysis rates represent the extend of that cyclopropyl orbital overlap contributing to the stabiliziation of the carbenium ion which is involved as a

reactive intermediate:

Me

Me

OTs

OTs

Cl

Cl

krel = 1 krel = 1

krel = 106 krel = 10-3

OTs

OTs

krel = 1

krel = 108

Me

Me

Me

OTs

TsO TsO TsO

Bridgehead Carbocations

1 10-7 10-13 104

Bridgehead carbocations are highly disfavored due to a strain increase in achieving planarity. Systems with the greatest strain increase upon passing from ground state to transition state react slowest.

why so reactive?

Cyclopropyl Carbocations

Carbocations in Bridged SystemsCarbocations In Bridged Systems

Carbocation [1,2] Sigmatropic Rearrangements

B

ACD

B

ACD

1,2 Sigmatropic shifts are the most commonly encountered cationic rearrangements. When either an alkyl substituent or a hydride is involved, the term Wagner-Meerwein shift is employed to identify this class of rearrangments.

S te reoe lectronic requirement for migra tion....

B

AC

D

bridging T.S .

re tention of s te reochemis try

Carbocation [1,2] Sigmatropic Rearrangements

Carbocation [1,2] Sigmatropic Rearrangements

OH

OH

O

Pinacol rearrangement (Driving force is the formation of C=O)

H+

Carbocation [1,2] Sigmatropic Rearrangements

Me

MeMe

MeH

Me

Me

H

HMe OH

Me

MeH

HMe

Me

Me

HOH

α-caryophyllene alcoholE. J . Corey J . Am. Chem. Soc. 1964, 86, 1652.

Demjanov-rearrangement (Driving force: relief of ring strain)

OH

HMe

Me

Me

Meequiv to

H2SO4

Carbocation [1,2] Sigmatropic Rearrangements

Pirrung, JACS 1979, 7130; 1981, 82.

MeMe

MeMe

(±)-IsocumeneMe

Me

Me Me

Me

Me

Me

H+

MeMe

MeMe

Synthesis of (±)-Isocomene

O

R1 H

R2

R1

R2

OH

OO

R1

R2

R2

R1

R2

OH- H+

HX

R1CHO

X-

R1

R2

OH X

+

O

R1 H

H

R2

OOH

R1

R2

R2

- H+

The Prins Reaction

The Prins Reaction

O

OMe

Ph

Me

Me

MeO

Ph

Me

O

Me

O

Me

MeMe

PhO

Me

Lewis Acid Prins

pinacol

The Tandem Prins–Pinacol Reaction

O

OMe

Ph

Me

Me

Me

LA

LAO

Ph

Me

O

MeLA

Me

Me

Me

Me

Tandem Prins-Pinacol Reaction

Overman’s Laurenyne

Synthesis

JACS, 1988, 110, 2248

O

Cl

Me(-)-Laurenyne

O

Cl

OR

O

TMS Cl

OR

TBDPSO

OEt

HO

1. SnCl4 (2 equiv.), 0 °C, CH2Cl22. TBAF

HO

Cl

OR

EtOOTBDPS

PPTS (cat.), CH2Cl2

TMS

PPTS =N

H OTs

TBDPS = (tert-butyldiphenylsilyl) SiTBAF = (tetrabutylammonium fluoride) Bu4N F

Overman’s trans-Kumausyne

Synthesis

JACS, 1991, 113, 5378

O

AcO

Et

Br

trans-Kumausyne

OH

OH

O

H

H

O

OR

O

H

H

ORO

O

RSO3H, rt

m-CPBA

4:1 regioselectivity

1. Protecting Group Removal2. Oxidation

O

H

H

OO

Me

SiMe3

BF3•OEt2-78 °C → rt

1.

