Gas-phase and solution basicities of some alkyl 2,6-dialkylphenyl ketones: A comparative analysis

Article abstract of DOI:10.1016/S0040-4020(00)00370-7

The gas-phase basicity of a number of alkyl 2,6-dialkylphenyl ketones (2,6-R₂C₆H₃COR') has been found to be almost insensitive to structural variations, as a result of a compensation of steric and electronic effects associated with the bulkiness and to the polarizability, respectively, of R and/or R'. On the contrary, the basicity in concentrated sulfuric acid undergoes, along the same series of compounds, a variation of nearly 8 pK units, as a consequence of steric inhibition of solvation of the protonated carbonyl as the main effect played by R and/or R'. The results in the condensed phase agree very nicely with recent findings relevant to some 4- substituted 2,6-dimethylacetophenones and 4-substituted acetophenones as well as with data for a large number of dialkyl or alkyl aryl ketones (either from the literature or determined herein) leading to an overall pK(BH⁺) vs. m* correlation (slope = 8.8, n = 31, r = 0.996; Eq. (3)) which appears to be of general significance and identifies steric inhibition of solvation as a common prevailing factor influencing the carbonyl basicity, at least in the absence of strong conjugative interactions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00370-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4565±4573
Gas-Phase and Solution Basicities of Some Alkyl
2,6-Dialkylphenyl Ketones: a Comparative Analysis
Carlo Dell'Erba,a,b Michelangelo Gruttadauria,c Angelo Mugnoli,a Renato Noto,c Marino Novi,a,b
e
Giorgio Occhiucci,d Giovanni Petrilloa,b, and Domenico Spinelli
*
a
Á
Dipartimento di Chimica e Chimica Industriale, Universita di Genova, Via Dodecaneso 31, I-16146 Genova, Italy
bC.N.R. Centro di Studio per la Chimica dei Composti Cicloalifatici ed Aromatici, Via Dodecaneso 31, I-16146 Genova, Italy
c
Á
Á
Dipartimento di Chimica Organica `E. Paterno', Universita di Palermo, Viale delle Scienze, Parco d'Orleans II, I-90128 Palermo, Italy
dIstituto di Chimica Nucleare del C.N.R., C.P. 10, I-00016 Monterotondo Stazione, Roma, Italy
Á
Dipartimento di Chimica Organica `A. Mangini', Universita di Bologna, Via S. Donato 15, I-40127 Bologna, Italy
e
Received 4 February 2000; revised 10 April 2000; accepted 27 April 2000
AbstractÐThe gas-phase basicity of a number of alkyl 2,6-dialkylphenyl ketones (2,6-R2C6H3COR0) has been found to be almost insensi-
tive to structural variations, as a result of a compensation of steric and electronic effects associated with the bulkiness and to the polariz-
ability, respectively, of R and/or R0. On the contrary, the basicity in concentrated sulfuric acid undergoes, along the same series of
compounds, a variation of nearly 8 pK units, as a consequence of steric inhibition of solvation of the protonated carbonyl as the main effect
played by R and/or R0. The results in the condensed phase agree very nicely with recent ®ndings relevant to some 4-substituted 2,6-dimethyl-
acetophenones and 4-substituted acetophenones as well as with data for a large number of dialkyl or alkyl aryl ketones (either from the
literature or determined herein) leading to an overall pKBH vs. mp correlation (slopeˆ8.8, nˆ31, rˆ0.996; Eq. (3)) which appears to be of
1
general signi®cance and identi®es steric inhibition of solvation as a common prevailing factor in¯uencing the carbonyl basicity, at least in the
absence of strong conjugative interactions. q 2000 Elsevier Science Ltd. All rights reserved.
The in¯uence of structural parameters (of electronic and
steric origin) and/or of solvation on the strength of weak
organic bases (B) is a long-standing point of debate1 which
continues to attract much interest.2 In particular, steric and/
or conformational factors should play a role in restricting
either the p-electron delocalization in conjugated systems
(and hence affecting the overall electronic distribution
within B and/or BH1) or the accessibility of the protonation
site to charge-stabilizing solvent molecules. On the other
hand, the comparison of protonation data in solution and
in the gas phase should conceivably allow a discrimination
between structural and solvent effects3 and permit well-
grounded conclusions on their relative in¯uence and/or
interdependence.
reactions at the carbonyl group. Thus, within this project,
steric crowding at C-2 and C-6 of the benzene ring of aceto-
phenones has been recently employed5 as a means to gauge
both electronic and steric effects on their protonation
(Scheme 1). A comparison of the carbonyl basicity of
some 4-X-acetophenones (1) and their 2,6-dimethyl deriva-
tives (DM1) clearly showed, for the two series of ketones, a
close similarity of the electronic effects of the 4-substituents
in the gas phase,5b mirrored by a near unity (0.89^0.06)
1
1
slope of the excellent pKBH
vs. pKBH
correlation.
ꢀDM1†
ꢀ1†
This result is in striking contrast with the effect played by
the two ortho-methyl groups in concentrated sulfuric acid,
where a very strong basicity decrease (mirrored in turn by
1
1
the lack of any overall pKBH
lation) was observed in going from DM1c to DM1f, i.e.
vs. pKBH
cross corre-
ꢀDM1†
ꢀ1†
In the last few years we have been involved in studying the
basicity of aromatic ketones, a task which is surely justi®ed
both by the interest that is attached to such a class of
compounds4 and, in particular, by the role that their
along the series of the electron-withdrawing 4-substituents
1
pKBH plays in a number of well-known acid-catalyzed
Keywords: ketones; solution basicity; gas-phase basicity; steric and elec-
tronic effects.
