N- vs O-protonation and the transannular substituent interaction in 8-(dimethylamino)-1-acetonaphthone

Article abstract of DOI:10.1021/jo000615e

Dynamic NMR measurements of 8-(dimethylamino)-1-acetonaphthone 1 in neutral solutions reveal a solvent dependency of the barrier to NMe group interchange similar to that reported for N,N-dimethylacetamide. Titrating 1 with TFA in solvents of varying donicities gives rise to equilibrium mixtures of N-protonated aminoketone 2 and the O-protonated transannular addition product 3, the interconversion rate of which is slow on the NMR time scale at ambient temperature. The preference for O- or N-protonation is medium-dependent, the amount of N-protonated 2 increasing with a decrease in the nucleophilicity of the solvent. The set of equilibria which govern the interconversion of 2 and 3 in the titration mixtures are identified and their equilibrium constants evaluated from the NMR data. X-ray analysis of the crystalline trifluoroacetate salt of O-protonated 3 indicates that the transannular N···CO bond of 3 is formed to an extent of only 80%. The equilibrium distribution of 2 and 3, paired with the tetrafluoroborate anion, depends on both the nucleophilicity and the polarity of the solvent. In PhNO₂ the enthalpy change 3 → 2 amounts to 2.6 kcal/mol.

Full text of DOI:10.1021/jo000615e

5752
J . Org. Chem. 2000, 65, 5752-5759
N- vs O-P r oton a tion a n d th e Tr a n sa n n u la r Su bstitu en t In ter a ction
in 8-(Dim eth yla m in o)-1-a ceton a p h th on e
Ingeborg I. Schuster,*,† Alan J . Freyer,‡ and Arnold L. Rheingold§
Department of Chemistry, Pennsylvania State University, Abington College,
Abington, Pennsylvania 19001 and the Department of Chemistry and Biochemistry,
University of Delaware, Newark, Delaware 19716
i1s@psu.edu
Received April 21, 2000
Dynamic NMR measurements of 8-(dimethylamino)-1-acetonaphthone 1 in neutral solutions reveal
a solvent dependency of the barrier to NMe group interchange similar to that reported for N,N-
dimethylacetamide. Titrating 1 with TFA in solvents of varying donicities gives rise to equilibrium
mixtures of N-protonated aminoketone 2 and the O-protonated transannular addition product 3,
the interconversion rate of which is slow on the NMR time scale at ambient temperature. The
preference for O- or N-protonation is medium-dependent, the amount of N-protonated 2 increasing
with a decrease in the nucleophilicity of the solvent. The set of equilibria which govern the intercon-
version of 2 and 3 in the titration mixtures are identified and their equilibrium constants evaluated
from the NMR data. X-ray analysis of the crystalline trifluoroacetate salt of O-protonated 3 indicates
that the transannular N‚‚‚CO bond of 3 is formed to an extent of only 80%. The equilibrium
distribution of 2 and 3, paired with the tetrafluoroborate anion, depends on both the nucleophilicity
and the polarity of the solvent. In PhNO2 the enthalpy change 3 f 2 amounts to 2.6 kcal/mol.
In tr od u ction
ment of the donor-acceptor pair that is especially con-
ducive to through-space orbital overlap. Crystallographic
analysis showed unidirectional in-plane displacements
of the exocyclic substituent bonds and pyramidization of
the carbonyl carbon out of the Ar/O/Me plane in the
direction of the nitrogen atom. These geometric distor-
tions were ascribed by Dunitz to the onset of sp2 f sp3
conversion of the carbonyl carbon.6
Interaction, through space, between tertiary amino and
carbonyl moieties was first discovered in cyclic azake-
tones by Leonard and co-workers1 in the 1950’s. Since
then, transannular >N‚‚‚CO interplay has been observed
in a number of other flexible bifunctional molecules and
studied by a variety of physical, chemical, and spectro-
scopic methods.2 There has been a suggestion of its
potential importance in the physiological activity of
relevant biomolecules.3 The interaction, which Leonard
referred to as transannular amide resonance, is believed
to involve the shifting of electronic charge from the
nucleophilic amino nitrogen to the antibonding π* orbital
of the electrophilic carbonyl carbon.4
Of great interest is a report by Dunitz et al.5 of
intramolecular donor-acceptor N‚‚‚CO interaction in
crystalline 8-(dimethylamino)-1-acetonaphthone 1. Here
the rigidity of the hydrocarbon framework and the
particular placement of the substituents gives rise to a
conformationally restricted system with a very short
transannular distance and a stereoelectronic arrange-
The chemistry of 1 in solution has not been investi-
gated. Because nucleophilic addition of neutral functional
groups results in higher dipole moments, the interaction
between the substituents of 1 could be quite sensitive to
solvent properties. For 1 dissolved in protonating media,
there arises, in addition, the question of choice, as in the
case of amides, between two proximate, conformationally
fixed, and electronically linked protonation sites, the
dimethylamino nitrogen and the carbonyl oxygen.
1
It was the purpose of the present work to use H and
13C NMR spectroscopy to investigate the behavior of the
electrophile-nucleophile substituent pair of 1 in neutral
and acidic nonaqueous environments.
† Pennsylvania State UniversitysAbington.
‡ Smithkline & Beecham Pharmaceuticals, King of Prussia, PA
19406.
§ University of Delaware.
(1) Leonard, N. J .; Morrow, D. F.; Rogers, M. T. J . Am. Chem. Soc.
1957, 79, 5476-5479. Leonard, N. J .; Adamaick, J . A.; Djerassi, C.;
Halpern, O. J . Am. Chem. Soc. 1958, 80, 4858-4862. Leonard, N. J .
Rec. Chem. Prog. 1956, 17, 243.
(2) Leonard, N. J . Acc. Chem. Res. 1979, 12, 423. Birnbaum, I. J .
Am. Chem. Soc. 1974, 96, 6165-6168. Spanka, G.; Rademacher, P.; J .
