Dynamic 1H NMR spectroscopic study of the ring inversion in N-sulfonyl morpholines - Studies on N-S interactions

Article abstract of DOI:10.1021/jo900454a

(Chemical Equation Presented) The effect of the exocyclic conjugation, via d-p orbital interaction and/or negative hyperconjugation (anomeric effect) of the N-S bond, on the inversion of the morpholine ring in some N-arylsulfonyl morpholines is studied by variable-temperature ¹H NMR spectroscopy in different solvents. The observed free energy barriers are 9.2-10.3 kcal mol^-1; the lower values were obtained with increasing conjugation (substituents of higher electron withdrawing power) along the series. The barrier to ring inversion of 1e was solvent independent. X-ray data of compounds 1b,d reveal the chair conformation of the six-membered ring, the flattened pyramidal orientation of the ring nitrogen atom, and the sulfonyl group in equatorial position with the plane containing the C_aryl-S-N bond perpendicular to the plane of the benzene ring. In addition, the sulfonamide group prefers a conformation with the S-C bond antiperiplanar with respect to the nitrogen atom lone pair and the -CH₂-N-CH₂- moieties in staggered conformation with the S-O bonds of the SO₂ group.

Full text of DOI:10.1021/jo900454a

1
Dynamic H NMR Spectroscopic Study of the Ring Inversion in
N-Sulfonyl MorpholinessStudies on N-S Interactions
Ali Reza Modarresi-Alam,*,† Homeyra Alsadat Amirazizi,† Hajar Bagheri,†
Hamid-Reza Bijanzadeh,‡ and Erich Kleinpeter§
Department of Chemistry, Faculty of Science, UniVersity of Sistan & Baluchestan, Zahedan, Iran, Department
of Chemistry, Tarbiat Modarress UniVersity, P.O. Box 14115-175, Tehran, Iran, and Chemisches Institut,
UniVersitat Potsdam, Karl-Liebknecht-Strasse 24-25, D-14476 Potsdam (Golm), Germany
modaresi@chem.usb.ac.ir
ReceiVed February 27, 2009
The effect of the exocyclic conjugation, via d-p orbital interaction and/or negative hyperconjugation
(anomeric effect) of the N-S bond, on the inversion of the morpholine ring in some N-arylsulfonyl
morpholines is studied by variable-temperature 1H NMR spectroscopy in different solvents. The observed
free energy barriers are 9.2-10.3 kcal mol-1; the lower values were obtained with increasing conjugation
(substituents of higher electron withdrawing power) along the series. The barrier to ring inversion of 1e
was solvent independent. X-ray data of compounds 1b,d reveal the chair conformation of the six-membered
ring, the flattened pyramidal orientation of the ring nitrogen atom, and the sulfonyl group in equatorial
position with the plane containing the Caryl-S-N bond perpendicular to the plane of the benzene ring.
In addition, the sulfonamide group prefers a conformation with the S-C bond antiperiplanar with respect
to the nitrogen atom lone pair and the -CH2-N-CH2- moieties in staggered conformation with the
S-O bonds of the SO2 group.
Introduction
herbicides and other pharmaceutical products such as anesthetics
and antiseptics.1-3 N-Substituted-2-heterocyclic morpholine
derivatives proved to be active as growth stimulants, bronchodi-
lators, antidepressants, and antiobesity agents.1-3
Sulfonamides constitute the largest class of antimicrobial
drugs and occur in numerous biologically active compounds
The two most important classes of nitrogen-containing
compounds are morpholines and sulfonamides. The morpholine
motif is found in numerous therapeutic areas such as migraine,
dermatitis, antidepressants, and diabetics.1-3 Various morpholine
derivatives are included in the production of insecticides and
† University of Sistan & Baluchestan.
‡ Tarbiat Modarress University.
(2) (a) Merck, Sharp, & Dohme, US-6051572. (b) Merck, Sharp, & Dohme,
WO-9961028.
(3) (a) Merck & Co., US-5077290. (b) Merck & Co., US-5124328. (c) Merck
& Co., US-5691336.
§ Universitat Potsdam.
(1) Array Biopharma, http://www.arraybiopharma.com.
