30 Chapter I Introduction— Molecular Struaure and Reactivity

known that one side of the equihbrium is favored, this may be indicated by a
longer arrow pointing to the side that is favored.

Example 1.14. An acid-base equilibrium.

CHXO.H
i3>^v^2 + H , 0 F=^ CHXO, + H,0+

Example 1.15. Tautomeric equilibria of ketones.

The keto and enol forms of aldehydes and ketones represent a common
example of tautomerism. The tautomers interconvert by an equilibrium
process that involves the transfer of a hydrogen atom from oxygen to carbon
and back again.

O OH

CH
A„.CH -- A
C-H. 3 C^Jrl 2
keto
enol
OH

keto keto

Hint 1.7 To avoid confusing resonance structures and tautomers, use the following criteria:
1. Tautomers are readily converted isomers. As such they differ in the place-
ment of a double bond and a hydrogen atom. The equilibration between the

I isomers is shown with a pair of half-headed arrows.

2. Resonance structures represent different TT bonding patterns, not different
chemical species. Different resonance structures are indicated by a double-headed
arrow between them.
3. All resonance structures for a given species have identical a bonding
patterns (with a few unusual exceptions) and identical geometries. In tautomers,
the a bonding pattern differs.
 7. Tautomers and Equilibrium 31

Example 1.16. Tautomerism versus resonance.

Compounds 1-36 and 1-37 are tautomers; they are isomers and are in A EH
equilibrium with each other:
31 jes
R I
R H P I
HO
s
3
I was
1-36
of si 1-37
yo 012553
On the other hand, 1-38, 1-39, and 1-40 are resonance forms. The hybrid of Eyal
these structures can be formed from 1-36 or 1-37 by removing the acidic
proton.

R R R
re
°Vv° '°vV° o,i^o- H
o-l o—' o-^
1-38 -39 -40

Note that 1-38, 1-39, and 1-40 have the same atoms attached at all positions,
whereas the tautomers 1-36 and 1-37 differ in the position of a proton.

W r i t e tautomeric structures for each of the following compounds. The PROBLEM 1.9
number of tautomers you should write, in addition to the original
structure, is shown in parentheses.
O OH YH
a. A (2)
CH3 NH2
tetaner
NH yCANHz II a
b. CH3CHO (1) tortured AS
c. CH3CH=CHCHO (1) Beseons

y d. A
NH
(2) Resor
HI class Ho
c
all
^fH2 NH2 H
Exc's d
OH c
e. Ph\ J^ (5) fetumer
6436535651
N NH,

2 s
Linda vase
32 Chapter I Introduction — Molecular Struaure and Reactivity

PROBLEM 1. 10 For each of the following sets of structures, indicate whether they are
tautomers, resonance forms, or the same molecule.

O O"

b. A _ A
H Crl2 H CH2

c.
HO O

PROBLEM Ml In a published paper, two structures were presented in the following

manner and referred to as resonance forms. A r e the structures shown
actually resonance forms? If not, what are they and how can you correct
the picture?

ArNH. .Nv/R ArNH^ .N R

^ ,
O OH

8. A C I D I T Y A N D BASICITY

A Bronsted acid is a proton donor. A Bronsted base is a proton acceptor.

CH,CO,H + CH,NH, CH3CO2" + CH3NH3
acid base conjugate base conjugate acid
If this equation were reversed, the definitions would be similar:
CH3NH3 + CH3CO2" CH3NH2 + CH3CO2H
acid base conjugate base conjugate acid
In each equation, the acids are the proton donors and the bases are proton
acceptors.
There is an inverse relationship between the acidity of an acid and the
basicity of its conjugate base. That is, the more acidic the acid, the weaker the
basicity of the conjugate base and vice versa. For example, if the acid is very
weak, like methane, the conjugate base, the methyl carbanion, is a very strong
base. On the other hand, if the acid is very strong, like sulfuric acid, the
 9. Nudeophiles and Bectrophiles 3 7

Using the values listed in Appendix C, calculate the equilibrium con- PROBLEM 1.14
stants for each of the following reactions and predict which direction,
forward or reverse, is favored.

a. CH.CO.Et + EtO" F=^ CHoCO.Et + EtOH

o 0
^^
U + H2O
Ph CHJ
c. PhjCH + "N(i-Pr)2 ^==^ PhjC'+HNO -Pr)2

Note: /-Pr = -CH(CH3)2.