Org. Chem. 1986, 51, 592-596. Spanka, G.; Rademacher, P.; Duddeck,
H. J . Chem. Soc., Perkin Trans. 2 1988, 2119-2121. Griffith, R.;
Bremer, J . B.; Titmuss, S. J . J . Comput. Chem. 1997, 18, 1211-1215.
Rademacher, P. Chem. Soc. Rev. 1995, 143-150.
(3) Bu¨rgi, H. B.; Dunitz, J . D.; Shefter, E. Nature (London). New
Biol. 1973, 244, 186.
(4) Sakakibara, K.; Allinger, N. J . J . Org. Chem. 1995, 60, 4044.
(5) Schweizer, W. B.; Proctor, G.; Kaftory, M.; Dunitz, J . D. Hev.
Chim. Acta 1978, 61, 2783-2808.
(6) Bu¨rgi, H. B.; Dunitz, J . D. Acc. Chem. Res. 1983, 16, 153-161.
10.1021/jo000615e CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/10/2000

1N- vs O-Protonation
J . Org. Chem., Vol. 65, No. 18, 2000 5753
Ta ble 1. Rota tion a l Ba r r ier s for N-Meth yl Gr ou p
Exch a n ge a n d Solven t-Dep en d en t 13C NMR Sh ift
Ch a n ges of 1.
a
∆Gq,
(298.15K) δ CO
solvent (ꢀ)
∆C1a
∆C8b
ET
c
c
(CD3)2CO (20.7) 14.005
PhNO2 (34.8)
DMSO (48.9)
200.010 141.252 150.568 42.2
200.435 -0.143
200.539 -0.333
200.856 -0.127
201.540 -0.702
-0.241 42.0
-0.150 45.0
0.051 46.0
CD3CN (38.0)
CDCl3 (4.8)
CD2Cl2 (9.1)
HOAc (6.2)
CD3OD (32.7)
TFE (26.1)
3, PhNO2
14.057
14.069
-0.438 39.1
202.409 -1.728
203.459 -1.081
205.970 -1.992
-0.759 51.2
-0.515 55.5
-0.919 59.5
14.610
15.279
120.115 -6.081d -6.016d
∆C1 ) δ 13C1 (solvent i) - δ 13C1 (acetone-d6). ∆C8 )
a
b
δ
13C8 (solvent i) - δ 13C8 (acetone-d6). c The chemical shift rela-
d
tive to δ 13C6H12 ) 26.92. ∆Ci(3) ) δ 13Ci(3) - δ 13Ci(1), in
PhNO2.
8-(Dim eth yla m in o)-1-a ceton a p h th on e 1 in Neu -
1
tr a l Solven ts. At ambient temperatures the H and 13C
NMR spectra of 1 in neutral solvents show broadened
NMe2 resonances due to slow interchange of the N-methyl
group environments. Experimental barriers to this ex-
change for 1 in CD2Cl2, CDCl3, acetone, methanol, and
TFE (2,2,2-trifluoroethanol) were obtained by dynamic
1H NMR spectroscopy and are summarized in Table 1.
The rate of interchange is seen to decrease with the
ability of the solvent to act as H bond donor. One obtains
the same linear correlation between ∆Gq (298 K) and the
empirical solvent parameter ET as that reported for N,N-
dimethylacetamide in a more extensive series of solvents7
except that the barrier for 1 is lower by 3.5 kcal/mol
(Figure 1a).
b
The rotational barrier of amides has been attributed
to the partial double bond character of the C-N bond
which arises from resonance in the ground state of
the molecule, a stabilizing interaction that is lost on
rotation of the amino group. Because transannular
N‚‚‚CO interaction as in 1 similarly involves the delo-
calization of charge by means of properly oriented or-
bitals, it is reasonable that the rotational barriers of
these two molecules could have similar solvent depend-
encies.
The 13C shifts of 1, measured in a more comprehensive
series of neutral solvents, are given in Tables 1 and 6S
(Supporting Information). Here an increase in the polar-
ity and/or H bonding ability of the solvent leads to a
progressive downfield movement of the 13CO resonance
with concomitant upfield shifts of the resonances of C1
and C8 (∆δ 13C1 > ∆δ 13C8). The three shifts correlate
smoothly, though nonlinearly, with ET, except for 1 in
chlorinated solvents, which are known for their anoma-
lous effects on NMR resonances (See Figure 1b for the
correlation of δ 13CO). However, sp2 f sp3 conversion of
the carbonyl carbon of 1 through acid-catalyzed N-CO
bond formation (3, vide infra ) causes an 80-ppm upfield
shift of δ 13CO. Transannular N‚‚‚CO interaction in the
azaketones likewise resulted in the carbonyl shift being
upfield of the shift of the corresponding monofunctional
ketones. Although 13C NMR shifts depend on a number
of parameters, the relative contributions of which are
often difficult to assess, the trend of solvent-induced
downfield movements of δ13CO observed here for 1 in
F igu r e 1. (a) Free energy of rotation of acetamide (9) and
8-(dimethylamino)-1-acetonaphthone 1 (() at 298 K. (b) Cor-
relation of the 13CO NMR shift with the solvent param-
eter, ET.
neutral media is more in line with increasing charge
separation within the carbonyl group than with ad-
ditional transfer of charge from NMe2 to CO. The direc-
tion and relative magnitudes of the shift changes of C1
and C8 of 1 support this idea because introducing posi-
tive charge within the substituent moiety of monosub-
stituted benzenes has been shown to cause shielding of
the ipso carbon resonance.8 In the case of 1-substituted
naphthalenes,9 there is, in addition, a smaller upfield
shift of the resonance of the adjacent unsubstituted C8,
as is observed here. Thus the increase in the rotational
barrier of 1 may be largely the result of greater stabiliza-
(8) Batchelor, J . G.; Feeney, J .; Roberts, G. C. K. J . Magn. Reson.
1975, 20, 19.
