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CHAPTER 4
R
Reactive
i Intermediates
I
di
LIMING JIANG
Department of Polymer Science and
Engineering,
g
g, ZJU
1
2014.10.
OUTLINE
Common features
Definition: a reaction intermediate or
an intermediate as a molecular entity
(
(atom,
i
ion,
molecule...)
l l ) with
i h a lifetime
lif i
appreciably longer than a molecular
vibration that is formed ((directlyy or
indirectly) from the reactants and
reacts further to give (either directly
or indirectly)
i di
tl ) the
th products
d t off a
chemical reaction.
 Low concentration
 Dot not obey the Lewis
octet rule with the exception of
carbanions, hence the high
reactivity
 Often generated on chemical
decomposition
 It is often possible to prove
the
h existence
i
off this
hi species
i bby
spectroscopic means
 Cage effects have to be taken
into account
 Often stabilisation by
conjugation
j g
or resonance
 Often difficult to distinguish
from a transition state
 Prove existence by means of
chemical trapping
Main carbon reactive intermediates:
|
|
|
|
Carbocations and their stabilized
equivalents such as oxonium ions
C b i
Carbanions
and
d their
h i stabilized
bili d
equivalents such as enolates
Free radicals
Carbenes
2
4 1 CARBOCATIONS
4.1
|
A carbocation is an ion with a positively-charged carbon atom.
Norris and
Kehrman (1902):
deep yellow
In 1962 Olah directly observed the tert-butyl carbocation by NMR as a
stable species on dissolving tert-butyl
tert butyl fluoride in magic acid.
acid
3
I. STRUCTURE AND STABILITY
In solution, the carbocation may be free (this is more likely in polar
solvents, in which it is solvated) or it may exist as an ion pair. Ion pairs
are more likely in nonpolar solvents.
A. Simple alkyl carbocations
Stability: tertiary > secondary > primary
The most stable
Th
bl off all
ll alkyl
lk l cations
i
i the
is
h tert‐butyl
b l cation.
i
M h
Methane,
ethane, and propane, treated with superacid, also yield tert‐butyl cation
as the main product.
4
No matter how
h
they
h are generated,
d study
d off the
h simple
l alkyl
lk l cations has
h
provided dramatic evidence for the stability. Both propyl fluorides gave
the isopropyl cation; all four butyl fluorides gave the tert‐butyl
tert butyl cation.
cation
Butane, in superacid, gave only the tert‐butyl cation.
5
+
2
2
2
2
5
3
3
+
5
3
2
3
3
4 9
3
2
3
3
3
3 2
3
3
5
T date,
To
d t no primary
p i
cation
ti
h
has
survived
i d long
l
enoughh for
f detection.
d t ti
+
3
3
5
2
3
+
3
+
6
6
 The field effect. The electron‐donating effect of alkyl groups
increases the electron density at the charge‐bearing carbon, reducing
the net charge on the carbon,
carbon and in effect spreading the charge over
the α carbons.
 Hyperconjugation. Tertiary carbocations are more stable (and form
more readily)
dil ) than
h secondary
d
carbocations;
b
i
primary
i
carbocations
b
i
are
highly unstable because, while ionized higher‐order carbons are
stabilized by hyperconjugation, unsubstituted (primary) carbons are
not.
6
K298 =1.97±0.20
K is 1.97, showing that 2 is more stable than 1. This is a secondary
isotopic effect; there is less hyperconjugation in 1 than 2.
It is a general rule that the more concentrated any charge is, the less
stable the species bearing it will be. 电荷越集中,荷电物种越不稳定
7
B. STABLE ALLYLIC‐TYPE CATIONS
Allyl cation and benzyl cation are more stable than most other carbocations.
Molecules which can form allyl
y or benzyl
y carbocations are especially
p
y reactive.
Stable allylic cations have been obtained by the reaction between alkyl halides,
alcohols, or alkenes (by hydride extraction) and SbF5 in SO2 or SO2ClF.