4740 J. Org. Chem. 2009, 74, 4740–4746
10.1021/jo900454a CCC: $40.75  2009 American Chemical Society
Published on Web 05/28/2009

Ring InVersion in N-Sulfonyl Morpholines
SCHEME 1
including saluretics, carbonic anhydrase inhibitors, insulin-
releasing sulfonamides, antithyroid agents, and a number of
other biological activities.4-6 In addition, the sulfonamide group
is used for protecting the nitrogen in amines.7 Another important
feature of sulfonamides is the ability to inhibit dihydropteroate
synthase.4-6
All these important bioactive properties are strongly affected
by the special features of the -CH2-SO2-NR- linker and
intramolecular mobility in its proximity.7,8 Thus, studies of
energetic and spatial properties of N-substituted sulfonamides/
morpholines are of great importance for improving our under-
standing of their biological activities and to enhance abilities
to predict new drugs. Thus, the successful study of the
interconversion about bonds to nitrogen in nitrogen-containing
organic molecules has been a cornerstone of research interest
for the last half century.6-22 For example, many studies of
azacyclic compounds have been performed in order to determine
the relative importance of such factors as steric, resonance,
hybridization, and solvent effects on both the ground state and
the transition state of the ring interconversion process.9-12
double bond was investigated;24,25 hereby several sets of methyl
sulfonyl and aryl sulfonyl compounds were studied. Within this
present study, the previous investigations of Sandstro¨m et al.28
and Lunazzi et al.29 on N-acyl morpholines were continued and
a series of analogous morpholine derivatives la-e investigated,
containing substituents of similar size but different electron-
withdrawing ability.
To the best of our knowledge, dynamic NMR spectroscopic
studies concerning both conformation and the dynamic behavior
of the N-S bond in the aryl- or alkyl-sulfonyl morpholines
1a-e have not yet been undertaken. Among three distinct
processessa ring inversion, nitrogen inversion, and N-S
rotationsthe observed free energy barriers are attributed to
the ring inversion. It is the major aim of this paper to determine
the effect of exocyclic conjugation on the barrier to morpholine
ring inversion by dynamic 1H NMR spectroscopy and to analyze
the factors (including the importance of (nN-dS)-π orbital
interaction and the negative hyperconjugationsanomeric effectsin
the N-S bond) on this dynamic parameter.
1
In recent years, we reported the synthesis and dynamic H
NMR spectroscopic study of several nitrogen-containing organic
molecules.23-27 Especially the rotation about the N-S partial
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Results and Discussion
Compounds 1 (Scheme 1) were prepared from morpholine
and sulfonylchlorides according to literature procdures.5d,30,31
The results of the variable-temperature 1H NMR study of
N-(aryl-alkylsulfonyl) morpholines 1a-e are given in Table 1.
Gradual cooling of the samples broadens the H NMR signals
of the CH2 protons of the morpholine ring in 1a-e which
decoalesence and, at lower temperatures, split furthermore into
1
1
two sets of signals (see Figure 1 for the H NMR study of
N-(methylsulfonyl) morpholine 1a in CD3COCD3 at ambient
temperature and 183 K). The ring protons of the morpholine
moiety in 1a appeared as two triplets at δ 3.7 and 3.2 (at a
ratio of 4:4) at room temperature; at lower temperatures, the
two triplets of the methylene protons broadened and decoalesced
at 210 K into two broadened signals each, which on further
cooling to 183 K formed broadened pairs of triplets and
doublets. The two doublets of the equatorial protons at δ 3.9
and 3.35 (2Jgem ) 11.1 Hz) are caused by geminal coupling
and coupling to unresolved vicinal axial/equatorial protons (two
broadened doublet-like signals), whereas the two triplets of the
axial protons at δ 3.44 and 2.8 (2Jgem ≈ Jaxax ≈ 10.9 Hz) are
3
caused by geminal and vicinal coupling to axial protons. In fact,
the system is AA′XX′ at low temperature. Since Jee ≈ Jae ≈ 0
it has been converted to AB2, that is a triplet for axial proton
and a doublet for equatorial proton. Similar dynamic behavior
was observed for the 1H NMR spectra of the other compounds
(21) Binsch, G.; Kessler, H. Angew. Chem., Int. Ed. Engl. 1980, 19, 411–
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(22) Binsch, G. Top. Stereochem. 1968, 3, 97–192.
