Page 349 - Advanced Organic Chemistry Part A - Structure and Mechanisms, 5th ed (2007) - Carey _ Sundberg

330 The effect of the same substituents on the adduct was evaluated by another isodesmic
reaction:
CHAPTER 3
– –
Structural Effects on XYCHO + 2 CH 3 H CH 3 O + CH 3 X + CH 3 Y
Stability and Reactivity
This analysis permits assignment of hydride affinity to the carbonyl compounds
relative to formaldehyde. The stabilization of the carbonyl compound by X relative to
H is shown in Table 3.25 as C=O. The stabilization of the hydride adduct is shown as
−
CHO . The difference, the hydride affinity relative to CH =O, is listed as HA. The
2
resonance donors NH and CH O have the largest stabilizing effect on the carbonyl
2
3
starting material, but F also has a very significant stabilizing effect. The stabilization
of the tetrahedral adduct is in the order of bond strength F > CH O > NH > CH . The
3
2
3
difference between the two values places the overall substituent effect for reactivity
toward hydride in the order F > H > CH > OCH > NH , in excellent agreement with
3 3 2
experimental data. The polar EWGs CN and CF strongly favor hydride addition by
3
strong stabilization of the anionic tetrahedral adduct. As a result, they have the largest
overall effect on the stability of the hydride adduct, followed by fluoro and formyl.
The stability relationships for carbonyl substitution reactions by an anionic nucle-
ophile are summarized in Scheme 3.3. The simplest substitution reactions consist of
two reversible steps, the formation of the tetrahedral intermediate and the subsequent
elimination of the original substituent. As we discuss in Chapter 7, the mechanism
is frequently more complex, often involving proton transfers. However, the stability
effects of the carbonyl groups can be illustrated in terms of the simple two-step mecha-
−
nisms. The stability order of reactants and products is F, Cl < OR < NR < O . The
2
order of stability of the anionic tetrahedral intermediates is F > RO > RN > O . The
−
2
−
diagram clearly indicates that the reactivity order will be F > RO > R N > O . Note
2
also that the relative rates for the two possible fates of the tetrahedral intermediate
−
−
(forward or reverse) are determined by the ease with which either X or Nu departs
−
−
−
from the tetrahedral intermediate. This order will be F > RO > NH > O ,sowe
2−
2
expect substitution on acyl fluorides (and other acyl halides) to be fast and irreversible.
On the other hand, nucleophilic substitution on carboxylate anions, which is at the
other end of the reactivity range, is nearly impossible. (We will see in Section 7.2.2.2
in Part B that organolithium compounds are strong enough nucleophiles to achieve
addition with carboxylate groups, at least in the presence of Li .) The relative stability
+
Table 3.25. Substituent Effects on Hydride Affinity of
XYC=O by an Isodesmic Reaction Sequence (in kcal/mol by
G2(MP2) Calculations) a
X Y C=O HCO − HA
H H 0 0 0
H CH 3 11 1 9 6 1 5
H NH 2 31 5 21 8 9 7
H CH 3 O 32 8 29 0 3 8
H F 26 1 38 2 −12 1
H CH=O 3 1 19 0 −15 9
H CF 3 −3 0 23 3 −26 3
H CN −2 4 25 9 −28 3
a. R. E. Rosenberg, J. Am. Chem. Soc., 117, 10358 (1993).