R-halo ketones.4 A composite of propiophenones with
meta/para substituents compared to ortho substituents
for eq 1 presents a notable set of contrasting behaviors,
which clarify the nature of delocalization in the reactive
chemical intermediate.
Dim in ish ed Rea ctivity of
Or th o-Su bstitu ted P h en a cyl Br om id es
tow a r d Nu cleop h ilic Disp la cem en t
Diane M. Kalendra and Barry R. Sickles*
Previous reports show a positive F value Hammett-
correlated stabilization trend for displacement intermedi-
ates in meta/para-substituted phenacyl halides.5 Like-
wise, we have shown (Table 1) a systematic increase in
the rate of tert-butylamine substitution on R-bromopro-
piophenones with meta or para substituents, which have
increasing electron-withdrawing ability. However this
pattern reverses with groups in the ortho position. The
compounds studied provide comparable electron donat-
ing/withdrawing properites and analogues with ortho-
steric bulk. Ortho substituents present a rotational
barrier in the transition state, which forces the phenyl
ring away from π-orbital collinearity with the reacting
“enolate type” transition state. This can be seen by AM1
minimization of the ground-state R-bromoketones (Table
1), which show greater phenyl-ring/carbonyl torsional
angles for the ortho-substituted compounds. In addition
to calculations, 13C NMR measurements by Dhami and
Stothers have demonstrated this type of twist for o-
phenacyl compounds, and 17O NMR studies on ortho-
substituted acetophenones by Oakley and Boykin showed
a deshielding pattern that was explained by steric
inhibition of resonance.6 From these studies, “in-plane”
and “out-of-plane” substitution for the substrates exam-
ined in this study are grouped based on the measured
13C chemical shift of the carbonyl carbon of the R-bro-
moketones. Note, the o-fluoro compound may be less
bulky, and by physical measurement (both 13C NMR and
reaction rate) that material is more appropriately in-
cluded with the “in-plane” substrates.
Chemical Development Department, GlaxoSmithKline Co.,
5 Moore Drive, Research Triangle Park,
North Carolina 27709
barry.r.sickles@gsk.com
Received November 1, 2001
Abstr a ct: A systematic increase of substitution rates by
tert-butylamine on R-bromopropiophenones is observed with
meta or para substituents with increasing electron-with-
drawing ability (k × 103 L M-1 min-1 ) 12.7 (p-CH3), 15.7
(o-F), 20.5 (H), 20.0 (p-Cl), 23.6 (m-Cl), 27.3 (p-CF3)). Within
an ortho-substituted series, the reactivities decrease (k ×
103 L M-1 min-1 ) 7.64 (o-OCH3), 5.31 (o-CH3), 2.85 (o-Cl),
2.40 ( o-CF3)). Ortho-substitution results occur from rota-
+
+
tional barrier effects and an Aδσ Bδσ repulsion. The major
bonding contribution between reaction and R-substituent
centers (A-B) is only the σ bond. When π bonding is allowed
between A and B (meta/para-substitution), delocalization
and stabilization of the reacting center occurs.
Nucleophilic substitution of R-bromoketones is syn-
thetically useful and a topic of earlier mechanistic
studies.1 The synthesis of bupropion hydrochloride, 1,
first prepared in these laboratories,2 relies on this
chemistry and is commercially important as the active
drug substance for the antidepressant Wellbutrin and the
smoking cessation therapy Zyban. In the course of
systematic modifications on the basic bupropion skeleton,
it was noted that analogues with ortho substituents
required significantly longer reaction times (eq 1).3 This
Meta and para electron-withdrawing groups cause a
rate increase, but ortho substitution {with accompanying
ortho-steric bulk} decreases this property. Trends within
the “in-plane” vs “out-of-plane” series warrant discussion.
The p-orbitals in the reactive region of the transition
state have a net negative charge, and meta/para-sub-
stitution allows alignment with the benzene ring (Figure
1). Hence, electron-withdrawing substituents enable
greater conjugative charge delocalization.
The steric effect of ortho substituents hinders such
extended π orbital alignment (Figure 2). Consequently,
geometry restricts conjugative delocalization of negative
charge.
Further, electron-withdrawing groups place ever-
increasing partial positive charge directly adjacent to the
electropositive carbonyl carbon of the reactive system.
This, in turn, leads to a repulsion between positive
charges that is most readily corrected by reduced polar-
offers a process advantage in the preparation of bupro-
pion, because low-level o-chloropropiophenone impurities
do not readily convert to bupropion analogues or give
impurities, which are difficult to remove. In this report,
we examine the effect ortho, meta, and para substituents
impose upon SN2 reaction rates for phenacyl bromides
with tert-butylamine.
Dewar’s delocalized transition state model has signifi-
cant appeal to explain accelerated displacement rates of
(4) Dewar, M. J . S. The Electronic Theory of Organic Chemistry;
Oxford University Press: London, England, 1949; p 73. And later:
Carey, F. A.; Sundberg, R. J . Advanced Organic Chemistry, 3rd ed.;
Plenum Press: New York, 1990; Part A, p 296.
(5) (a) Forster, W.; Laird, R. M. J . Chem. Soc., Perkin Trans. 2, 1982,
135. (b) Baker, J . W. J . Chem. Soc. 1938, 445.
(6) (a) Dhami, K. S.; Stothers, J . B. Can. J . Chem. 1965, 43, 479.
(b) Dhami, K. S.; Stothers, J . B. Tetrahedron Lett. 1964, 631. (c) Oakley,
M. G.; Boykin, D. W. J . Chem. Soc., Chem. Commun. 1986, 439.
(1) (a) Thorpe, J . W.; Warkentin, J . Can. J . Chem. 1973, 51, 927.
(b) Bordwell, F. G.; Brannen, W. T., J r. J . Am. Chem. Soc. 1964, 86,
4645.
(2) Mehta, N. B.; Yeowell, D. A. Wellcome Foundation Ltd., German
patent 2,059,618, 1971; Chem. Abstr. 1972, 76, 3551k.
(3) Musso, D. L.; Mehta, N.; Soroko, F. E. Bioorg., Med. Chem. Lett.
1997, 7, 1.
10.1021/jo011042o CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/23/2003
1594
J . Org. Chem. 2003, 68, 1594-1596