2
2
+
2
4
2
2
8
2
3
3
+
The blue color of
the mushroom
Lactarius indigo is
due to the azulene
derivative (7i
isopropenyl-4l4
methylazulen-1yl)methyl stearate
Azulene 薁
Both triphenylmethyl (I) and diphenylmethyl cations have been isolated
as solid salts and, in fact, Ph3C+BF4 and related salts are available
commercially. Positively charged benzylic carbon (II) is stabilized by two
azulene rings.
9
C CYCLOPROPYLMETHYL CATIONS
C. C
Cyclopropylmethyl cation are
even more stable than the benzyl
type. Compound (c) has been
prepared by solution of the
corresponding alcohol in H2SO4.
Compounds
p
a,, b,, and similar ions
have been prepared by solution of
the alcohols in FSO3H‐SO2‐SbF5.
CH3
C
CH
C
CH3
(a)
(b)
(c)
1H
NMR spectrum of a dimethyl
derivative (a), identical signals
are found
f
d for
f
the
h two methyl
h l
groups.
J Am Chem Soc 1970, 92, 3234–3235
J. Am. Chem. Soc.
1970 92 3234 3235
10
E. O
OTHER STRUCTURAL TYPES
Another structural feature that increases carbocation stability is the
presence, adjacent to the cationic center, of a heteroatom bearing an
unshared pair.
3
3
¡ Simple acyl cations (RCO+) have been prepared
in solution and the gas state. The acetyl (CH3CO+) is
about as stable as the tert
tert‐butyl
butyl cation.
cation The 2,4,6
2 4 6‐
trimethylbenzoyl cations are especially stable (for
steric reasons) and are easily formed in 96% H2SO4.
11
¡ Friedel‐Crafts acylation
Haworth reaction:
1-tetralone
12
Carbocation Structure: planar sp2 hybrid
tert‐butyl cation
y
demonstrating planar geometry
13
¡ An important tool for the investigation of carbocation structure is
measurement of the 13C NMR chemical shift of the carbon atom bearing
the positive charge. This shift approximately correlates with
electron density on the carbon.
TABLE 1.The 13C chemical shift values for the charged
g carbon atom of
some carbocations in SO2ClF-SbF5,SO2-FSO3H-SbF6, or SO2-SbF5.
ion
Chemical
shift ppm
shift,
°C
ion
Chemical
shift ppm
shift,
°C
Et2MeC+
−139.4
−20
C(OH)3+
+28.0
−50
Me2EtC+
−139.4
−60
PhMe2C+
−61.1 High
−60
Me3C+
−135.4 High −20
PhMeCH+
−40
−60
Me2CH+
−125.0
−20
Ph2CH+
−5.6
M 2COH+
Me
−55.7
−50
Ph3C
Ph
C+
−18.1 Low
−60
Me2C(OH)+
−1.6
−30
Me2(cyclopropy)C+
−86.8
−60
HC(OH)2+
+17 0 Low −30
+17.0 Low
30
14
II THE GENERATION AND FATE OF CARBOCATIONS
II.
Two general ways to form carbocations:
The reaction of carbocations:
+
-
+
15
iii. Rearrangement
16
HO
NH2
OH
HO
HNO2
OH
N2+
HO
-N2
CH2+
O
iv. Addition
17
III NON‐CLASSICAL CARBOCATIONS 非经典碳正离子
III. N
Non‐classical ions are a special type of carbonium ions displaying
delocalization of sigma bonds in 3‐center‐2‐electron bonds of bridged
systems.
S.Winstein (1949): Acylation (solvoysis) of norbornyl brosylate 降冰片烷醇酯
endoexoexo
A key observation is that in this nucleophilic displacement both isomers
give the same reaction product an exo-acetate 2. Also the reaction rate
for the exo-reaction is 350 times the reaction rate for the endo reaction.
18
In a related experiment both enantiomers 1 and 2
of the exo‐brosylate
y g
give on solvolysis
the same racemic
reaction product. The optical activity of the reaction disappears at the same reaction rate
as that of the h
f h
solvolysis.
19
Sigma electrons in the C1-C6 bond assist
by neighbouring group participation with the
expulsion of the leaving group
7
4
1
2
6
exo1
2
6
3. A non-classical ion: pentavalent, symmetrical
endoIn a non-classical carbocations, the positive
charge is delocalized by a double or triple bond
that is not in the allylic position or by a single bond.