* Corresponding author. Dipartimento di Chimica e Chimica Industriale,
Á
Universita di Genova, Via Dodecaneso 31, I-16146 Genova, Italy. Tel.:
139-10-353-6121; fax: 139-10-353-6118;
Scheme 1.
e-mail: petrillo@chimica.unige.it
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00370-7

4566
C. Dell'Erba et al. / Tetrahedron 56 (2000) 4565±4573
Table 2. FT-ICR gas-phase basicities (DG8, kcal mol21, at 303 K) for
ketones 1c and DM1c±DP3c, and calculated (AM1) torsion angles (t,
degrees) for both the ketones themselves (B) and their conjugate bases
(BH1)
examined.5a On the grounds of the behaviour of the mp
parameter of the excess-acidity method employed for the
1
experimental determination of the pKBH values (see
below), the latter outcome has been attributed to an unprece-
dented, rather surprising in¯uence of the far substituent X
on the differential solvatability within each B/BH1 couple
in the DM1 series.
c
tB
c
#
Ketone
R
R0
DG8a
dDG8b
tBH1
1
2
3
4
5
6
7
8
9
10
1c
H
Me
Me
Et
198.2d
198.8
199.6
200.2
199.5
200.2
200.5
199.6
200.4
200.8
0
ca. 0
89
89
81
85
84
70
84
78
76
ca. 0
16
22
30
DM1c
DM2c
DM3c
DE1c
DE2c
DE3c
DP1c
DP2c
DP3c
Me
Me
Me
Et
0.6
1.4
2.0
1.3
2.0
2.3
1.4
2.2
2.6
Pri
Me
Et
With the aim of gaining further knowledge of the interplay
of the effects involved, we have extended the comparison
between solution and gas-phase protonation to some alkyl
2,6-dialkylaryl ketones (2,6-R2C6H3COR0: R, R0ˆMe, Et,
Pri; see formula I) characterized by variable crowding
around the carbonyl group, stemming from either R or R0,
and the results are reported herein. A preliminary compara-
tive analysis of carbonyl basicities of some alkyl methyl
(MeCOR0) and alkyl phenyl ketones (PhCOR0) has also
been carried out, in order to gauge the effects played by
R0 groups of variable size (R0ˆMe, Et, Pri, But).
24
28
43
45
Et
Et
Pri
Me
Et
Pri
Pri
Pri
52/56e
56
Pri
a Estimated experimental error: ^1.0, in kcal mol21
.
b DG82DG81c: in kcal mol21
.
c Torsion angle between the benzene ring and the acyl group [C(2)±
C(1)±C(a)±O] for the optimized (AM1) geometry.
d Ref. 6a: see footnote c of Table 1.
e Two geometries corresponding to similar energy minima have been
found.
and an overall 2.7 kcal mol21 increase is to be compared
with the 6.9 kcal mol21 increase from acetone to pinaco-
lone. Such an outcome can be justi®ed on the grounds of
some levelling of the electronic effects of R0, exerted by the
phenyl group: as a matter of fact, the ability of the latter to
stabilize BH1 more effectively than B by conjugation is
mirrored by a basicity increase of more than 11 DG8 units
from acetone to acetophenone.
Results and Discussion
Gas-phase basicities
In the framework of the trends from Table 1 we have to
rationalize the gas-phase basicities of Table 2, relevant to
acetophenone (1c) and to ketones DM1c±DP3c. With the
exception of the parent acetophenone itself, whose basicity
has been taken from the literature,6a the data have been
obtained by means of the FT-ICR technique described in
Experimental, using 1c as the starting reference base. The
Table 1 collects the gas-phase thermodynamic basicity
values (DG8) for some alkyl methyl (MeCOR0) and alkyl
phenyl ketones (PhCOR0) characterized by a parallel size
increase in the R0 moiety. In the sequence MeCOMe!
MeCOEt!MeCOPri!MeCOBut (entries 1±4) the electronic
effect of R0 is revealed to be sizeable and base-strength-
ening: a result which can be straightforwardly rationalized
essentially on the grounds of charge dispersal, in the conju-
gate acid BH1, by R0, whose polarizability increases from
methyl to t-butyl.3,7 Along the corresponding series of alkyl
phenyl ketones (entries 5±8) the same basicity order is
observed, although the variations in going from R0ˆMe to
R0ˆBut are appreciably lower than for the MeCOR0 series
®gure (198.8^1.0 kcal mol21
)
for 2,6-dimethylaceto-
phenone (DM1c), redetermined herein for the sake of
consistency, matches that previously reported (199.0^
0.5 kcal mol )
21 5b and compares well with a recent literature
value obtained with both an equilibrium and a kinetic
method again using 1c as the reference base.8
In a previous paper,5b we interpreted the slight increase in
the carbonyl basicity when going from 1c to DM1c as a
prevalence of the base-strengthening electronic effects of
the two ortho-methyl groups over a conceivable negative
effect associated with some rotation of the protonated probe
group out of the plane of the phenyl ring. Herein, the picture
which clearly emerges from the DG8 data of Table 2 is that
of a feeble dependence of the gas-phase basicity on the
molecular complexity9 throughout the series of alkyl aryl
ketones examined. Although most of the dDG8 values prac-
tically fall within the estimated experimental error, at least
some `trends' seem apparent. In particular, it can be
observed that, when keeping the R groups at C-2 and C-6
of the phenyl ring constant, the basicity increase brought
about by R0 in going from Me to Et and to Pri (cf. entries 2
vs. 4, 5 vs. 7, 8 vs. 10 of Table 2: dDG8ˆ1.4, 1.0 and
1.2 kcal mol21, respectively) is lower than that in Table 1
for either the alkyl methyl (dDG8ˆ5.4 kcal mol21) or the
Table 1. Gas-phase basicities (DG8, kcal mol21) for some methyl and phen-
yl ketones (RCOR0)
#
R
R0
DG8
dDG8a
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Me
Et
186.9b
190.1b
192.3b
193.8b
198.2b,c
199.8d,e
200.6d
200.9d
0
3.2
5.4
6.9
0
1.6
2.4
2.7
Pri
But
Me
Et
Pri
But
a DG8(R )2DG8(R ˆMe): in kcal mol21
.