9. NUCLEOPHILES A N D ELECTROPHILES

Nudeophiles are reactive species that seek an electron-poor center. They

have an atom with a negative or partial negative charge, and this atom is
referred to as the nucleophilic atom. Reacting species that have an electron-
poor center are called electrophiles. These electron-poor centers usually have
a positive or partial positive charge, but electron-deficient species can also be
neutral (radicals and carbenes, see Chapter 5). Table 1.4 lists common
nudeophiles and Table 1.5 common electrophiles.
Reactivity in reactions involving nudeophiles depends on several factors,
including the nature of the nucleophile, the substrate, and the solvent.

A . Nucleophillcity
Nucleophilicity measures the ability of a nucleophile to react at an
electron-deficient center. It should not be confused with basicity, although
often there are parallels between the two. Whereas nucleophilicity considers
the reactivity (i.e., the rate of reaction) of an electron-rich species at an Sn
electron-deficient center (usually carbon), basicity is a measure of the position log
of equilibrium in reaction with a proton.
Table 1.6 shows nudeophiles ranked by one measure of nucleophilicity.
These nucleophilicities are based on the relative reactivities of the nucle-
ophile and water with methyl bromide at 25°C. The nucleophilicity n is
calculated according to the Swain-Scott equation:

S I
Isn
log -7- = sn Green more nuclofile
log
r i n
Sh
g
s
log more na
38 Chapter I Introduction—Molecular Structure and Reactivity

TABLE L4 Common Nucleophiles^

F", Cr, Br- ,r

ROH, RO", RO—O
O*
li * 1: *
[R-- C - - 0 ] -, [Ar-
-c- -o]-
RSH,RS-,ArSH,ArS-

RSR',[S—Sp- (disulfide)
RNH2, RR'NH, RR'R'TSr, ArNH2, etc.
H2NNH2 (hydrazine)
[ N = N = N ] - (azide)
* *
*
[ N = C = 0 ] ~ (isocyanate)
O

N~ (phthalimidate)

*
i
R3P (phosphine)
*
(ROjP (phosphite)
* * *
LiAlH4, NaBH4, LiEtjBH
RMgX,ArMgX
RCuLi
RC=C-
''An asterisk indicates a nucleophihc atom.
log sn

where k is the rate constant for reactions with the nucleophile, k^ is the rate n
constant for reaction when water is the nucleophile, 5 = 1.00 (for methyl
bromide as substrate), and n is the relative nucleophilicity. The larger the n we
value, the greater the nucleophilicity. Thus, Table 1.6 shows that the thiosul-
fate ion (S2O3", n = 6.4) is more nucleophihc than iodide (I", n = 5.0).

B. Substrate
The structure of the substrate influences the rate of reaction with a
nucleophile, and this effect is reflected in the s values defined in the previous
 9. Nudeophiles and EJearophiks 39

TABLE 1.5 Common Electrophiles''

* • *
ZnCl2, AICI3, BF3

— *C—X(X = Cl,Br,I)

— * C - - 0 — S 0 2 R ( R =/7-tolyl, CF3, CH3)

X X X O
I I I II
— *C—CO2H, —C—CO2R, —C—C—R
I I I
o o
II II
— C—OR, —CR

CH 2 N2 (diazomethane)
* *
H — O — O — H (hydrogen peroxide)

(epoxide)

N=0^ (generated from HNO2)

'^An asterisk indicates an electrophilic atom.

^To react as an electrophile, CH2N2 (di-
azomethane) must first be protonated to form the
methyl diazonium cation:
H2C=N=N ^ H3C—N=N.

section. For example, methyl bromide and chloroacetate both have s values
of 1.00, so they react at the same rate. On the other hand, iodoacetate, with
an s value of 1.33, reacts faster than methyl bromide, whereas benzyl
chloride, with an s value of 0.87, reacts more slowly.