(9) Schuster, I. I. J . Org. Chem. 1985, 50, 1656-1662.
(7) Wiberg, K. B.; Rablen, P. R.; Rush, D. J .; Keith, T. A. J . Am.
Chem. Soc. 1995, 117, 4261-4270.

5754 J . Org. Chem., Vol. 65, No. 18, 2000
Freyer and Rheingold
Ta ble 2. Selected Bon d Len gth s a n d Bon d An gles of
Cr ysta llin e 3,TF A-
bond angles (deg)
N1-C8-C9
bond lengths (Å)
110.2
127.9
130.6
111.1
113.2
105.1
110.5
111.9
N1-C11
1.679
1.469
1.503
1.525
1.498
1.371
1.215
1.229
N1-C8-C7
C11-C1-C2
C11-C1-C9
C8-C9-C1
C8-N1-C11
C1-C11-O1
C12-C11-O1
N1-C8
N1-C13
C11-C1
C11-C12
C11-O1
C15-O3
C15-O2
drawing, Figure 3S, Supporting Information). Table 2
lists selected geometric parameters for one of these
structures. Here the transannular +N-C(OH) bond length
is 1.679 Å, much greater than typical +N-C distances in
pyrrolidinium moieties (at most, 1.507 Å)13 or the 1.42-
1.62 Å C-C single bond distance in a number of similarly
strained acenaphthenes.14 In contrast, the length of the
C-O(H) bond is only 1.37 Å, compared to 1.42 Å, the
typical value for the exocyclic C-O bond of glycopyra-
noses.15,16 By using the experimental bond lengths of 3
in equations formulated by Bu¨rgi et al.,17 one obtains
bond orders (n) of 0.76 and 1.20, respectively, for the
N-CO and C-(OH) single bonds. These numbers indi-
cate that the transannular N-CO bond in 3 has gone to
only 80% completion and must, therefore, be quite labile.
The two CO bonds of the trifluoroacetate counterion
differ in length by an average 0.03 Å (enantiomeric ion
pairs), the longer of these being that nearest the hydroxyl
group of the cation. This difference is like that reported
for the trifluoroacetate complex of protonated pyridine18
and suggests the presence of inter-ion H bonding between
the hydroxyl hydrogen of cation 3 and one carboxylate
oxygen of TFA-. The corresponding average O‚‚‚O dis-
tance is 2.562 Å, well within the 2.5-2.8 Å range
generally observed for O‚‚‚H‚‚‚O hydrogen bonds.19 The
other, slightly less electron-rich carboxylate oxygen of
TFA- lies 3.811 Å away from the positively charged
nitrogen, allowing for favorable inter-ion electrostatic
interaction.
F igu r e 2. 1H NMR shifts of NMeA ()), NMeB(0), COMe of 3
(4), and of +NHMe2(() and COMe of 2 (2), as function of
equivalents of added TFA in the titration of 1 in CD2Cl2.
tion of the ground state conformation by means of
increasingly favorable electrostatic interaction between
the NMe2 lone electron pair and an increasingly polarized
carbonyl bond.
P r oton a tion of Am bid en t Sites in 1. Spectra of 1
in neat acetic acid (pKa ) 4.75) show only hydrogen
bonding between the acid and the carbonyl oxygen.
However, titrating 1 with trifluoroacetic acid (TFA; pKa
) 0.5110) in CD2Cl2, PhNO2-d5, or CD3CN produces
changes in the NMR spectrum which can be ascribed to
the formation of mixtures containing free base 1, N-
protonated 2, and the O-protonated transannular addi-
tion product 3. With fewer than 2 equiv of TFA in solution
(TFA/(1) ) A/B < 2), these species are in rapid equilib-
rium because the proton NMR spectrum shows only time-
averaged signals. As more TFA is added, the progressive
depletion of free base causes the rate of this intermo-
lecular proton transfer to decrease.11,12 The averaged
signals gradually split into the separate resonances of 2
and 3, and one observes coupling between the N-methyl
and NH hydrogens of 2 which amounts to ca. 4.7 Hz, a
value typical of protonated NMe2 moieties. Figure 2
demonstrates these trends for selected 1H NMR reso-
nances of 1 in CD2Cl2. Similar titration curves were
obtained for 1 in the other two solvents, but the titration
in more basic acetone-d6 produced only equilibrium
mixtures of 1 and 3 .
Table 3 summarizes the 13C chemical shifts of 2 and 3
in solution with excess TFA and of 3 as the tetrafluo-
roborate salt. Included, for comparison, are the shifts of
the tetrafluoroborate salts of the O-ethyl derivative 4 and
of N-protonated methyl dimethylamino carboxylate 5,
(13) Williard, P. G.; Tata, J . R.; Schlessinger, R. H.; Adams, A. D.;
Iwaniwicz, E. J . J . Am. Chem. Soc. 1988, 110, 7901-7903. Wahlberg,
A. Acta Crystallogr. 1979, B35, 485-487. Harusawa, S.; Hamada, Y.;
Shioiri, T. Acta Crystallogr. 1981, B27, 1881-1884. Nasser, F. A. K.;
Wilson, A.; Zuckerman, J . J . Organometallics 1985, 4, 2073-2080.
Emsley, J .; Freeman, N. J .; Parker, R. J . J . Mol. Struct. 1987, 159,
173-182. Kashino, S.; Kataoka, S.; Haisa, M. Bull. Chem. Soc. J pn.
1978, 51, 1717-1722.
(14) Gupta, M. P.; Gupta, T. N. P. Acta Crystallogr. 1975, B31, 7-9.
LeBihan, M. T.; Perucaud, M. C. Acta Crystallogr. 1972, B28, 629-
634. Haltiwanger, R. C.; Beurskens, P. T.; Vankan, J . M. J . J .
Crystallogr. Spectrosc. Res. 1984, 14, 589-597.