0
0
b Data from Ref. 6a.
c The quoted value corrects that (197.4 kcal mol21) reported in a
previous gas-phase data compilation (Ref. 6b).
d Obtained herein by the FT-ICR technique described in Experimental,
using acetophenone as the reference base.
e Ref. 6a quotes 199.7 kcal mol21
.

C. Dell'Erba et al. / Tetrahedron 56 (2000) 4565±4573
4567
alkyl phenyl ketones (dDG8ˆ2.4 kcal mol21); thus, the
2,6-dialkylphenyl moiety exerts a levelling effect on the
in¯uence of R0 on the carbonyl basicity which is more
pronounced than that displayed by the unsubstituted phenyl
group. On the other hand, with constant R0 the effect played
by R appears to be even more feeble [cf. entries 2 vs. 5 and 8
(dDG8ˆ0.7 and 0.8 kcal mol21), 3 vs. 6 and 9 (dDG8ˆ0.6
and 0.8 kcal mol21), 4 vs. 7 and 10 (dDG8ˆ0.3 and
0.6 kcal mol21) of Table 2], in spite of the contemporaneous
presence of such a group at both C-2 and C-6.10
fading conjugative effects: i.e. a trend towards the sizeable
dependence of DG8 on the size of R0 experienced by the
alkyl methyl ketones of Table 1 (entries 1±4), although
the overall effect of R0 should also take account of the
1
in¯uence of such a group on tBH
.
With regard to point (a) above, particularly intriguing is the
observation that, at constant R0, carbonyl basicity proves
practically insensitive to variations of tBH1 which amount
to not less than 308 when replacing Me with Pri at C-2 and
C-6 (cf. DM1c vs. DP1c, DM2c vs. DP2c or DM3c
vs. DP3c): rather, a slight basicity increase, if any, is
experienced. Thus, some base-strengthening effect must
be in play, capable of compensating for the envisaged nega-
tive in¯uence of the increasing tBH1 value on carbonyl
basicity. In this regard, it should be pointed out that the
tabulated s values for Et or Pri are not signi®cantly different
from that for Me and therefore the inductive effects of R at
C-2 and C-6 can hardly be responsible for the experimental
results herein, although, as already mentioned, they have
been actually invoked5b in order to explain the basicity
increase observed from acetophenone (1c) to 2,6-dimethyl-
acetophenone (DM1c).
The very narrow DG8 range spanned by the ketones
examined (ca. 2.6 kcal mol21) is surprising enough as one
would expect, as a size-dependent main impact of R and/or
R0, an effective hampering of the through conjugation
between the probe and the aromatic ring, caused by distor-
tion of the two moieties from coplanarity (steric inhibition
of conjugation). In order to attain a more quantitative
picture of any such factor of steric origin, we have
performed semiempirical (AM1) geometry optimizations;
the calculated values of the torsion angles between Ar and
COR0 in the ketones (tB) and in their conjugate acids (tBH1
)
are reported in Table 2. As far as the unprotonated ketones
are concerned, the 2,6-bisalkylated system complies with
the constraints imposed by R or R0 assuming throughout a
nearly orthogonal relative arrangement of Ar and COR0,
which prevents extensive p-orbital overlap and hence
presumably causes, with respect to the parent acetophenone
1c, the loss of any effective through-conjugation between
the two moieties.11 It should be noted that tB is somehow
in¯uenced by R and/or R0, surprisingly enough decreasing
with increasing size of R (at constant R0) or of R0 (at
constant R); the overall tB decrease from DM1c
(RˆR0ˆMe) to DP3c (RˆR0ˆPri) amounts to 138 (from
89 to 768), but the lowest torsion has been observed for
DE3c (708), although no easy explanation can be advanced.
Whatever the dependence of tB on the size of R and/or R0,
well in keeping with previous results con®ned to the
DM1a±f series of Scheme 1,5b carbonyl protonation causes
a reduction of the torsion angle (column 8 of Table 2), most
probably because of a compelling demand for stabilizing
conjugative interactions between Ar and the COH1 group.
Recently,10b the stronger gas-phase acidity of the sterically
hindered 2-tert-butylbenzoic acid with respect to 2-methyl-
benzoic acid has been attributed to a pole/induced-dipole
favourable interaction in the anion in the former case,
acknowledging only a minor contribution to the steric
inhibition of resonance. A similar polarizability effect12
can be invoked herein as a stabilizing factor of the positive
charge of the protonated carbonyl. It is conceivable that the
polarizability of the different alkyl groups at C-2 and C-6
[most likely increasing in the order CH3,C2H5,CH(CH3)2]
might favour a parallel increase in the aromatic p-electrons
polarization towards the electrophilic center (p-polari-
zation)13 with a consequent increase in the stability of
BH1 by means of a charge/induced-dipole interaction (see
the canonical structure A).
Nonetheless, although protonation seems to represent a
driving force suf®cient to partially overcome geometric
constraints in pursuit of stabilization, the tBH1 data exhibit
throughout a torsion between the protonated carbonyl group
and the aromatic ring which is always sizeable and more
heavily in¯uenced by the substituents in the ring (i.e. R)
than by the R0 group directly linked to the carbonyl [cf.
e.g. entry 2 (tBH1ˆ168) with entries 8 (t1BHˆ458) and 4
(tBH1ˆ458), respectively].
The participation of p-polarization would thus allow the
aryl moiety to exert throughout a signi®cant positive in¯u-
ence on the carbonyl basicity, notwithstanding the fading of
the conjugative effects. This occurrence would also contri-
bute to explaining the meagre sensitivity of the system to the
polar effects of R0 at constant R [see point (b) above], as a
result of a levelling analogous to that observed for the alkyl
phenyl ketones of Table 1 (entries 5±8) in comparison with
the variations experienced by alkyl methyl ketones (entries
1±4).