2. TBSCl

O

H

H

OO

Et

OSiR3O

HO

Et

OSiR3

H

O

DIBAL-78 °C CHO

H

O

OR

O

AcO

Et

Br

Overman’s trans-Kumausyne

Synthesis O

AcO

Et

Br

trans-Kumausyne

OH

OH

O

H

H

O

OR

RSO3H, rt

H

O

OR

O

OH

OR

HO

HO

ORH H

OHO

ORH H

OHO

ORH HH

OO

ORH HH

Prins

Pinacol

Allyl– & Vinylsilanes react with electrophiles

Mechanism - the simple picture: -Silicon stabilizes the carbocation

R3SiE E

SiMe3E

E

R3SiE

R3Si ENu

E

SiMe3

E

H2C SiMe3

E

Nu

E

"R3Si+"

"R3Si+"

The -Silicon EffectThe -Silicon Effect

-Silicon Effect: the origin of regioselectivity

SiσSi–C → pz empty

σSiC

pz

Eσocc

pz

H3Si

HH

CH2 versusH3C

HH

CH2

Calculation: A more stable than B by 38 kcal/mol.

Jorgensen JACS 1985, 107, 1496.

Magnitude of the β-Silicon Effect

Me3C

H

SiMe3

OCOCF3

HH

1

Me3C

H

Me

OCOCF3

HH

2

Solvolysis (CF3CH2OH)

k1

k2

= 2.4 x 10+12

Me3C

H

H

OCOCF3

SiMe3H

3

Me3C

H

H

OCOCF3

MeH

4

Solvolysis (CF3CH2OH)

k3

k4

= 4 x 10+4

"These figures established the β-effect as one of the kinetically

strongest in organic chemistry": J. Lambert

A B

The β-Silicon EffectThe -Silicon Effect

Allylsilanes add to aldehydes and acetals under Lewis acid promotion

regioselectivity: Allyl inversion

Me3Si PhO

Me

TiCl4

OH

n-C3H7

Ph

Me3SiO

MePh

+

+TiCl4

OH

n-C3H7Ph

Acetals can be used as well Me3Si Me

Me

Me3Si

Me Me

OCH3

H3CO n-C4H9+

+

OCH3

H3CO n-C4H9

TiCl4

TiCl4

n-C4H9

OCH3

Me Me

n-C4H9

OCH3

Me

Me

(80%)

(83%)

H

H

Felkin Selectivity also holds with this class of nucleophiles

The Sakurai Reaction (Enone Conjugate Addition)

Me

O

Me3Si

TiCl4

CH2Cl2

Me

OTiCl4

SiMe3

Me

O

MeO

Me3Si

75%

17%Fleming, Org. Reactions 1989, 37, 127-133

Reactions of AllylsilanesReactions of Allylsilanes

NR1

R2 R4

R3

R1

R2

O NR4

R3H N

R1

R2R4

R3

N

OR2

R1N R1

Common Methods of Generation:

H+, -H2O

H+, -ROH

or Lewis Acid

or Lewis Acid

NMe

NMe

Hg

H

HX–

X

NMe

H

Hg(0)

HX

X–

rds

Oxidation of Amines

HgX2

X-

Iminium IonsIminium Ions

NMe3Si

Ph

N

Ph

Me3Si

NH

Ph

H

N H

Ph

SiMe3

H

H

TFA

(E)

(Z)

Overman et al. TL 1984, 25, 5739.

Only in the case of the (Z) vinylsilane is the emerging p orbital coplanar with C-Si bond. Full stabilization of the empty orbital cannot occur with the (E)

vinylsilane.....hence the rate difference.

rel rates: 7000/1

TFA

(Z) vinylsilane)

N H

Ph

HH

SiMe3

(E) vinylsilane)

Iminium Ions

Iminium Ions

N-Acyliminium Ion Rearrangements

Synthesis of (-)-hastanecine: Hart JOC 1985, 50, 235.

NaBH4,

MeOH,

(-)-hastancine

NMe

OMe

O

BnO

OAc OAc

BnO

OH

Me O

NMe

N

OAc

Me

Me

OBn

O

OAc

OMe

Me N

N

OAc

OMe

Me

N

OH

BnO

HO

OBn

H

[3,3]

N

OAc

OMe

Me

HCO2

BnO

O

H OH

HO

H OH

H

N-Acyliminium Ion Rearrangements

N

OR

HO

NR2

N

OR

HO

NR2

The Aza-Cope-Mannich Reaction Sequence

CH2O, Na2SO4

MeCN, 80˚C

[3,3] N

OR

HO

NR2

N

ONR2

OR

Axial Attack

N

N

OO

H

H

H

strychnine

Overman et al. JACS 1995, 117, 5776.