20
George A Olah
g
((1964): direct evidence for 9 4)
the norbornyl cation by NMR analysis
Olah, G.A., J. Am. Chem.
(
)
Soc. 104,, 7105(1982)
21
IV. Neighbouring group participation (NGP) 邻基参与
Neighbouring group participation or NGP has been defined by IUPAC as
the interaction of a reaction centre with a lone pair of electrons in an
atom or the electrons present in a σ bond or π bond. When NGP is in
operation it is normal for the reaction rate to be increased. It is also
possible for the stereochemistry of the reaction to be abnormal (or
unexpected) when compared with a normal reaction.
A. NGP by heteroatom lone pairs
The rate of reaction is much higher for the sulfur mustard and a
nucleophile than it would be for a primary alkyl chloride without a
heteroatom. 芥子气
芥 气
22
B.
NGP BY AN ALKENE ((C=C AS A NEIGHBORING GROUP)
TsO
H
H
TsO
O
The rate of
acetolysis
100
Configuration retention
1
retention
Ts = H3C
S
O
23
EVEN IF THE DOUBLE BOND IS MORE REMOTE FROM THE REACTING CENTER THE
ALKENE CAN STILL ACT IN THIS WAY.
H
OBs
OBs
O
s
H
BsO : Br
O
S O
O
(A)
Relative rate
of acetolysis 140,000
(B)
1
(A):
-(syn-7-norbornenyl)
ethyl brosylate
24
DISCUSSION
(i) Evidence for the non-classical
cations.
(ii) A neighboring group lends
anchimeric assistance only when
there is sufficient demand for it.
it
(iii) The ability of C=C to serve
as a neighboring group can
depend on its electron density.
MosO
H
R1
Mos = MeO
SO2
R2
Relative rates of the solvolysis
y
R1 = R2 = H
1.4x1012
R1 = H, R2 = CF3
1.5x106
R1 = R2 = CF3
1
25
C. NGP BY AN AROMATIC RING
An aromatic ring can assist in the formation of a carbocationic intermediate
called a phenonium ion by delocalising the positive charge.
QUESION: please give a mechanism which forms A and B.
26
D. CYCLOPROPYL AS A NEIGHBORING GROUP
Where cyclopropyl lends considerable anchimeric
assistance, the developing p
i t
th d l i orbital of the bit l f th carbocation is orthogonal to the participating bond of the cyclopropane ring.
27
E The C‐C single bond as a neighboring group
E. The C
C single bond as a neighboring group
i. The 2‐norbornyl system
+
28
ii The Cyclopropylmethyl
y p py
y System
y
CH2Cl
EtOH/H2O
CH2OH +
OH
48%
17%
+
CH2OH
homoally alcohol
5%
CH2X
or
or
OH
H2C
CH
H2C
CH2+
H2C
CH
CH2
CH2
H2C
CH
CH2
CH2
CH2=CHCH2CH2Cl
The carbocationic intermidate is delocalised onto manyy different
carbons through a reversible ring opening.
29
iii Methyl or Hydrogen as Neighboring Group
iii. Methyl or Hydrogen as Neighboring Group
3
3
3
3
3
3
3
30
CH3CH2CDCD3
CH3CHDCHCD3
CH3CHCDHCD3
CH3CDCH2CD3
open cations
in equilibrium
no NGP byy hydrogen
y g
H
O
T = H3C
Ts
S
S-
OTs
H3C C
O
C CD3
H
D
NGP by hydrogen
H
CH3
CH
CD
(e)
CD3
31
4.2 CARBANIONS
A carbanion is an anion in which carbon has an unshared pair of
electrons and bears a negative charge usually with three substituents
for a total of eight valence electrons.
Formally a carbanion is the conjugate base of a carbon acid.
R C H
R C: + H+
Stable carbanions do however exist although in most cases they are reactive.
Olmstead (1984):
32
I. STABILITY AND STRUCTURE
The stability of the carbanion is directly related to the strength of the
conjugate acid. The weaker is the acid, the greater is the base strength and
the lower is the stability of the carbanion.