Thus, in the light of the well-acknowledged dependence of
a conjugative charge delocalization on the degree of copla-
narity between the moieties involved,11 we are left with the
need to rationalize a very meagre variation of the gas-phase
basicity along the DM1c±DP3c series which clearly
contrasts with expectations such as (a) a decreasing basicity
due to the increasing torsion in the protonated ketones,
brought about in particular by the R groups on the phenyl
ring, or (b) a restored effectiveness of the base-strengthen-
ing electronic effects of R0 at constant R, paralleling the
Solution basicities
As compared to the feeble basicity increase along the 1c±DP3c

4568
C. Dell'Erba et al. / Tetrahedron 56 (2000) 4565±4573
Table 3. Basicity parameters for ketones 1c±DP3c in water/sulfuric acid
mixtures (the ionization ratios have been evaluated by means of H NMR
spectroscopy in deuterated sulfuric acid, see Experimental)
On the contrary, the decrease in basic strength from
4-nitroacetophenone (1f, pKBH1ˆ25.02) to 2,6-dimethyl-
4-nitroacetophenone (DM1f, pKBH1ˆ29.53) mirrors a
strong effect played by the differential solvation of the
two conjugate acids (mp 0.58 and 1.08, respectively).
1
a
1
#
Ketone
R
R0
pKBH
mp
% D2SO4
1
2
3
4
5
6
7
8
9
1c
H
Me 24.08^0.24b 0.65^0.05b
75±98%
75±98%
75±98%
75±98%
80±98%
80±98%
80±98%
87±98%
87±98%
87±98%
DM1c Me Me 24.85^0.15b 0.62^0.02b
An accurate analysis of the mp values in Table 3 reveals a
behaviour which is not homogeneous along the whole series
of examined ketones: while 1c and DM1c share (within the
experimental error) the same mp value, this parameter
undergoes, in going from DM1c to DP3c, an increase
which tightly parallels the pKBH1 decrease. The very good
correlation of Eq. (1) quantitatively testi®es for such a
dependence, while Fig. 1 clearly enlightens the failure of
1c (B) to correlate along with the other ketones.
DM2c Me Et
DM3c Me Pri
26.30^0.06
25.93^0.11
27.49^0.16
28.50^0.24
28.14^0.17
210.8^0.6
212.4^0.8
212.3^1.0
0.71^0.01
0.66^0.01
0.85^0.02
0.98^0.03
0.92^0.02
1.22^0.07
1.42^0.10
1.40^0.12
DE1c
DE2c
DE3c
DP1c
DP2c
Et
Et
Et
Pri
Pri
Pri
Me
Et
Pri
Me
Et
10 DP3c
Pri
a Sulfuric acid (wt.%) concentration.
b Ref. 5a.
1
2pKBH ˆ 2ꢀ0:22 ^ 0:27† 1 ꢀ8:96 ^ 0:26†mp
series in the gas phase, a both qualitatively and quantita-
tively strikingly different behaviour for the protonation of
the same ketones in solution is clearly testi®ed by a huge
(more than 8 pK units) basicity decrease from 1c to DP3c in
water/sulfuric acid mixtures (Table 3).14
ꢀ1†
n ˆ 9; r ˆ 0:997
Accordingly, if one must comply with the signi®cance
assigned above to the mp parameter, the basicity of the
hindered DM1c±DP3c appears to be strongly governed by
solvation, which is progressively precluded by crowding
around the protonation site and overwhelmes the basicity
levelling observed, along the same series, in the gas phase.
Actually, the effect of R on solvation is de®nitely more
pronounced than that of R0: thus, the replacement of Me
with Pri both at C-2 and C-6 of the phenyl ring10 causes a
basicity decrease of ca. 6 pK units (cf. entries 2 and 8, 3 and
9, 4 and 10 of Table 3), while the same structural change at
the carbonyl causes a basicity decrease of only 0.7±1.5 pK
units (cf. entries 2 and 4, 5 and 7, 8 and 10 of Table 3). In
this regard, it should also be noticed that, as the only excep-
tion, the replacement of COEt with COPri leads to a slight
but signi®cant basicity increase, paralleled by a feeble mp
decrease, irrespective of the nature of R: an outcome for
Steric inhibition to conjugation between Ar and the probe
group and/or steric hindrance to solvation15 of the proto-
nated carbonyl group would offer a rationale for the
observed behaviour. As a matter of fact, the basicity
decrease (0.8 pK units) caused by the introduction of the
two methyl groups at C-2 and C-6 of the phenyl ring when
going from 1c to DM1c (cf. entries 1 and 2 of Table 3) has
been justi®ed5a as a steric inhibition to conjugation, on the
grounds of a detailed analysis encompassing two equivalent
series of 4-substituted aryl ketones (i.e. 1a±f vs. DM1a±f;
see Scheme 1). Particular signi®cance can be attributed, in
this respect, to the value of the mp parameter, which report-
edly1 represents in essence a measure of the degree of
solvation of the protonated species: thus, the similar values
of mp for 1c and DM1c seem to leave little role to solva-
tional differences between the two relevant conjugate acids.
Figure 1. Correlation of carbonyl basicity with mp along the series DM1c±DP3c [1c (B) has not been included in the correlation analysis].

C. Dell'Erba et al. / Tetrahedron 56 (2000) 4565±4573
4569
Table 4. Basicity parameters ꢀ2pKBH and mp) for some ketones in water/sulfuric acid mixtures (see Scheme 1). The data are graphically reported in Fig. 2,
together with those relevant to compounds DM1c±DP3c
1
mp
Ref.
No
Compound
2pKBH
mp
Ref.