MannichRxn

N

O

ROH2C

H

NR2

N

OR

HO

NR2

N

OR

HO

NR2

Aza-Cope Manich Reactions

nepetalactoneoil of catnip

steroid hormones

cholesterol

citronellallemon oil

nootkatonegrapefruit flavor

chrysanthemicacid

(R)-carvonespearmint

(S)-carvonecaraway

menthol

Terpenes - natural products whose carbon skeletons are built up largely from isoprene subunits:

isoprene

periplanonesex attractant pheromone of the

American cockroach

Me

O

OH

Me

MeMe Me

OMe H

HMe

H

H

Me

Me

Me

Me

Me

Me

Me Me

HO H

Me

O

H H

O

Me

Me

Me O

OH

H

HMe

Me

Me

H2C

Me

Me

OO

O

H

MeMe

O

Me

H

Me O

Me Me

(an insecticide)

Terpenes

n

Isoprene : Nature's Building Block

2-methyl-1,3-butadiene isoprene

head tail

geraniol citronellol menthol camphor

ß-carotene

natural rubber

monoterpenes : 10 C-atoms (2 isoprene units)sesquiterpenes : 15 C-atoms (3 isoprene units)

Classification of terpenes

h

t

h

t

diterpenes : 20 C-atoms (4 isoprene units)triterpenes : 30 C-atoms (6 isoprene units)

Me

OH OH

OH O

Isoprene : Nature's C5 Building Block

≡≡

geraniol

H2O/OH-

geranyl pyrophosphateDMAP

The general reaction process: alkene addition to electrophiles:

tosylate: chemist's leaving group

pyrophosphate: nature's leaving group

γ,γ-dimethylallyl pyrophosphate (DMAP)

isopentenyl pyrophosphate (IPP)

enzyme

Two isoprene units are used to build terpenes:

Terpene Biosynthesis

Me

OX OX

Me

Me

R O P O

O

P

O

O

OH R O S

O

O

CH3

O

OX

Me

Me Me

Me

CH2OX

Me

Me

Me Me

OX

H H

Me Me

OX

MeMe

Me

Me

OH

-HB-OX-

B-

ROX ROTs

Terpene Biosynthesis

bornene

≡1,2 shift

α−pinene

≡

limonene

isomerization

geranyl pyrophosphate

From isoprene to α−pinene and bornene

OX

Me

Me

Me

Me

OX

Me

MeMe Me

Me

Me Me

OX

MeMe

OX

Me

Me MeMe

MeMeMe

Me Me

Me

Me

Me

Me

-H+ -H+

-H+-OX-

-OX-

Terpene Biosynthesis

Me Me OMe

Me

Squalene and Squalene Oxide Biosynthesis

Me MeMe

Me

MeMe Me

Me

squalene (C30)farnesyl pyrophosphate(C15)

P P dimerization

epoxidation

Me MeMe

Me

MeMe Me

Me

squalene oxide

O

Steriod and Squalene Oxide Cyclization

Steriod Biosynthesis; Squalene Oxide Cyclization

Me MeMe

Me

MeMe Me

Me

squalene oxideO

Me

Me

O

Me HMe

Me

Me

Me

Me

Me

HO

Me HMe

H MeH

Me

Me

Me Me

Me

Me

HO

Me

H

Me

Me

Me

Me

Me

H

lanosterol

H+

The enzyme folds the squalene oxide into the chair-boat-chair conformation

A series of 1,2-hydride and methyl shifts occur

Me

Me

HO

Me

H

Me

Me

Me

Me

Me

HH

Higher Steriods

elimination

H

Steriod Biosynthesis; Squalene Oxide Cyclization