Factors determining the stability and reactivity of a carbanion:
The inductive effect. Electronegative atoms adjacent to the charge will
stabilize the charge;
|
Hybridization of the charge‐bearing atom. The greater the s‐character
of the charge‐bearing atom, the more stable the anion;
|
The extent of conjugation of the anion. Resonance effects can stabilize
the anion. This is especially true when the anion is stabilized as a result of
aromaticity.
|
33
RELATIVELY STABLE CARBANIONS WITH CERTAIN
STRUCTURAL FEATURES
Conjugation of the
unshared pair of
R
R
Y C
C:
R R
:Y
unsaturated bond
R
CH2
Carbanions increase in
stability with an increase in
the amount of s character at
the carbanionic carbon.
C CH
H
(Y=C, O or N)
R
R
electrons with an
C C
CH2:
CH2
R
C CH
H
CH2
CH2
CH2
Stability: RC≡C−> R2=CH− ≈ Ar− > RCH2−
34
|
Stabilization by sulfur or phosphorus.
|
Field effect:
¾ Ylides
Ylid are more stable
t bl than
th the
th corresponding
di
simple
i l carbanions.
b i
¾ Carbanions are stabilized by a field effect if there is any hetero
atom ((O,, N or S)) connected to the carbanionic carbon,, p
provided that
the hetero atom bears a positive charge in at least one important
canonical form.
35
II. THE GENERATION AND FATE OF CARBANIONS
a) A group attached to a carbon leaves without its electron pair.
b) A negative ion adds to a carbon‐carbon double or t i l b d
triple bond.
Reactions:
36
37
4.3 FREE RADICALS
|
|
|
A free radical may be defined as a species that contains one or more
unpaired electrons.
Radicals play an important role in combustion, atmospheric chemistry,
polymerization, plasma chemistry, biochemistry, and many other
processes,, including
g human p
physiology.
y
gy
chemical p
The first organic free radical identified was
triphenylmethyl radical, by Moses Gomberg
(the founder of radical chemistry) in 1900.
yellow
In benzene the concentration
of the radical is 2%.
The 1H NMR (ppm)
25 aromatic protons: 6.8 - 7.4
4 olefinic protons: 5.8 - 6.4
a single aliphatic proton: 5
Moses Gomberg
1866-1947
1866
1947
38
I. STABILITY AND STRUCTURE
Alkyl radical intermediates are stabilized by similar criteria as
carbocations: the more substituted the radical center is, the more
stable
t bl it is.
i
The stability order for radical: tertiary > secondary > primary
Hyperconjugation:
H H
H
H H
|
R
C C
H H
R
C
C
R
C
C
H H
H H
TABLE. The D298 values for R-H bonds
R
D (kJ/mol) R
D (kJ/mol)
R
D (kJ/mol)
Ph
464
Et
419
M 3C
Me
401
CF3
446
Me3CCH2
418
Cyclohexyl
400
CH2=CH
444
Pr
417
PhCH2
368
Cyclopropyl
444
Cl3C
401
HCO
364
Me
438
Me2CH
401
CH2=CH-CH2
361
Free radical stability is in reverse order.
order
39
 Radicals
R di l nextt to
t functional
f
ti
l groups, such
h as carbonyl,
b
l nitrile,
it il and
d
ether are even more stable than tertiary alkyl radicals.
PUSH-PULL EFFECT
 Organic radicals can be long lived if they occur in a conjugated π
system.
40
The radical derived from alpha-tocopherol
 Persistent radical compounds
p
are those whose longevity
g
y is due to
steric crowding around the radical center and makes it physically difficult
for the radical to react with another molecule.
Examples: Gomberg's triphenylmethyl
radical 2,2‐Diphenyl‐1‐picrylhydrazyl (DPPH)
22,2,6,6‐Tetramethylpiperidine‐1‐oxyl
2 6 6 Tetramethylpiperidine 1 oxyl
(TEMPO)
Ph
Ph
NO2
N N
NO2
NO2
Application
pp cat o o
of TEMPO:
O: as a radical
ad ca ttrap,
ap, as a st
structural
uctu a p
probe
obe for
o
biological systems in conjunction with electron spin resonance
spectroscopy, as a reagent in organic synthesis, and as a mediator in
controlled free radical polymerization.
polymerization
41
II. THE GENERATION
|
|
AND FATE OF
FREE RADICALS
The formation of radicals may involve breaking of covalent bonds
homolytically, a process that requires significant amounts of energy.