1
1
No
Compound
2pKBH
1
2
3
4
5
6
7
8
DM1a (XˆMeO)a
DM1b (XˆMe)a
DM1d (XˆF)a
DM1e (XˆBr)a
DM1f (XˆNO2)a
4-CF3C6H4COMe
4-CNC6H4COMe
4-NO2C6H4COMe
4-MeOC6H4COMe
4-MeC6H4COMe
4-PhC6H4COMe
PhCOMe (1c)
3.96
4.50
6.08
6.93
9.53
4.75
4.59
5.02
3.13
3.68
3.96
4.08
4.15
4.56
3.89
3.97
0.48
0.56
0.76
0.83
1.08
0.56
0.50
0.58
0.54
0.61
0.55
0.65
0.57
0.60
0.44
0.44
5b
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Bus2CO
But2CO
4.30
6.80
3.40
3.06
3.48
4.25
3.48
3.63
3.88
3.55
2.95
4.52
5.06
6.25
4.71
0.47
0.78
0.35
0.35
0.40
0.45
0.40
0.42
0.44
0.42
0.38
0.64
0.71
0.72
0.67
2, 15
2, 15
2
15, 16
16
16
16
16
5b
5b
5b
5b
5a
5a
5a
5a
5a
5a
5a
5a
5a
2, 15
2
cis-2,6-But2cyclohexanone
Me2CO
MeCOBut
Pri2CO
MeCOEt
MeCOPri
9
Et2CO
16
16
16
10
11
12
13
14
15
16
c-C6H11COMe
c-C3H5COMe
PhCOEt
This work
This work
2, 15
16
4-FC6H4COMe
4-BrC6H4COMe
Bun2CO
PhCOPri
PhCOBut
Ph2CO
Bui2CO
a See Scheme 1.
which a sound explanation cannot be provided at the
moment.
solvation.
1
2pKBH ˆ 2ꢀ0:50 ^ 0:21† 1 ꢀ9:18 ^ 0:22†mp
It should be noted that the basicity values5b of the 4-X-2,6-
dimethylacetophenones DM1a±f (entries 1±5 of Table 4)
ꢀ2†
n ˆ 14; r ˆ 0:997
display a sensitivity to mp ‰2pKBH ˆ 2ꢀ0:80 ^ 0:34† 1
1
ꢀ9:39 ^ 0:46†mp; nˆ6, rˆ0.995] which very well matches
the slope of Eq. (1) herein (8.96): as a consequence, the
relevant pKBH1 values line up with the least-squares straight
line of Fig. 1, leading to the excellent correlation of Eq. (2)
(see Fig. 2, where ketones DM1c±DP3c and DM1a,b,d±f
are represented by A and B, respectively). This outcome
strongly suggests that the thermodynamic basicity along the
DM1a±f and the DM1c±DP3c series is governed by a
common factor gauged by the mp parameter and which
can most likely be identi®ed as a steric hindrance to
Within the DM1a±f series, the strong dependence of mp on
the 4-substituent, viz. the increase in such a parameter
(corresponding to a signi®cant decrease in the solvation of
the protonated species) when going from electron-releasing
to electron-withdrawing substituents in Ar, can be rationa-
lized on the grounds of the relative weight of the canonical
structures B and C for BH1. Thus, an electron-releasing
4-substituent should favour the `carbocationic' structure
B, whose OH group is both a donor and an acceptor of
Figure 2. Correlation of carbonyl basicity vs. mp for aliphatic and aromatic ketones. DM1c±DP3c: A; DM1a,b,d±f: B; 4-X-acetophenones: K; dialkyl
ketones: W; PhCOEt and PhCOPri: q; PhCOBut: w; PhCOPh: [. The solid line corresponds to the correlation of Eq. (3), from which the numbered compounds
(see Table 4) have been excluded. The dashed line corresponds to the correlation of Eq. (2), based on the 2,6-dialkylphenyl ketones (A and B).

4570
C. Dell'Erba et al. / Tetrahedron 56 (2000) 4565±4573
1
exclusive, steep dependence of pKBH on solvation.
hydrogen bonds and hence could well account for a rela-
tively high solvatability (i.e. low mp); on the contrary, in the
case of electron-withdrawing 4-substituents, the increased
contribution of structure C could reasonably reduce the
capability of the oxygen atom as an H-bond acceptor, there-
fore decreasing the solvatability of COH1 (higher mp).
1
2pKBH ˆ 2ꢀ0:04 ^ 0:10† 1 ꢀ8:76 ^ 0:14†mp
ꢀ3†
n ˆ 31; r ˆ 0:996
It must be ®nally pointed out that, to our knowledge, we deal
herein with unprecedented (at least as far as the protonation
of ketones is concerned) mp values higher than unity, widen-
ing the available experimental range and thus boosting the
signi®cance of a correlation such as that of Eq. (3).
It is relevant to note that, among the previously studied6a
2,6-unsubstituted acetophenones, only the presence of a
strong electron-withdrawing 4-substituent (i.e. CF3, CN,
Experimental
NO2) allows the experimental pKBH and mp values to ®t
1
Melting points were determined on a BuÈchi 535 apparatus
and are uncorrected. Distillations were performed with a
the correlation of Eq. (2), sizeable deviations being
otherwise observed (Fig. 2, K). The outcome seems a
clear indication that in the absence of strong conjugative
delocalizing effects played by the aryl moiety onto COH1
(e.g. in the case of electron-withdrawing para substituents),
charge stabilization is mainly governed by solvation,
causing lining-up with 2,6-dimethylacetophenones, where
internal effects (i.e. electronic ones) are limited by steric
hindrance to conjugation, and external factors (i.e. solva-
tion) prove in turn predominant.
È
Kugelrohr apparatus. NMR spectra (in CDCl3, if not
otherwise stated) were obtained with a BruÈker AC-E250
instrument; TMS was used as internal standard and chemi-
cal shifts are reported as d values (ppm). IR Spectra (nujol
mull) were recorded on a Perkin±Elmer 881 Infrared
Spectrophotometer and data are given in cm21
.
Materials
Well in keeping with the reasoning above, a number of
dialkyl ketones (W) also lie on the straight line of Fig. 2.