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Bijanzadeh, H.-R.; Kleinpeter, E. J. Org. Chem. 2007, 72, 2208–2211.
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H.; Nasrollahzadeh, M.; Bijanzadeh, H.-R.; Kleinpeter, E. J. Mol. Struct. 2007,
841, 61–66.
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1991, 47, 7465–7470.
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D. A.; Appelt, K.; Smith, W. W.; Janson, C. A.; Villafranca, J. E.; Bacquet,
R. J.; Howland, E. F.; Booth, C. L. J.; Herrmann, S. M.; Ward, R. W.; White,
J.; Moomaw, E. W.; Bartlett, C. A.; Morse, C. A. J. Med. Chem. 1996, 39,
904–917.
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Tetrahedron 2004, 60, 1525–1530.
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Tetrahedron 2002, 58, 2621–2625.
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192.
J. Org. Chem. Vol. 74, No. 13, 2009 4741

Modarresi-Alam et al.
a
1
TABLE 1. Dynamic H NMR Data for N-(Aryl-alkylsulfonyl) Morpholines 1a-e in CD3COCD3 and for 1e in Different Solvents
c d
,
entry
compd
R
δ (ppm)
∆νb (Hz)
Tc, °C (K)
kc (s-1
)
∆Gq (kcal mol-1
)
1
2
3
4
1a
1b
1c
1d
1e
1e
1e
CH3
4-CH3C6H4
C6H5
4-BrC6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
3.440, 3.357
3.792, 3.423
3.758, 3.417
3.835, 3.483
3.888, 3.572
3.833, 3.555
3.931, 3.685
41.34
184.50
170.89
176.13
158.00
139.00
123.00
-63 (210)
-50 (223)
-56 (217)
-65 (208)
-73 (200)
-73 (200)
-75 (198)
110.08
409.60
379.38
391.00
350.99
308.78
273.24
10.2
10.3
10.0
9.6
9.2
9.3
5
6e
7f
9.4
a Lowest temperature reached was 183 K. b ∆ν obtained by the difference between the midpoint of a doublet and the middle peak of a triplet.
d
c Margin of error (0.2 kcal. It is assumed that ∆Sq is zero. e In CD3OD. f In CD2Cl2.
FIGURE 2. X-ray structure for N-(4-methylbenzenesulfonyl) morpho-
line 1b.
lescence temperature (Tc) that are in reasonable agreement with
the values obtained by complete line shape analysis.33 The rate
constants, k, for the interconversion of the N-(aryl-alkylsulfonyl)
morpholines 1a-e were estimated from the Gutowsky-Holm
equation (kc ) π∆ν/(21/2), for singlets, and kc ) π[(∆ν2 +
6JAB2)/2]1/2 for the doublets and triplets, respectively.11-14,23-27
Assuming the transmission coefficient, κ, to be unity, the free
energies of activation (∆G‡) were calculated from the Eyring
equation (∆G‡ ) RTc[ln Tc - ln kc + 23.76]).11-14,23-27
Generally, the preferred conformation of the morpholine ring
is the chair conformer.7-11,17,18 Our results of an X-ray
FIGURE 1. Variable-temperature 1H NMR (500 MHz) spectra of
N-(methylsulfonyl) morpholine 1a in CD3COCD3 (top at 298 K and
bottom at 183 K).
diffraction study supported this conformational preference for
1b and 1d (see Figures 2 and 3 and Tables 2-4 for selected
geometrical parameters). In addition to the chair conformer in
1b and 1d the ring nitrogen proves to be in the flattened
pyramidal arrangement with the sulfonyl group in the equatorial
position; furthermore, the plane containing the Caryl-S-N bond
was found to be perpendicular to the benzene ring plane. At
the present time there is not any significance argument for the
preferred conformer. However, there appears to be an electro-
statically attractive 1,5-interaction between oxygen and the
o-phenyl hydrogen in every case (Table 4 and Figures 2 and
3).7b
With respect to the conformation of the S-Caryl bond in the
sulfonamides 1a-e, it was found to be antiperiplanar with
respect to the nitrogen atom lone pair and the -CH2-N-CH2-
ring unit usually proves to be in the staggered conformation
with the S-O bonds of the SO2 group (cf. also 8a in Scheme
2).