Homolytic bond cleavage most often happens between two atoms of
similar electronegativity.
R
C
O O
C
O
R
h t
heat
2 R
O
R
hv
Cl2
R
C
R
O
heat
2 R + N2
2 Cl
hv
vapor
phase
R
C + R
O
O
Ph
C
O
O
O
R
N N
C
Ph + CO2
42
|
F
Free
radicals
di l take
t k partt in
i radical
di l addition
dditi and
d radical
di l substitution
b tit ti as
reactive intermediates.
|
Ch i reactions
Chain
ti
i
involving
l i free
f
radicals
di l can usually
ll be
b divided
di id d into
i t three
th
distinct processes: initiation, propagation, and termination.
Termination reactions → stable products
(i) R∙ + R’∙ → R─R
(ii) 2CH3CH2∙ → CH3CH3 + CH2=CH
CH2
Propagation reactions → other radicals (which usually react further)
(iii) abstraction of another atom or group usually a hydrogen atom:
(iii) abstraction of another atom or group, usually a hydrogen atom:
R∙ + R’─H → R’∙ + RH
(iv) addition to a multiple bond:
43
|
Radicals attack double bonds, but unlike similar ions, they are
not as much directed by electrostatic interactions.
• The
Th electrophilic/neutrophilic
l t
hili /
t
hili character
h
t off radicals
di l
O
O
O
+
O
O
O
n
(electrophilic) (slightly nucleophilic)
alternating copolymer
44
ATMOSPHERIC RADICALS ⎯ OZONE DEPLETION
|
Refrigerants: Freon. Freon-11 is trichlorofluoromrthane, while
Freon-12 is dichlorodifluoromethane. Freon-113 (1,1,2-Trichloro1 2 2 t ifl
1,2,2-trifluoroethane).
th
)
CFCl3 + hν → CFCl2 + Cl•
These free radicals then react with
ozone in a catalytic chain reaction
which destroys the ozone:
| Cl
Cl• + O3 → ClO
ClO• + O2
| ClO• + O3 → Cl• + 2 O2
|
Image of the largest Antarctic ozone
hole ever recorded (September 2006)
45
III RADICAL IONS
III.
|
|
A radical ion is a free radical species that carries a charge.
Many aromatic
M
ti compounds
d can undergo
d
one-electron
l
reduction
d i
b
by
alkali metals.
Sodium naphthalenide: the reaction of naphthalene with sodium in an
aprotic solvent.
46
KETYL
|
A ketyl group is an anion radical with the general structure C-O.
in which an oxygen radical is bonded directly to carbon.
carbon
Benzophenone radical anion
Sodium reduces benzophenone to the
soluble ketyl radical, which reacts
quickly with the water and oxygen
dissolved in the solvent. The deep blue
coloration qualitatively indicates dry,
o gen free conditions.
oxygen‐free
conditions
Na + Ph2CO → Na+ + Ph2CO⋅−
The intense blue coloration due to the
benzophenone ketyl radical shows that
the toluene is considered free of air and
moisture.
47
RADICAL CATIONS
|
Cationic radical species are much less stable. They appear
prominently
p
y in mass spectroscopy
p
py ((MS).
) When a g
gas-phase
p
molecule is subjected to electron ionization, one electron is
abstracted by an electron in the electron beam to create a radical
cation M+.. This species represents the molecular ion or parent ion
and will tell the precise molecular weight.