Their thermodynamic parameters can be picked-up from the
Tetrahydrofuran (THF) was puri®ed by standard methods
and distilled from potassium benzophenone ketyl before
use. Column chromatography was performed on silica gel
using petroleum ether and gradients (or appropriate
mixtures) with CH2Cl2, Et2O, or AcOEt as eluants, the
solvents being distilled before use. Acetophenone (1c),
propiophenone (PhCOEt), phenyl isopropyl ketone (PhCO-
Pri) and tert-butyl phenyl ketone (PhCOBut) were commer-
cial samples distilled to match reported physical constants.
The synthesis of 2,6-dimethylacetophenone (DM1c) has
been reported elsewhere.13a The alkyl 2,6-dialkylphenyl
ketones DM2c±DP3c were synthesized by a common
procedure from the corresponding commercially available
2,6-dialkylanilines via (i) diazotization followed by bromo-
dediazotization, (ii) preparation of the 2,6-dialkylphenyl-
magnesium bromide, and (iii) reaction of the latter with
the appropriate acyl chloride.
1
recent literature (entries 15±27 of Table 4) and their pKBH
values, in the absence of any reasonable strong conjugative
interactions, must essentially be governed by solvation,
which is in turn negatively in¯uenced (higher mp) by steric
hindrance to solvating water molecules.
In order to test and better de®ne the applicability range of
Eq. (2), we have measured the basicity of some alkyl phenyl
ketones (PhCOR0, Table 4). Actually, for R0ˆMe, Et, Pri the
experimental points deviate signi®cantly from the straight
line of Fig. 2 (points 12, 28 and 29, respectively), suggesting
a prevalence of conjugative stabilization. On the other hand,
tert-butyl phenyl ketone (R0ˆBut) perfectly lines up (Fig.
2, w), as the result of a restored predominance of the effect
represented by steric hindrance to solvation with respect to
conjugative stabilization of COH1. In this regard it should
be noted that a recent thermodynamic analysis of the
transfer from the gas phase to solution, combined with
gas-phase proton af®nities, has established, for the hindered
But2CO and PhCOBut, a steric effect of exclusively enthalpic
origin (i.e. steric hindrance to solvation) on their protonation
in water/sulfuric acid mixtures.15 The ®tting of both
compounds to the correlation of Eq. (2) should therefore
guarantee the validity of the same conclusion at least for
all those ketones which line up in the same correlation.
2,6-Diethyl- and 2,6-diisopropyl-aniline were purchased
from Aldrich and distilled before use. 2-Bromo-1,3-
dimethylbenzene was itself a commercial product (Aldrich),
used without further puri®cation. 2-Bromo-1,3-diethyl-
benzene17a and 2-bromo-1,3-diisopropylbenzene17 were
synthesized (in 50% and 63% yield of chromatographically
pure product, respectively) from the corresponding dialkyl-
anilines.18
2,6-Dimethyl-, 2,6-diethyl- and 2,6-diisopropyl-phenyl-
magnesium bromide were prepared from the corresponding
bromoderivatives with Mg turnings (1.1 mol. equiv.) in
anhydrous THF and immediately transferred by cannulation
into the solution of the appropriate acyl chloride assuming a
quantitative yield.
1
As an obvious conclusion, we have extended the pKBH vs.
mp correlation to the ketones which qualitatively showed a
good ®t to Eq. (2) (see caption to Fig. 2), obtaining Eq. (3).
In Eq. (3), (a) the intercept is not signi®cantly different from
zero and (b) the slope well matches that of Eq. (2), indi-
cating, for protonated ketones where conjugative charge-
stabilizing effects play only a secondary role, an almost
Acetyl, propionyl and isobutyryl chloride were commercial
samples distilled before use.

C. Dell'Erba et al. / Tetrahedron 56 (2000) 4565±4573
4571
each, two partly overlapped d, Jˆ6.8 Hz each), 2.10 (3H, s),
3.40 (2H, hept, Jˆ6.8 Hz), 4.92 (1H, d, Jˆ1.4 Hz), 5.42
(1H, d, Jˆ1.4 Hz), 7.15 (2H, m), 7.33 (1H, m). Found: C,
78.0; H, 9.0% (C16H22O2 requires: C, 78.1; H, 8.9%).
1-(2,6-Diisopropylphenyl)-1-propenyl propionate (4c).
1H NMR (in mixed chromatographic fractions with
DP2c): d 1.15 and 1.17 [9H in all, partly overlapped t
(3H, Jˆ7.6 Hz) and d (6H, Jˆ6.8 Hz)], 1.23 (6H, d, Jˆ
6.8 Hz), 1.73 (3H, d, Jˆ6.8 Hz), 2.40 (2H, q, Jˆ7.6 Hz),
3.48 (2H, hept, Jˆ6.8 Hz), 5.23 (1H, q, Jˆ6.8 Hz), 7.14
(2H, m), 7.30 (1H, m).
Scheme 2.
2,6-Dimethylpropiophenone (DM2c). Pale-yellow oil
(50%), distilled bulb-to-bulb at 1258C/0.5 mmHg (lit.:19
General procedure for the synthesis of the alkyl
2,6-dialkylphenyl ketones DM2c±DP3c
1
bp 120±1218C/21 mmHg). H NMR: d 1.20 (3H, t, Jˆ
7.2 Hz), 2.21 (6H, s), 2.72 (2H, q, Jˆ7.2 Hz), 7.00 (2H,
m), 7.15 (1H, m). 13C NMR: d 7.55, 19.06, 37.80, 127.67,
128.38, 132.36, 142.60, 211.15. IR: 1700.0 cm21 (CvO).
Found: C, 81.3; H, 8.7% (C11H14O requires: C, 81.4; H, 8.7%).