1b-e in acetone-d6 and other solvents32 (cf. Table 1 and the
Supporting Information). However, there is a small shift
difference between the O-methylene axial proton (triplet) and
the N-methylene equatorial proton (doublet) at the low-temper-
ature spectrum of the later compounds. So, the resulted peak
appears as unresolved pseudotriplets at about 3.4-3.5 ppm. The
coalescence temperatures, the chemical shift differences at low
temperature, and the coupling constants thus obtained along the
dynamic NMR study were employed to estimate the free
energies of ring interconversion of the morpholine ring moiety
in the studied compounds 1a-d.
The complete line shape analysis of the dynamic NMR spectra
of compounds 1 was not undertaken; free energies of activation
were calculated only by approximation equations at the coa-
(32) Shainyan, B. A.; Ushakov, I. A.; Tolstikova, L. L.; Koch, A.; Kleinpeter,
E. Tetrahedron 2008, 64, 5208–5216.
(33) Yamagami, C.; Takao, N.; Takeuchi, Y. Aust. J. Chem. 1986, 39, 457–
463.
4742 J. Org. Chem. Vol. 74, No. 13, 2009

Ring InVersion in N-Sulfonyl Morpholines
is much faster than the ring inversion. This actually becomes
apparent from the observation that only the signals of the
morpholine ring protons in 1 and not the methyl resonances or
protons of the phenyl unit (Ar) are affected by changes in the
temperature.
Furthermore, the rotation about the N-S bond has to be
considered.11,15,39,40 Only a few reports about the restricted rotation
around the N-S bond have been published: The dynamic NMR
study of sulfenamides,11,15,39,40 of sulfinamides,11,15,39,40 of dieth-
ylsulfamyl chloride 5,41 of nonafluorobutane-1-sulfonamides 6,35
and of 1,3,5-tris (trifluoromethylsulfonyl)-1,3,5-triazine 742 indi-
cated, however, a considerable barrier to N-S rotation (cf. Scheme
3). The measured rotational barrier is considered to arise from the
torsion of the N-S bond rather than from the inversion of the
nitrogen atom, and thus the results are interpreted in terms of
directional pπ-dπ bonding and/or negative hyperconjugation
(anomeric effect) between nitrogen and sulfur atoms.
FIGURE 3. X-ray structure for N-(4-bromobenzenesulfonyl) morpho-
line 1d.
TABLE 2. Selected Bond Distances (Å) Calculated by X-ray
Crystallographic Analysis for N-(4-Methylbenzenesulfonyl)
Morpholine 1b and N-(4-Bromobenzenesulfonyl) Morpholine 1d
We have recently demonstrated that the observed rotational
barrier for imidoyl iminoposphoranes 224 and imidoyl azides
3
25 is due to the restricted rotation about the N-S bond. In the
N-(4-methylbenzenesulfonyl)
morpholine 1b
N-(4-bromobenzenesulfonyl)
morpholine 1d
course of that work we found that compounds 4 undergo N-S
bond rotation rapidly on the NMR time scale even at -100 °C,
indicating a barrier of less than 8 kcal mol-1. Similar results
also have been reported for other simple sulfonamides.6-8,34,43
In fact, the double bond character between the nitrogen and the
sulfur and the energy barrier to rotation around the N-S bond
are enhanced when the electronegativity of the attached group
is increased as the chlorido atom in 5 and the perfluoro group
in 6. These sulfonamides are known to possess planar or almost
planar structures with the S-N bond adopting a considerable
double bond character. This means that strong electron with-
drawing substituents should be in the phenyl ring of 1 and 4
for increasing the conjugation along the whole system; influ-
ences on the barrier of rotation about the N-S bond will be
expected. Because the magnitude of the ring interconversion
barrier observed for 1 is close to those obtained for similarly
substituted cyclohexane derivatives and other six-membered
N-heterocycles,9-13,16 and because both methyl and phenyl (Ar)
proton resonances are not affected by temperature changes, the
process responsible for the observed dynamic process has been
assigned to the ring inversion process with the N-inversion still
fast on the NMR time scale. To our surprise, the restricted
rotation about the S-N bond was also still fast on the NMR
time scale at the temperature obtained with the present NMR
equipment.