(15) Sanger, W.; Beyer, K.; Manor, P. C. Acta Crystallogr. 1976, B32,
120-128. Sanger, W.; Noltemeyer, M. Chem. Ber. 1976, 109, 503-
517. J effrey, G. A. Carbohydr. Res. 1973, 28, 213-241.
(16) Since the electronegativities of the NH+ of 3 and the ring oxygen
of the pyranose ring are similar, the lengths of the exocyclic C-O single
bond of these structures are also expected to be comparable.
(17) d (CN) ) - 1.701 log n + 1.479; d (CO) ) - 0.71 log( 2 - n) +
1.426. Bu¨rgi, H. B.; Dunitz, J . D.; Shefter, E. J . Am. Chem. Soc. 1973,
95, 5065-5067.
X-ray analysis of the crystalline 1:1 trifluoroacetate
salt of 3, obtained by precipitation from dichloromethane-
ether solution, shows the presence of two independent,
nonsuperimposable mirror image molecules (ORTEP
(10) Speakman, J . C. Struct. Bonding 1972, 12, 141.
(11) Sudmeier, J . L.; Occupati, G. J . Am. Chem. Soc. 1968, 90, 154-
159.
(12) Giger, W.; Simon, G. Helv. Chim. Acta 1970, 53, 1609-1612.
Olah, G. A.; White, A. M.; O′Brien, D. H. Chem. Rev. 1970, 70, 561-
591.
(18) Dega-Szafran, Z.; Gdaniec, M.; Grunddwald-Wysianska, M.;
Kosturkiewicz, Z.; Koput, J .; Ryzyzanowski, P.; Szafran, M. J . Mol.
Struct. 1992, 270, 99-124.
(19) Pauling, L. The Nature of the Chemical Bond; Cornell Univer-
sity Press: New York, 1960; p 485.

1N- vs O-Protonation
Ta ble 3. 13C NMR Sh iftsa of Ca tion s 2-5
3,
J . Org. Chem., Vol. 65, No. 18, 2000 5755
equilibrating 1, 2, and 3 in the initial stages of the
titration of 1 with TFA (A/Be 2) were calculated using
the shifts of 1 in neutral solution (δi (B°)), the observed,
time-averaged shifts δi of 1, 2, and 3 in the equilibrium
mixture, and the shifts of nonexchanging 2 and 3, δi
(NH+) and δi (+HO), respectively, measured in solutions
of high acid content:
-
-
-
-
3,BF4 A/B ) 18.5 3,BF4 4,BF4 2‚TFA, 5‚BF4 5‚TFA,
Ci
C1
PhNO2
CD3CN CD3CN CD3CN neat PhNO2 neat
135.03
122.09
130.14
127.39
127.26
129.21
115.13
144.31
126.59
131.53
134.85
122.08
130.28
127.61
127.61
128.85
115.38
144.40
126.38
132.00
49.64
135.09 133.02 130.76 122.57 122.45
122.09 123.09 141.23 137.42 138.92
130.37 130.44 127.68 127.14 126.95
127.56 127.91 140.33 137.78 138.96
127.56 127.77 134.62 133.57 134.40
129.08 129.14 126.51 126.13 126.54
115.65 115.39 122.79 123.45 122.61
144.54 145.15 138.67 138.23 137.58
127.04 127.14 123.32 123.47 123.43
131.73 131.83 137.44 136.16 136.65
49.66 52.54 46.45 47.46 46.96
49.21 47.91
C2
C3
C4
C5
C6
C7
C8
C9
C10
δi ) f3(δi (+OH)) + f2(δi (NH+)) + f1(δi (B°)) (1)
Figure 3 shows the mole fractions of 1, 2, and 3 in
dichloromethane, thus determined, and those of 2 and 3
at the higher acid concentrations, obtained by integration
of the separated resonances, as function of the number
of equivalents (A/B) of TFA in solution. The plot indicates
O-protonated 3 to be the major product in solutions of 1
with up to ca. 2 equiv (A/B ≈ 2) of TFA. At this point its
mole fraction is a maximum 0.83, and little unprotonated
reactant 1 remains in solution. Further addition of TFA,
however, reverses the trend. The amount of O-protonated
3 begins to decrease, and that of N-protonated 2 in-
creases, until in neat TFA 2 exceeds 3 by a factor of 4.
Similar trends were obtained in the titration of 1 in
PhNO2 and in CD3CN. These results are in contrast with
the protonation behavior reported for unhindered cyclic
azaketones, such as1-benzyl-1-azacyclooctan-5-one, which
even in neat TFA forms exclusively the O-protonated
transannular addition product.23
In the present case, the preference for N- or O-
protonation of 1 clearly depends on the acidity of the
protonating medium. The most basic available site among
all species present in solution in the initial stages of the
titration must be the carbonyl oxygen of 1, by virtue of
transannular N-CO bond formation which accompanies
proton transfer from TFA. O-Protonation thus predomi-
nates as long as there is an abundance of 1 in solution.
The product conjugate acid 3 is too weakly acidic to
transfer the captured proton to any but another equally
basic carbonyl oxygen so that the initial equilibrium
involves mainly proton exchange between 1 and 3. The
2:1 acid:base stoichiometry at the point of maximum 3
suggests nearly quantitative formation of 3 with homo-
conjugated TFA-‚TFA as the counteranion. Thereafter,
any additional TFA will be complexed by this anion to
form the higher aggregate TFA-(TFA)2. Such complex
formation is likely to weaken OH‚‚‚TFA-‚TFA inter-ion
hydrogen-bonding that may be stabilizing cation 3. With
increasing amounts of the more highly acidic trimeric
TFA-(TFA)2, in solution, N-protonation begins to compete
with O-protonation, and the equilibrium shifts toward
the formation of 2.24
b
NMeA 50.66
NMeB 48.011
C-O 120.115
COMe 25.302
49.08
119.22
23.71
118.56 122.64 210.59 172.71 173.65
23.91 21.84 28.98 54.80 53.57
64.57 (O-CH2-CH3)
14.24 (O-CH2-CH3)
a
b
Relative to δ(C6H12) ) 26.92. NMeA is on same side of the
aromatic plane as the acetyl methyl group.