In a ¯ame-dried 100 mL three-neck ¯ask, equipped with a
thermometer, an argon inlet, a rubber septum, and a
magnetic stirring bar, the appropriate acyl chloride
(R0COCl, 62 mmol) was dissolved in 28 mL of THF and
cooled to 08C with an external ice bath. The freshly prepared
Grignard reagent (6.2 mmol) in THF was slowly added by
cannula under magnetic stirring. The reaction mixture was
kept at 08C for 2.5 h, then poured into ice/5% HCl. After
extraction with diethyl ether the organic phase was washed
with saturated aqueous NaHCO3, then with brine to
neutrality, dried (Na2SO4) and evaporated to dryness. The
residue was chromatographed on silica gel. The desired
ketone was generally accompanied by variable amounts of
secondary products whose nature depends on the acyl
chloride. Thus, in the reactions with propionyl (R0ˆEt)
and isobutyryl (R0ˆPri) chlorides the crude ketone from
chromatography was contaminated by the corresponding
2,6-dialkylphenyl ester (2,6-R2C6H3OCOR0); such
compounds could be almost completely removed by trans-
esteri®cation (EtONa/EtOH, re¯ux, 1 day) followed by
chromatography. The formation of the acetophenones
DE1c and DP1c (R0ˆMe) as well as of the propiophenone
DP2c (R0ˆEt) was accompanied by that of the correspond-
ing enol esters 4 (22, 30 and 29%, respectively, as deter-
mined by 1H NMR analysis of mixed chromatographic
fractions), originating from acylation of the enol of the
expected ketone with the excess acyl chloride; acid hydro-
lysis (50% H2SO4, re¯ux, 15±20 h) allowed, after usual
work up and chromatographic separation, to recover the
relevant ketone (see Scheme 2).
2,6-Dimethylisobutyrophenone (DM3c). Colourless oil
(66%), distilled bulb-to bulb at 1258C/0.5 mmHg. 1H
NMR: d 1.19 (6H, d, Jˆ6.9 Hz), 2.22 (6H, s), 2.98 (1H,
hept, Jˆ6.9 Hz) 7.02 (2H, m), 7.16 (1H, m). 13C NMR: d
17.87, 19.65, 42.16, 127.83, 128.46, 133.13, 141.80, 214.04.
IR: 1693.0 cm21 (CvO). Found: C, 81.8; H, 9.0% (C12H16O
requires: C, 81.8; H, 9.1%).
2,6-Diethylacetophenone (DE1c). Colourless oil (30%),
distilled bulb-to bulb at 1258C/0.5 mmHg (lit.:20 bp 85±
1
868C/5 mmHg). H NMR: d 1.21 (6H, t, Jˆ7.6 Hz), 2.50
and 2.53 [7H in all, s overlapped to a quartet (Jˆ7.6 Hz)],
7.08 (2H, m), 7.26 (1H, m). 13C NMR: d 15.71, 26.11,
33.01, 126.04, 128.79, 138.51, 141.72, 208.31. IR:
1695.0 cm21 (CvO). Found: C, 81.7; H, 9.2% (C12H16O
requires: C, 81.8; H, 9.1%).
2,6-Diethylpropiophenone (DE2c). Colourless oil (34%),
distilled bulb-to bulb at 1408C/0.5 mmHg. 1H NMR: d 1.20
(9H, t, Jˆ7.5 Hz), 2.47 (4H, q, Jˆ7.5 Hz), 2.72 (2H, q,
Jˆ7.5 Hz), 7.08 (2H, m), 7.26 (1H, m). 13C NMR: d 7.64,
15.73, 26.12, 38.71, 125.93, 128.72, 138.72, 141.64, 211.12.
IR: 1698.0 cm21 (CvO). Found: C, 82.0; H, 9.5% (C13H18O
requires: C, 82.1; H, 9.5%).
2,6-Diethylisobutyrophenone (DE3c). Colourless oil
(42%), distilled bulb-to-bulb at 1408C/0.5 mmHg. 1H
NMR: d 1.18 and 1.21 [12H in all, d (Jˆ7.0 Hz) partly
overlapped to a t (Jˆ7.5 Hz)], 2.47 (4H, q, Jˆ7.5 Hz),
2.92 (1H, hept, Jˆ7.0 Hz), 7.10 (2H, m), 7.27 (1H, m).
13C NMR: d 15.69, 18.03, 26.46, 42.67, 125.94, 128.76,
139.41, 140.68, 214.16. IR: 1693.0 cm21 (CvO). Found:
C, 82.3; H, 9.8% (C14H20O requires: C, 82.3; H, 9.9%).
The ketones DM2c±DP3c were all isolated as oils and
distilled bulb-to-bulb in a Kugelrohr apparatus (the quoted
temperature being that of the oven); when formation of the
enol ester 4 occurs, the yield reported (referred to the
bromoderivative) is inclusive of the product recovered by
hydrolysis of 4.
1-(2,6-Diethylphenyl)vinyl acetate (4a). 1H NMR (in
mixed chromatographic fractions with DE1c): d 1.21 (6H,
t, Jˆ7.6 Hz), 2.10 (3H, s), 2.77 (4H, q, Jˆ7.6 Hz), 4.93 (1H,
d, Jˆ1.5 Hz), 5.41 (1H, d, Jˆ1.5 Hz), 7.10 (2H, m), 7.26
(1H, m).
2,6-Diisopropylacetophenone (DP1c). Colourless oil
(24%), distilled bulb-to-bulb at 1408C/0.1 mmHg; solidi®ed
after distillation: mp 45.6±47.78C (lit.:20b mp 49.9±50.08C).
1H NMR: d 1.24 (12H, d, Jˆ6.8 Hz), 2.50 (3H, s), 2.73 (2H,
hept, Jˆ6.8 Hz), 7.16 (2H, m), 7.32 (1H, m). 13C NMR: d
24.34, 31.02, 33.87, 123.04, 128.96, 140.56, 143.20, 208.94.
IR: 1698.0 cm21 (CvO). Found: C, 82.4; H, 9.9% (C14H20O
requires: C, 82.3; H, 9.9%).