S1
S1
S1
S1
O3
O3
N1
N1
C1
C6
C8
C10
O1
O2
N1
C7
C9
C10
C8
C11
C7
C7
C9
C11
1.4369(15)
1.4288(17)
1.6461(16)
1.7693(17)
1.424(3)
1.422(4)
1.472(2)
1.481(2)
1.384(2)
1.388(3)
1.515(3)
1.512(4)
S1
S1
S1
S1
O3
O3
N1
N1
C1
C5
C7
C9
Br1
O1
O2
N1
C6
C8
C9
C7
C10
C6
C6
C8
C10
C3
1.432(7)
1.443(9)
1.644(9)
1.789(8)
1.431(15)
1.419(14)
1.466(13)
1.473(14)
1.367(12)
1.393(13)
1.527(16)
1.517(15)
1.924(8)
The sulfonamide group can be found also in the syn-periplanar
conformation 8c (Scheme 2). These conformational preferences
of syn- or antiperiplanar structures 8a and 8c have been
generally observed in most of the sulfonamides, even in the
planar sulfonamides 6 and 7 (cf. Scheme 3), and have been
rationalized in terms of negative hyperconjugation (anomeric
effect) between the nitrogen lone pair and the electron-deficient
C-S bond (σ*C-S).7,8,34-37 The relevant negative hyperconju-
gation is suggested theoretically to be strongly enhanced in
R-sulfonyl carboanions, which are isoelectronic to pyramidal
sulfonamides.35,38 The localization of the nitrogen lone pair in
the pyramidal arrangement, which increases the electron-
donating ability of the nitrogen nonbonding orbital, was
postulated to counterbalance the attenuation of negative hyper-
conjugation due to the elongation of the N-S bond.
Previously, the stereodynamics of a number of N-substituted
morpholines was studied.9-13,28,29,32,44-46 When the N-substitu-
ent is capable of conjugative interactions with the morpholino
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J. Org. Chem. Vol. 74, No. 13, 2009 4743

Modarresi-Alam et al.
TABLE 3. Selected Bond angles (deg) Calculated by X-ray Crystallographic Analysis for N-(4-Methylbenzenesulfonyl) Morpholine 1b and
N-(4-Bromobenzenesulfonyl) Morpholine 1d
N-(4-methylbenzenesulfonyl) morpholine 1b
N-(4-bromobenzenesulfonyl) morpholine 1d
O1
O1
O1
O2
O2
N1
C9
S1
S1
S1
S1
S1
S1
S1
O2
N1
C7
N1
C7
C7
C10
C8
C11
C11
C7
C3
C5
119.47(9)
106.74(9)
108.37(8)
106.19(9)
108.86(9)
106.49(8)
110.50(19)
115.79(13)
116.53(13)
111.75(16)
119.05(18)
121.90(18)
117.60(17)
120.59(15)
119.30(13)
120.08(13)
108.51(19)
111.20(19)
111.3(2)
O1
O1
O1
O2
O2
N1
C8
S1
S1
S1
S1
S1
S1
S1
O2
N1
C6
N1
C6
C6
C9
C7
C10
C10
C6
C3
C4
C5
C1
C5
C8
C7
C10
C9
C2
C4
119.1(6)
108.3(5)
107.5(4)
105.9(5)
107.7(5)
107.8(4)
110.2(9)
117.3(7)
116.0(6)
111.4(8)
120.2(9)
117.0(9)
122.6(8)
121.7(8)
120.3(7)
118.0(6)
108.2(9)
111.1(9)
111.6(9)
109.4(8)
118.9(7)
118.5(7)
O3
N1
N1
N1
C1
C2
C3
C7
C7
C7
C8
C9
C10
C11
C3
C3
O3
N1
N1
N1
C1
C2
C3
C6
C6
C6
C7
C8
C9
C10
C3
C3
S1
S1
C8
C2
C1
C2
C1
S1
C7
C2
C1
C2
C1
S1
C6
C1
C6
C9
S1
S1
N1
O3
O3
N1
C2
C4