• Examples:
E
l
48
4 4 CARBENES
4.4
A carbene is a highly reactive species containing a carbon atom
with six valence electrons and having the general formula RR
RR’C:,
C:,
practically all having lifetimes considerably under 1 sec.
i. Structure and bonding
|
125-140o
the total spin=0
bond angle = 102o
for single methylene
the total spin
spin=1;
1;
paramagnetic, may be
observed by
electron spin resonance
spectroscopy
Triplet carbenes are generally stable in the gaseous state, while singlet
carbenes occur more often in aqueous media.
media
49
II.
|
REACTIVITY
Singlet and triplet carbenes exhibit divergent reactivity. Singlet
generally
y p
participate
p
in cheletropic
p reactions. Singlet
g
carbenes g
carbenes with unfilled p-orbital should be electrophilic. Triplet
carbenes can be considered to be diradicals, and participate in
stepwise radical additions.
Addition to C=C:
cheletropic reaction
stereospecific
stepwise radical addition, may be stereoselective
50
INSERTION REACTION
• The order of preference: X−H (where X is not carbon) > C−H > C−C
Insertions may or may not occur in single step.
step
• When an intramolecular insertion
is possible,
bl
no intermolecular
l
l
insertions are seen. In flexible
structures, five
structures
five-membered
membered ring
formation is preferred to sixmembered ring formation.
O
R'
R
O
Cu, PhH, reflux
N2
H
R'
O
R'
R
H
R
51
N–
N+
C
H
|
H +
Ph
Rh2(S-DOSP)4
CO2Me
Ph
CO2Me
(intermolecular insertion of carbene)
Alkylidene carbenes are alluring in that they offer formation of
cyclopentene moieties.
moieties To generate an alkylidene carbene a
ketone can be exposed to trimethylsilyl diazomethane.
An alkylidene carbene
52
III.
|
GENERATION OF CARBENES
Disintegration of diazoalkanes and their analogs, via photolytic,
thermal or transition metal (Rh,
thermal,
(Rh Cu)
Cu)-catalyzed
catalyzed routes.
routes
2
+
–
hv
2
hv
2
2
2
2
53
|
Base-induced α-elimination
H
R C Cl
R
H+
Cl3C COO
R C Cl
R
Cl
R C
R
CCl2 + CO2 + Cl
+
CH2
• Carbenes
C b
are intermediates
i t
di t in
i the
th Wolff
W lff rearrangementt.
R'
2
R
2
O
54
IV.
|
APPLICATIONS OF CARBENES
A large scale application of carbenes is the industrial production
off tetrafluoroethylene.
f
Tetrafluoroethylene
f
is generated via the
intermediacy of difluorocarbene:
CHCl3 + 2 HF → CHClF2 + 2 HCl
CHClF2 → :CF2 + HCl
2 :CF
CF2 → F2C=CF
C CF2
•
Polytetrafluoroethylene (PTFE, mp 327°C
the
h DuPont brand
b d name Teflon)
fl ) is a
synthetic
fluoropolymer
of
tetrafluoroethylene which finds numerous
applications: used as a non‐stick coating for
pans and other cookware.
55
4.5 NITRENES
|
A nitrene (R-N:) is the nitrogen analogue of a carbene. The
g
atom has only
y 6 electrons available and is therefore
nitrogen
considered an electrophile. A nitrene is a reactive intermediate
and is involved in many chemical reactions.
• Formation of nitrenes
¾ from thermolysis or photolysis of azides.
¾ from isocyanates,
isocyanates with expulsion of CO.
CO
56
REACTIONS OF NITRENE
|
Nitrene C-H insertion. A nitrene can easily insert into a C-H bond
yielding an amine or amide.
amide
Org. Lett. 9, 981(2007)
57
|
Nitrene cycloaddition With alkenes, nitrenes react to aziridines.
Nitrene cycloaddition.
With alkenes nitrenes react to aziridines
NO2
Ex. 1
Ex. 2
C2H5 O
C O
Cu(acac)2, acetonitril
NO2
H
O S O
N
N
(N-sulfonyloxy
precursor)
O
O S
O
ethoxycarbonylnitrene
th
b
l it
stilbene
O S O
N
A precursor
I
of nitrene
J Org.
J.
Org Chem.
Chem 71,
71 5876(2006)
C2H5 O
C O
N
C2H5 O
C O
O
N
O
Tetrahedron Letters,
Letters 25,
25 4271(1984)
58
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