C. Solvent
Nucleophilicity is often solvent-dependent, but the relationship is a com-
plex one and depends on a number of different factors. Ritchie and co-workers
have measured solvent-dependent relative nucleophilicities, N+, in various
40 Nt
log
i
Chapter I Introduction — Molecular Structure and Reactivity

TABLE 1.6 Nucleophilicities toward Carbon^

Nucleophile n Nucleophile n

S2O3'- 6.4 pyridine 3.6

SH" 5.1 Br" 3.5
CN- 5.1 PhO- 3.5
S03^"
r
5.1
5.0
CH3C02~
cr
2.7
2.7
2.5
logfs.SI
PhNH2 4.5 HOCH2CO2"
SCN" 4.4 so|- 2.5
OH- 4.2
4.1
C1CH2C02~
F"
2.2
2.0 log N
(NH2)2CS
N3- 4.0 NO3- 1.0
HCO3- 3.8 H2O 0.0
H2PO4" 3.9

"From Wells, P. R. Chem. Rev. 1963, 63, 171-219.

I solvents, using the equation Jolt

log = 7V, solvent
^H.O

where k^ is the rate constant for reaction of a cation with a nucleophile in a

given solvent, and /c^ o i^ the rate constant for reaction of the same cation
with water in water. Some A^+ values are given in Table 1.7. Note that
nucleophilicity is greater in dipolar aprotic solvents like dimethyl sulfoxide
and dimethylformamide than in protic solvents like water or alcohols. For this
reason, dimethyl sulfoxide is often used as a solvent for carrying out nucle-
ophilic substitutions.
Sometimes relative nucleophilicities change in going from a protic to an
aprotic solvent. For example, the relative nucleophilicities of the halide ions
in water are I"> Br~> CI", whereas in dimethylformamide, the nucle-
ophilicities are reversed, i.e., Cl"> Br~> I~.

TABLE 1.7 Relative Nucleophilicities in Common Solvents'^

Nucleophile (solvent) ^+ Nucleophile (solvent) N,

H2O (H2O) 0.0 PhS" (CH3OH) 10.51

CH3OH (CH3OH) 1.18 PhS" [(CH3)2SO] 12.83
CN- (H2O) 3.67 N3- (H2O) 7.6
CN- (CH3OH) 5.94 N3- (CH3OH) 8.85
C N - [(CH3)2SO] 8.60 N3- [(CH3)2SO] 10.07
CN- [(CH3)2NCHO] 9.33

"From Ritchie, C. D. / . Am. Chem. Soc. 1975, 97, 1170-1179.

 Chapter I Answers to Problems 41

In each of the following reactions, label the electrophlllc or nucleophilic PROBLEM 1.15
center In each reactant. In a, b, and c, different parts of acetophenone
are behaving as either a nucleophile or an electrophile.
O O
ele nu
a. NO2 +

nu
elec
b. g
H2SO4 + + Hso;

OMgBr
nu
c. CH3 —MgBr + Tec
W elee
d. + H—CI
l

A N S W E R S T O PROBLEMS

For all parts of this problem, the overall carbon skeleton is given. There- Problem 1.1
fore, a good approach is to draw the skeleton of the molecule with single
bonds and fill in extra bonds, if necessary, to complete the octet of atoms
other than hydrogen.

a. Electron supply = (3 X 4)(C) + (1 X 6XO) + (4 X 1)(H) = 22. Electron

demand = (3 X 8)(C) + (1 X 8)(0) + (4 X 2)(H) = 40. Estimate of bonds
= (40 - 22)/2 = 9. This leaves two bonds left over after all atoms are
joined by single bonds; thus, there is a double bond (as shown) between
the CH2 and CH groups and a double bond between the second CH and
the oxygen to give the following skeleton:
H
H ^=0

H H
Calculation of the number of rings and/or TT bonds also shows that two TT
bonds are present. The molecular formula is C3H4O. The number of
hydrogens for a saturated hydrocarbon is (2 X 3) + 2 = 8. There are
(8 - 4 ) / 2 = 2 rings and/or ir bonds.
56 Chapter I Answers to Problems

Problem 1.9 OH OH

CH2 NH2 CH3 NH

b. CH2=CHOH

c. CH, = CH—CH=CHOH

NH, NH,

HN NH2 H2N
A.^NH
O OH
N
e NH NH2 ^ NH'
^ ^ — \ NH I T H
H
O.^ ^NH, O.-. .NH,

H
There are two more possible structures in which there is isomerism about
the imine nitrogen:

K ^ a NH2 Ky NH2

Problem 1.10 a. The first structure is the same compound as the last; the second is the
same as the fourth. The first, second, and third structures meet the basic
requirement for tautomers: interconversion involves only movement of a
double bond and one hydrogen atom. However, most chemists would not
call them tautomers because the allylic proton that moves is not very
acidic. Its pK^ can be estimated from the pK^ of the allylic proton of
1-propene: 47.1-48.0 (from Appendix C). Thus, the intermediate anion
necessary for the interconversion of these isomers would be formed only
under extremely basic conditions. When the equilibration is this difficult to
effect, the different isomers usually are not called tautomers. On the other
hand, if another double bond were added to the structure, the compound
would be very acidic (from Appendix C the related cyclopentadiene has a
 Chapter I Answers to Problems 57

pK^ = 18.1 in DMSO, which is more acidic than the a protons in acetone, Problem 1.10
pK^ = 19.2). Thus, most chemists would call compounds 1-71 and 1-72 continued
tautomers.

-72

The structures in the problem are not reasonable resonance forms, be-
cause conversion from one structure to another involves movement of a
hydrogen atom and rehybridization of two carbon atoms. Therefore, if the
double bond were moved in either direction to the next ring location, it
would leave one carbon with only three bonds (carbon 5 in the right-hand
structure following) and place five bonds on another (carbon 2 in the
right-hand structure following). These other structures would have ex-
tremely high energies and contribute nothing to a resonance hybrid.

CH,

H2C

b. These two structures are resonance forms. They represent the simplest
enolate ion that can exist.

c. These compounds are tautomers. They differ in the placement of a double

bond and a proton, and they could readily be in equilibrium with each
other.

The two structures are tautomers because they differ in the placement of a Problem 1.11
double bond and a proton, and they could readily be in equilibrum with
each other. If the resonance arrow is changed to ^ , the picture will be
correct.

a. CH2=CH" is more basic than H C ^ C " . That is, according to Ap- Problem 1.12
pendix C, ethene is less acidic than ethyne, so the conjugate base of ethene
is more basic than the conjugate base of ethyne.

b. [(CH3)2CH]2N" is more basic than "CH2CON(Et)2. The diisopropy-

lamide anion cannot be stabilized by resonance, because the N is bonded
only to 5p^-hybridized carbons. On the other hand, "CH2CON(Et)2 is
 Chapter I Answers to Problems 61

This value is only an approximation, because the two acidities are not Problem 1.14
measured in the same solvent. Nonetheless, the value indicates that continued
equilibrium favors starting material to a large extent.
c.
K^ = 10 -30.6 /lO -35.7 = 10 5.1

In this case the reaction goes substantially to the right. By using the
alternative pj^^ of 39 for the amine, the answer would be 10^ '^.

a. '^N02 is the electrophile. Writing a Lewis structure for this species Problem 1.15
( : 0 : :N: : 0 0 indicates that the nitrogen is positive and will be the atom
that reacts with the nucleophile. In acetophenone, the TT electrons of the
ring act as the nucleophile. In keeping track of electrons, it is helpful to
think of the nucleophile as the electron pair of the ir bond to the carbon
where the nitrogen becomes attached:

b. The electrophile is the proton of sulfuric acid that is transferred to the

oxygen of acetophenone. Thus, the oxygen of acetophenone acts as the
nucleophile in this reaction. The product shown would be a direct result of
a lone pair of electrons on the oxygen acting as a nucleophile. One could
also show the TT electrons of the C ^ O group acting as the nucleophile.
This would give the following structure:

This structure and the structure drawn in the problem are the same,
because they are both resonance forms that contribute to the same
resonance hybrid.
This reaction could also be described as an acid-base reaction, where
the acid is the proton of sulfuric acid and the base is the oxygen of the
carbonyl group.
62 Chapter I Answers to Problems

Problem 1.15 c This bond of the Grignard reagent is a highly polarized covalent bond, so
continued that the carbon bears a negative charge. This nucleophilic carbon of the
Grignard reagent becomes attached to the electrophilic carbon of the
carbonyl group in acetophenone.

d. The electron pair, constituting the rr bond in cyclohexene, is the nucle-

ophile, and a proton from HCl is the electrophile.