N1
O3
O3
N1
Br1
Br1
C8
C11
C10
C4
108.86(17)
121.81(19)
120.6(2)
C5
TABLE 4. Selected Torsion Angles (deg) Calculated by X-ray Crystallographic Analysis for N-(4-Methylbenzenesulfonyl) Morpholine 1b and
N-(4-Bromobenzenesulfonyl) Morpholine 1d
N-(4-methylbenzenesulfonyl) morpholine 1b
N-(4-bromobenzenesulfonyl) morpholine 1d
O1
O2
C7
O1
O2
C7
N1
O2
N1
O1
O2
O1
C10
C9
C11
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
O3
O3
N1
N1
N1
N1
C1
C6
C8
C10
N1
N1
N1
N1
N1
N1
C7
C7
C7
C7
C7
C7
C9
C10
C8
C8
C11
C11
C7
C7
C9
C11
C8
C8
C8
C11
C11
C11
C6
C1
C1
C1
C6
C6
C8
C11
C9
C9
C10
C10
S1
-46.90(13)
-175.39(12)
68.71(13)
178.58(13)
50.10(14)
-65.81(14)
-89.42(17)
-25.63(17)
88.47(16)
-157.02(15)
156.48(16)
25.09(19)
-60.6(2)
O1
O2
C6
O1
O2
C6
N1
O2
N1
O1
O2
O1
C9
C8
C10
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
O3
O3
N1
N1
N1
N1
C1
C5
C7
C9
N1
N1
N1
N1
N1
N1
C6
C6
C6
C6
C6
C6
C8
C9
C7
C7
C10
C10
C6
C6
C8
C10
C7
C7
C7
C10
C10
C10
C5
C1
C1
C1
C5
C5
C7
C10
C8
C8
C9
C9
S1
177.8(7)
49.0(8)
-66.2(8)
-47.0(8)
-175.9(7)
69.0(8)
83.0(8)
150.8(8)
-95.3(8)
21.3(10)
-30.9(9)
-160.4(8)
60.4(11)
-59.1(11)
56.6(10)
-166.3(7)
-55.9(10)
166.4(7)
179.9(7)
-179.4(8)
-58.7(11)
56.5(11)
60.2(2)
-55.70(19)
167.68(13)
55.5(2)
-168.27(16)
-177.49(16)
177.03(17)
357.8(2)
C8
S1
C2
C5
N1
O3
C7
S1
C2
C4
N1
O3
S1
O
N1
S1
O3
N1
-56.9(2)
4-H and 8.0 kcal mol-1 for 4-NH2) lowers the ring inversion
barrier of the saturated six-membered ring. This observation is
in complete agreement with the ring interconversional barriers
of exo-methylenecyclohexane (8.4 kcal mol-1) and of cyclo-
hexanone (4.0 kcal mol-1) which are likewise lower than the
barrier to inversion of cyclohexane itself, which is 10.2 kcal
SCHEME 2. Important Conformations of Sulfonamides
mol-1
.
Thus as seen in Table 1, the differences observed in barriers
to ring inversion in 1 caused by the various substituents at aryl
(9.2 to 10.3 kcal mol-1) prove to be significant and can be
attributed to the exocyclic conjugation via pπ-dπ orbital
interaction and/or negative hyperconjugation (anomeric effect)
of the N-S bond. This means that the aryl substituent has
appreciable influence on the observed energy barrier. Each of
the compounds 1a-e with an N-sulfonyl substituent that is
capable of conjugative interaction with the morpholine nitrogen
atom shows a lower barrier to ring inversion than the corre-
nitrogen atom, a substantially lower barrier to ring inversion
was observed; therefore, as a reason the flattening of the six-
membered ring (due to increasing sp2 hybridization of nitrogen)
as the ground state of the ring inversion process was suggested.