structural analogues of 3 and 2, respectively. The proton
NMR shifts of 2, 3, 4, and 5 are given in Table 4. The
chemical shifts of cations 3 and 4 are quite comparable
except for hydrogens and carbons nearest the site of OH
f OEt substitution. This helps to confirm the assign-
ments of the NMR resonances of 3. Nearly identical, also,
are the 1H and 13C shifts of the NMe2 and aromatic atoms
of the N-substituted rings of 2 and 5, the values of the
H-C-N-H coupling constants, and the shift of the NH
protons: δ NH, 13.7 (2, BF4-); 13.8 ppm (2, trifluoro-
acetate, 18.9 equivalents of TFA); 13.6 ppm (5, BF4-),
all measured in PhNO2. Therefore, cations 2 and 5 must
also have quite similar geometries and electronic proper-
ties. We have previously shown that the NH proton of
the crystalline picrate salt of the ethyl ester related to
520 is intramolecularly H bonded with the CdO oxygen
in a nearly linear N-H‚‚‚O arrangement, achieved
through rotation of the carboxyl group from the aromatic
plane by 21° (N-H-O angle, 173.7°). The NH‚‚‚O dis-
tance of 1.697 Å is considerably shorter than the sum of
the van der Waals radii of O and H (2.50 Å). Thus the
NH‚‚‚OdC hydrogen bond of the ester, and by extension,
of N-protonated 2, must be fairly strong.
The geometry of N-protonated 2, postulated here on
the basis of the NMR data, is supported by a calculation
of its optimized structure which uses the density func-
tional method of the SPARTAN program21 with a basis
set equivalent to 6-31 g**. This yielded structural
parameters similar to those of the crystalline ester, 18.7°
for the angle of rotation of the COMe group from ring
coplanarity and 166.7° for the angle of the N-H-O
hydrogen bond. The internal NH‚‚‚OdC arrangement of
2 and 5 in solution is additionally confirmed by the fact
that the shift of their NH proton, ca. δ 14, is so much
further downfield than the usual 8-10-ppm shifts of
protonated NMe2 groups reported for monofunctional
aromatics12 or for some other 8-substituted-1-(dimeth-
ylamino)naphthalenes.22
Figure 4 compares the mol fractions of 3 in the titra-
tion of 1 with TFA in CD2Cl2, PhNO2-d5, CD3CN, and
acetone-d6. The plots show that for solutions containing
excess TFA (A/B > 2), equilibrium 3 f 2 becomes
increasingly biased against N-protonation as the
basicity of the solvent increases: CD2Cl2 < PhNO2
<
CD3CN < (CD3)2CO. For 1 in CD2Cl2, and PhNO2-d5, the
following equilibria were found to fit the titration data
for A/B > 2:
Th e Solven t Effect on th e OH (3) f NH (2) P r oton
Exch a n ge Equ ilibr iu m . The mole fractions of rapidly
(20) Parvez, M.; Schuster, I. I. Acta Crystallogr. 1991, C47, 446-
448.
(21) Wavefunction, Inc., Irvine, CA. 92715.
(22) N-Protonated 8-Z-1-(dimethylamino)naphthalenes: Z ) CN, 9.2
ppm (tetrafluoroborate salt in CD3CN); Z ) Br, 10.5 ppm (in CD2Cl2
with excess TFA), I. I. Schuster, unpublished results.
(23) Leonard, N. J .; Klamer, J . A. J ., Org. Chem. 1968, 33, 4269-
4270.
(24) The existence of an apparent pKa threshold here resembles the
situation reported for the reaction of carboxylic acids with amino groups
in some biological systems: Pant, N.; Hamilton, A. D. J . Am. Chem.
Soc. 1988, 110, 2002-2003.

5756 J . Org. Chem., Vol. 65, No. 18, 2000
Ta ble 4. 1H NMR Sh iftsa of Ca tion s 2-5.
δ NMeA δ NMeB δ COMe δ H2 δ H3 δ H4 δ H5
Freyer and Rheingold
shift ion, solvent
δ H6
δ H7
δ Etb,c δ NH,d δ OHe
2, TFA (neat)
3.4246 (J ) 4.656)
3.3978 (J ) 4.864)
3.1217
3.0613
3.0732
3.0132
3.1766
3.1537
4.280
2.2086
2.1438
2.1114
2.1257
2.4956
2.3143
8.8823 7.8638 8.4372 8.2728 7.8999 8.1426 14.0125d
8.7343
8.3768 8.2018 7.8726 8.1565 13.2584d
8.8279 7.8513 8.4470 8.2574 7.8732 8.0097 14.3617d
2, BF4-, CD2Cl2
2, CD2Cl2, A/B ) 12.41 3.3287 (J ) 4.672)
2, BF4-, CD3CN
2, BF4-, PhNO2
2, PhNO2, A/B ) 18.9
5, BF4-, PHNO2
3, neat TFA
3.3043 (J ) 4.850)
3.7298 (J ) 4.44)
3.6505 (J ) 4.68)
3.811
8.8061 7.8541 8.4392 8.2588
8.1397 12.9672d
8.9068 7.8463 8.4565 8.3939 7.9549 8.2320 13.7331d
8.8981 7.8223 8.3733 8.3538 7.8483 8.2076 13.8497d
8.699
7.747
8.560
8.381
7.933
8.244
13.557d
3.5226
3.5650
3.3863
3.4135
3.8562
3.5323
3.4175
3.2586
3.2590
3.2868
3.6492
3.4602
7.7327 7.8535 8.0843 8.0717 7.7996 7.6876
7.6737 7.8035 8.0087 8.0087 7.7442 7.6253
7.7128 7.8230 8.0819 8.0653 7.7888 7.7838
7.7139 7.8227 8.0707 8.0707 7.7940 7.7502
7.9733 7.8454 7.9976 7.9976 7.8290 7.8152
7.9308 7.8973 8.1991 8.1651 7.8891 8.0981
3, BF4, CD2Cl2
3, BF4, CD3CN
3, CD3CN, A/B ) 23.4
3, BF4-, PhNO2
4, BF4-, DMSO
7.5006e
6.9504e
3.5764, 3.5845 (CH2)b,c
1.1593 (CH3)b
,
4, BF4, CD3CN
3.5522
3.4807
2.3340
7.9010 7.9273 8.2133 8.1792 7.9041 8.1154
3.6068, 3.5684 (CH2)b,c
1.1745 (CH3)b
a
b
Shifts relative to δ C6H12 ) 1.42. O-Ethyl group. c Diastereotopic hydrogens.