1-(2,6-Diisopropylphenyl)vinyl acetate (4b). White solid,
mp 50.5±52.58C (benzine). H NMR: d 1.19 and 1.22 (6H
1

4572
C. Dell'Erba et al. / Tetrahedron 56 (2000) 4565±4573
2,6-Diisopropylpropiophenone (DP2c). Pale-yellow oil
(32%), distilled bulb-to-bulb at 1408C/0.1 mmHg. 1H
NMR: d 1.20 (15H, m), 2.61 (2H, hept, Jˆ6.8 Hz), 2.73
(2H, q, Jˆ6.8Hz), 7.16 (2H, m), 7.31 (1H, m). 13C NMR:
d 7.64, 24.36, 31.11, 39.41, 122.97, 128.90, 140.49, 143.56,
211.33. IR: 1699.0 cm21 (CvO). Found: C, 82.4; H, 10.3%
(C15H22O requires: C, 82.5; H, 10.2%).
the experimental error associated with this kind of determi-
nation.
1
pKBH Measurements in water/sulfuric acid
1
The pKBH values for compounds DM2c±DP3c were calcu-
lated by means of the excess-acidity method (Eq. (4)).25
log I 2 log CH ˆ pKBH 1 mpX
ꢀ4†
1
1
2,6-Diisopropylisobutyrophenone (DP3c). Pale-yellow oil
(35%), distilled bulb-to-bulb at 1608C/0.1 mmHg. 1H NMR:
d 1.19 and 1.22 [18H in all, d (Jˆ7.0 Hz) overlapped to a
multiplet], 2.60 (2H, hept, Jˆ6.8 Hz), 2.87 (1H, hept,
Jˆ7.0 Hz), 7.16 (2H, m), 7.32 (1H, m). 13C NMR: d
18.05, 23.29, 25.56, 31.40, 43.26, 123.02, 128.95, 139.44,
144.30, 214.36. IR: 1692.0 cm21 (CvO). Found: C, 82.8;
H, 10.4% (C16H24O requires: C, 82.7; H, 10.4%).
1
Ionization values ꢀI ˆ CBH =CB† were determined at 298 K
in aqueous deuterated sulfuric acid solutions (0.05
1
mol dm23 in substrate) by a H NMR technique whose
essential features have been described previously.5a
Trimethylammonium ion (0.05 mol dm23) was used as
internal standard to minimize solvent effects on chemical
shifts.26 The chemical shift of the methyl groups of the ortho
substituent R (see formula I) was chosen as a probe for
evaluating the amount of protonation at the carbonyl
Gas-phase-basicity measurements
Gas-phase basicities (DG8) of ketones DM1c±DP3c have
been determined by ICR measurements. All experiments
were performed using a double cell FTMS 2001 FT-ICR
spectrometer from Extrel (now Finnigan), Wisconsin,
USA, equipped with an Autoprobe for the direct insertion
of solid samples. Liquid ketones were introduced through a
batch inlet at a pressure of about 5£1028 mmHg, while the
solid samples, introduced with the Autoprobe, initially
reached a higher pressure (1026 mmHg) which, after a
convenient delay time, decreased and was stabilized at
about 3£1028 mmHg. Pressures were measured with a
Bayard±Alpert ionization gauge; its readings were cali-
brated with methane21 and corrected for relative sensitivity
to the various gases.22 Ions were formed by electron impact
at 70 eV, with a beam duration of 50 ms and emission
current of 10 mA. The ion of interest was isolated with the
SWIFT method23 and thermalized by collisions with argon
introduced through a pulsed valve at a pressure of
1026 mmHg; the thermalization was con®rmed by the linear
decrease of the logarithmic intensity of the ion during the
reaction time.
1
group. The CH and X values used in Eq. (4) were calculated
by interpolation of literature data.1
Semiempirical calculations
For the considered alkyl aryl ketones the conformational
study of the isolated molecules was performed by semi-
empirical molecular-orbital calculations at the AM1
level.27 The starting models were generated using a graphical
interface and a common structural template, which was
edited for every compound; each model was then re®ned
with a full optimization.28
Acknowledgements
Financial support by the Universities of Bologna, Genova
and Palermo (ex 60%) and by C.N.R. is gratefully acknowl-
edged. Investigation supported by the University of Bologna
(funds for selected research topics).
The DG8 values reported in the literature are mostly deter-
mined by measuring the equilibrium constant of the proton
transfer reaction between the protonated sample and a
reference base whose DG8 is known. In the present case
this method failed because, notwithstanding the low
pressure of the samples into the reaction cell, the protonated
ketones, beside the proton transfer to the reference base,
gave rise to the formation of adducts with their neutral
counterparts and with the base itself; these adducts were
actually the `sink' of the reaction and prevented the achieve-
ment of equilibrium. For this reason we were forced to the
alternative approach based on the determination of Keq as
the ratio of forward and reverse rate constant for the proton
transfer24 calculated at the beginning of the reaction, when
the formation of adducts is still negligible. Each ketone was
tested using at least another ketone of the investigated series
as the reference base. From Keq, gas-phase basicity
differences (dDG8) could be calculated, and absolute DG8
values were derived with reference to 2,6-dimethylaceto-
phenone (DM1c); the DG8 value of the latter, redetermined
herein for the sake of consistency against acetophenone
(1c), perfectly matches that previously reported5b within
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25. Cox, R. A.; Yates, K. J. Am. Chem. Soc. 1978, 100, 3861.
26. Bonvicini, P.; Levi, A.; Lucchini, V.; Modena, G.; Scorrano,
G. J. Am. Chem. Soc. 1973, 95, 5960.
14. This variation is to be compared with the overall less than 2 pK
units increase in the gas phase, as obtainable from Table 2 on
the grounds of the relationship: DpKg ˆ dDG8=2:303RT ˆ
dDG8=1:3865 (Rˆ1.987 cal K21 mol21, Tˆ303 K).
27. Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P.
J. Am. Chem. Soc. 1985, 107, 3902.
28. spartan, version 5.1; Wavefunction, Inc.: 18401 Von Karman
Avenue, Suite 370, Irvine, CA 92612, USA, 1998.