F igu r e 3. Mole fraction of 1 ()), 2 (9), and 3(0) in the titration
of 1 with TFA in D2Cl2 at 293 K.
K1: 3,TFA-‚TFA + TFA Ω 3, TFA-(TFA)2 (2a)
F igu r e 4. Mole fraction of 3 as function of added TFA in the
titration of 1 in CD2Cl2 ((), PhNO2 (O), CD3CN (0), and
acetone-d6 (4).
K2: 3,TFA- (TFA)2 Ω 2, TFA-(TFA)2
Kd: 2 TFA Ω (TFA)2
(2b)
(2c)
in eq 2b. Therefore, a was replaced by (1 + f2/K2) in the
above equations. Figure 5 demonstrates the goodness of
fit of the data to the correlation lines for the equilibria
in CD2Cl2, PhNO2, and CD3CN. The equilibrium con-
stants for eqs 2a-c are collected in Table 5. Here Kd )
4.78 L/mol for the dimerization of TFA in CD2Cl2. This
figure is reasonable when compared with 1.5 L/mol for
equilibrium 2c by itself in 1,2-dichloroethane.26 TFA
dimerization appears to be negligible in PhNO2 and in
Values of the equilibrium constants were determined
by assuming that the measured mole fraction of cation 3
is the sum of both ion-paired forms of eq 2a, and by
varying trial values of Kd and K2 until a linear plot of
ln(f2/K2)/(1 - f2a) versus ln(b - 2f) was obtained. This
coincided with minimum deviation of the data from the
correlation line. Here a ) (1 + 1/K2), b ) (A/B - 2 - f2a
), f2 is the mol fraction of 2,TFA-(TFA)2, and f is the
fraction of TFA dimer, (TFA)2, which equals (1/8Kd)((4bKd
+ 1) - (8bKd + 1)1/2). The intercept furnished the value
of K1. The slope of the line was 1.0 which confirms the
proposed stoichiometry of eq 2a. Similar strategies gave
equilibrium constants for eqs 2a-c in CD3CN, except that
a better fit of the data was obtained by postulating the
formation of 2,TFA-(TFA)2 as the separated ion pair25
(25) Since PhNO2 and CD3CN have similar dipolar and dielectric
properties, such ion separation in CD3CN alone must be due to the
greater nucleophilicity of this solvent. CD3CN displaces TFA-(TFA)2
by coordinating with the NH hydrogen of 2. In the case of the
O-protonated cation 3 such displacement is not necessary for H bonding
of its OH hydrogen by solvent to occur. See Meyer, U. Coord. Chem.
Rev. 1976, 21, 159-179.
(26) Kirszenbaum, M.; Corset, J .; J osien, M. L. J . Phys. Chem. 1971,
75, 1327-1330.

1N- vs O-Protonation
J . Org. Chem., Vol. 65, No. 18, 2000 5757
-
Ta ble 6. F r a ction of N-P r oton a ted 2,BF 4 a s F u n ction of
Solven t Don icity.
solvent (ꢀ)a
donor number
f2
0.0
CD3OD (32.7)
(CD3)2CO (20.7)
CD3CN (37.5)
PhCN (25.2)
PhNO2 (34.8)
TFE (26.1)b
CDCl3 (4.8)
CD2Cl2 (8.9)
HOAc (6.2)
19
17
0.041
0.125
0.185
0.342
0.475
0.133
0.204
0.139
14.1
11.9
4.4
0.0
0.0
0.0
0.0
a
Reichert, C. Solvent Effects in Organic Chemistry. Monographs
in Modern Chemistry; Verlag Chemie: New York, 1979; Vol. 3.
b
Kaspi, J .; Rappoport, Z. J . Am. Chem. Soc. 1980, 102, 3829-
3837.
point of maximum mole fraction of O-protonated 3 at
which the concentration of free base 1 extrapolates to
zero. This point is reached with 2.3 (CD2Cl2), 2.5 (PhNO2),
and 4.3 (CD3CN) equiv of TFA in solution. These num-
bers follow the order of increasing solvent basicities and
suggest progressively decreasing values of the equilibri-
um constant for the initial 1 f 3 conversion.
The titration data for 1 in acetone-d6 best fits equi-
libria 3.
F igu r e 5. Correlations of eqs 2a-c in CD2Cl2 ()), PhNO2 (0),
and CD3CN (4).
K1: 1 + TFA Ω 3, TFA-
(3a)
(3b)
Ta ble 5. Equ ilibr iu m Con sta n ts for 2A, 2B, a n d 2c in
CD2Cl2, P h NO2, a n d CD3CN Solu tion .
K2: 3,TFA- + TFA Ω 3,TFA-‚TFA
Ki/solvent
CD2Cl2
(0.0)
PhNO2
(4.4)
CD3CN
(14.1)
(DN)a
K1 (L/mol)
K2
0.14
55.0
4.78
10.45
2.04
0
1.63
Values of K1 ) 0.46 L/mol and K2 ) 14.8 L/mol were
obtained by assuming that fOH, the nominal mole fraction
of 3 calculated by eq 1, equals the sum of the mole
fractions of 3,TFA- (f) and 3,TFA-‚TFA (fOH - f). Trial
values of K1 were varied until a plot of ln((fOH - f)/f)
versus ln(A/B - 2fOH - f) became linear. The slope of the
line was 1.0, and the intercept furnished the value of K2.
Here the acidity-reducing effect of the solvent on the
protonating agent TFA is reflected in a low value of K1.
The δ1 H(solvent)/(A/B) correlation (not shown) was
nonlinear and without break because this solvent com-
petes successfully with unprotonated 1 for reaction with
TFA throughout the entire titration.
5.4 × 10-3 (mol/L)b
Kd (L/mol)
0
a
Donor number. b The calculations are in better agreement with
formation of 2,TFA-(TFA)2 as the separated ions in eq 2b.
CD3CN, probably because the acid prefers coordinating
with these more basic solvents.27 A change of solvent from
CD2Cl2 (ꢀ ) 9.1) to PhNO2-d5 (ꢀ ) 34.8) increases the
value of K1 (eq 2a) from 0.14 to 10.45 L/mol, which
accords with a report that anionic complexes of higher
stoichiometries are favored28 in more polar solvents.
However, K1 is only 1.63 L/mol for the equilibrium in
acetonitrile (ꢀ ) 37.5) because the formation of strong
CF3COO-H‚‚‚NtC hydrogen bonds diminishes the acid-
ity of the protonating agent, nominally TFA.
Nucleophilic solvents can stabilize O-protonated 3 by
H bonding its OH hydrogen. H-bonding of the NH proton
of N-protonated 2 by such solvents is expected to be less
important because this hydrogen is already intramolecu-
larly bound to the carbonyl oxygen and is also sterically
less accessible. Therefore, eq 2b is predicted to shift
increasingly to the left in progressively more nucleophilic
solvents. That this is the case is seen in the decreasing
values of K2 (Table 5) with increasing solvent donor
number.
Equ ilibr ia In volvin g th e Tetr a flu or obor a te Sa lts
of 2 a n d 3. Dissolving the pure tetrafluoroborate salt of
3 in solvents of varying acid-base and dielectric proper-
-
ties produces equilibrium mixtures of 2,BF4- and 3,BF4
,
1
the H NMR spectra of which show distinct resonances
for each cation at ambient temperature. Thus, intercon-
version of the O- and N-protonated forms of the cation,
paired with BF4-, is also slow on the NMR time scale.
The mole fractions of N-protonated 2 in the equilibrium
mixtures are summarized in Table 6. Figure 7 demon-
strates that the amount of 2 again decreases with
increasing donicity of the solvent. This is due to the
greater acidity of cation 2 relative to that of tautomer 3.
However, there are large deviations from the correlation
line for the equilibrium in solvents of low polarity (ꢀ <
10). Here the amount of N-protonation is considerably
less than what one would predict from the equilibrium
distribution of the cations in the polar solvents. TFE,
HOAc, and the chlorinated solvents of this study are all
poor electron donors (DN ) 0). However, the mole fraction
of 2,BF4- in TFE (ꢀ ) 26.1) is 0.48, compared to only 0.20
in CDCl3 (ꢀ ) 4.8), 0.14 in HOAc (ꢀ ) 6.2), and 0.13 in
CD2Cl2 (ꢀ ) 8.9). This result is similar to that obtained
The onset of reaction between TFA and solvent in the
titration of 1 in PhNO2 and CD3CN is evident in Figures
6a,b which show superimposed plots of δ1 H(solvent) and
mole fraction of 3 versus equivalents of added TFA. Here
the solvent NMR shift reverses direction precisely at the
(27) Kirszenbaum, M.; Corset, J .; J osien, M. L. C. R. Acad. Sci. 1970,
Ser. B, 630-633. Bednar, R.; J encks, W. P. J . Am. Chem. Soc. 1985,
107, 7117-7126.
(28) Huyskens, P.; Platteborze, K.; Zeegers-Huyskens, T. J . Mol.
Struct. 1997, 436-437, 91-102.

5758 J . Org. Chem., Vol. 65, No. 18, 2000
Freyer and Rheingold
-
F igu r e 7. Mol fraction of 2,BF4 (0) and of 2,TFA(TFA)2 ())
as function of solvent donicity.
The relative contributions of ∆H° and T∆S° to the free
-
-
energy difference of equilibrium 3,BF4 f 2,BF4 in
CD2Cl2 and in PhNO2 were determined from its temper-
ature dependence over ca. 50° C. Values of ∆H°, ∆S° of
2.85 kcal/mol, 6.86 eu (CD2Cl2) and 2.56 kcal/mol, 7.58
eu (PhNO2) were obtained by assuming negligible amounts
of 1 present in solution. At room temperature the two
terms are of nearly equal importance. It is thus under-
standable that even modest changes in solvent properties
can reverse the relative thermodynamic stabilities of the
O- and N-protonated tautomers of 1.
1
-
The room temperature H NMR spectra of 3,BF4 in
acetone, methanol, and DMSO show progressive in-
creases in the ratio of the COMe:NMeA(B) signal intensi-
ties. This result is due to higher rates of N-Me group
exchange because of increasing amounts of deprotonated
1 in these basic media. The degree of deprotonation 3 f
1 must be quite small in all the other solvents of this
study because here the NMe and COMe NMR line widths
of 3 are nearly identical and like those of O-alkylated
-
4,BF4 which has no OH hydrogen to lose. However,
spectra of 4,BF4- in methanol-d4 show deuteration of the
C(O)-methyl group. This indicates that cleavage of its
transannular N‚‚‚CO bond is taking place. Under the
same conditions, deuterium exchange within the COMe
1
F igu r e 6. (a) H NMR shift of solvent PhNO2 (4) and mole
fraction of 3 (9) as function of equivalents of added TFA. (b)
1H NMR shift of CD3CN (0) and of mole fraction of 3 (() as
function of equivalents of added TFA.
-
group of 3,BF4 is not observed but is only evident in
1-day-old solutions. Loss of the proton from the OH group
must, therefore, be considerably more facile than from
COMe. Conversion of 3 to 2 then is most likely to occur
by means of such O-deprotonation, followed by reproto-
nation at the nitrogen, rather than by direct site-to-site
proton transfer following N-CO bond cleavage.
in a study of amides in which the amount of O-protona-
tion was also seen to increase in progressively less polar
media.29 In the present case, this solvent effect can be
ascribed to destabilization of the more polar N-protonated
tautomer in nonpolar solvents. There are no such devia-
tions when trimeric TFA-(TFA)2 is the counterion (top
correlation of Figure 7, f2 calculated from eq 2b). The
larger anion evidently confers similar polarities on the
two tautomeric ion pairs, possibly through steric shield-
ing of their polar moieties.
Exp er im en ta l Section .
1
NMR An a lyses. The H and 13C chemical shifts of 1-5 in
solution were referenced to TMS or to internal cyclohexane.
For the latter, conversion to the TMS scale was made using δ
13C(C6H12) ) 26.92 and δ 1H(C6H12) ) 1.42. Solution concentra-
tions were 0.2-0.5 M (13C NMR spectra) and 0.04-0.18 M (1H
(29) Perrin, C. L.; Lollo, C. P. J . Am. Chem. Soc. 1984, 106, 2754-
2757.

1N- vs O-Protonation
J . Org. Chem., Vol. 65, No. 18, 2000 5759
NMR spectra). All solvents were dried for 2 days prior to use
over 3 Å molecular sieves.
Cr ysta l Str u ctu r e An a lysis. Crystals of 3,TFA- suitable
for X-ray analysis were obtained by slow precipitation from a
solution of 1 in dichloromethane-ether containing 2 equiv of
TFA. Crystal, data collection, and refinement parameters are
given in Table 1S. The systematic absences in the diffraction
data were uniquely consistent for the monoclinic space group
P21/n, which yielded chemically reasonable and computation-
ally stable results of refinement. The structure was solved
using direct methods, completed by subsequent difference
Fourier syntheses and refined by full-matrix least-squares
procedures. Two independent, but chemically equivalent,
molecules per asymmetric unit are present. All non-hydrogen
atoms were refined with anisotropic displacement coefficients,
and hydrogen atoms were treated as idealized contributions.
All software and sources of scattering factors are contained
in the SHElXTL(5.10) program library (G. Sheldrick, Siemens
XRD, Madison, WI).
Assignment of the proton NMR resonances of 1-5 were
made by means of homonuclear decoupling experiments and
by observing NOE enhancement of relevant resonances on
irradiation of either the COMe or NMe2 group hydrogens. This
latter technique identified NMeA as the N-methyl substituent
of 3 and 4 that is cis to the C(O)Me methyl group.
Assignments of the 13C resonances of the aromatic carbons
were made on the basis of the three-bond H-C coupling
patterns, by matching the shift values with those published
for correspondingly monosubstituted naphthalenes, and by
means of 2D (NOESY/COSY) experiments.
Syn th eses. Compound 1 and the unprotonated methyl ester
related to 5 were synthesized according to procedures pub-
lished by Dunitz et al.4 The tetrafluoroborate salt of 3 was
obtained by adding an ether solution of tetrafluoroboric acid
(Aldrich) to an equimolar amount of 1 in dry dichloromethane
(distilled from CaH2). After the mixture was stirred for 1 h,
the volume was reduced and the precipitated salt recrystallized
from methanol-ether; mp 154-155 °C. All peaks of the proton-
decoupled 13C NMR spectrum of the salt in solution could be
Ack n ow led gm en t. Partial support for this research
by Sigma Delta Epsilon (Graduate Women in Science,
E. Gerry Fellowship) is gratefully acknowledged (I.S.).
Special thanks to Professor Mislow for generously
providing access to the NMR facility of Princeton
University and to Dr. Wei Wang (Parke-Davis Phar-
maceuticals, Detroit, MI) for carrying out the 2-D NMR
experiments.
-
accounted for by the sole presence of tautomers 3,BF4 and
2,BF4- in equilibrium (Figure 4S: 3,BF4- in CD3CN, Support-
ing Information). The salt of the corresponding ester 5 was
prepared by the same procedure; mp 133-135.5 °C. The
proton-decoupled 13C NMR spectrum (Figure 2S: a,b; Sup-
porting Information) confirms its purity. The tetrafluoroborate
salt of 4 was obtained by addition of a 1 M dichloromethane
solution of triethyloxonium tetrafluoroborate (Aldrich) to an
equimolar amount of 1 dissolved in the same (dried) solvent
under an inert nitrogen atmosphere. The mixture was stirred
overnight, the solvent was removed, and the viscous residue
was recrystallized twice from methanol-ether, yielding a white
Su p p or tin g In for m a tion Ava ila ble: Tables of atomic
coordinates, anisotropic displacement coefficients, H-atom
coordinates, bond lengths and bond angles for 3,TFA- and
details concerning crystal data, data collection, and structure
refinement (Tables 1S-5S); 1H and 13C NMR shifts of 1 in
various solvents (Tables 6S, 7S); proton-decoupled 13C NMR
1
powder: mp 106-116 °C. The H NMR spectrum showed this
-
-
spectra of 4,BF4 in DMSO (Figure 1S: a,b), of 5,BF4 in
PhNO2 (Figure 2S: a,b), and of 3,BF4- in CD3CN (Figure 4S);
ORTEP drawing of 3,TFA- (Figure 3S). This material is
available free of charge via the Internet at http://pubs.acs.org.
-
to be a mixture of O-alkylated 4,BF4- and O-protonated 3,BF4
.
Several attempts were made to obtain a purer product, the
best effort of which produced a compound whose proton-
decoupled 13C NMR spectrum (Figure 1S: a,b, Supporting
Information) indicated a nearly pure product.
J O000615E