The efforts of Sandstro¨m,28 Lunazzi,29 and their co-workers were
based on the understanding that the increase in the double bond
character of the exocyclic bond to the nitrogen of N-substituted
morpholines [e.g., N-CHO (7.5 kcal mol-1), N-COMe (6.9 kcal
mol-1), N-COPh (7.6 kcal mol-1), N-cyclohexenyl (9.1 kcal
mol-1), N-aryl (5.5 kcal mol-1 for 4-NO2, 7.2 kcal mol-1 for
4744 J. Org. Chem. Vol. 74, No. 13, 2009

Ring InVersion in N-Sulfonyl Morpholines
SCHEME 3. Sulfonamides Possessing Significant Rotation Energy Barrier about N-S Bonds
sponding N-alkyl morpholines; for example, the barrier of ring
negligible. This means that the role of solvation and/or
29
inversion for N-methyl morpholine is 11.5 kcal mol-1
.
The
intermolecular hydrogen bonding is less important to the
compounds studied. This is consistent with a ring inversion
process that involves relatively similar polarity (dipole moment)
structures of both the ground state and the transition state. This
fact can be due to conformations 8a and 8c (cf. Scheme 2)
predicting partial double bond character and not partially polar
structures like 9 for the N-S bond as a result of nN-π*S-O
bonding between the nitrogen and the sulfur in 8b, Scheme 2.
These conformations obtained for the N-sulfonyl morpholines
are generally favored by sulfonamides as evidenced from
extensive X-ray data in the literature.47 Evidently, the results
obtained are comparable to those routinely determined for
perfluorinated sulfonamides.35 Since the perfluorinated sulfona-
mides (e.g., 6 in Scheme 3) possess planar or almost planar
structures, we expected a similar effect for the sulfonamides 1
and, therefore, were interested to obtain exact structural
parameters by single-crystal X-ray analysis and studied accord-
ingly 1b and 1d (Figures 2 and 3). The structural data reveal
that the -(CH2)2-N-S(O)2-C(methyl or aryl) fragment adopts
an almost perfectly symmetrical staggered conformation with
the flattened pyramidal nitrogen moiety of morpholine and that
the S-C bond is antiperiplanar with respect to the nitrogen atom
lone pair. This indicates that the S-N bond can have the
suggested partial double bond character, which was the result
of several factors (vide supra).
The staggered conformation creates minimum crowding
around the S-N bond, which suggests that besides electronic
also steric effects could be responsible for the observed restricted
rotation. Indeed, the S-N bond [1b: 1.6461(16) Å and 1d:
1.644(9) Å] seems to exhibit not the appreciable double-bond
character expected: it is slightly longer than the mean value for
acyclic sulfonamides [1.63(2) Å]; comparison of the influence
of the electron-withdrawing perfluorinated substituent on the
barrier to rotation in sulfonamides 6 vs. carboxylic acid amides
was already studied and found to be similar. Unlike carboxylic
acid amides, both the steric demands of substituents at the N
atom and the electron-withdrawing ability of the substituent at
the S-atom should stabilize the symmetrically staggered ground
state conformation 8a (Scheme 2 and TOC), in which a desirable
(nN-σ*S-C)-π overlap is most efficiently attained. The dynamic
NMR effects for N,N-diisopropyl sulfonamides 6 with other
electronegative substituents at the S-atom were expected to be
importance of conjugation is corroborated by the ring inversion
barrier of 4-bromobenzene sulfonyl morpholine 1d lying
between those of the 4-methylbenzene sulfonyl 1b and 4-ni-
trobenzene sulfonyl 1e derivatives. In the latter compound, the
electron-withdrawing nitro group increases the conjugation of
the morpholine nitrogen with the sulfur atom of SO2 via the
phenyl ring and leads to the lowest ring inversion barrier of all
1. As the electron-withdrawing substituent effect of a para-
substituted phenyl group increases along the series CH3, H, Br,
and NO2 the barrier to ring inversion in 1 decreases from 10.3
to 9.2 kcal mol-1, respectively, which is putatively linked to
the double bond character in this exocyclic bond. A relatively
linear relationship was found for the Hammet equation log(kX/
kH) ) Fσ, R2 ) 0.94 (F equal to +1.0 and +1.1 for σp+ and σp,
respectively) and ∆G‡ ) Fσ, R2 ) 0.94 (F equal to -1.0 and
+
-1.1 for σp and σp, respectively). The reaction constants (F)
mean that the electron-withdrawing substituents in the phenyl
ring increase the rate of ring inversion and decrease the energy
barrier of ring inversion. This result confirms perfectly our
experimental results.
Furthermore, this result is consistent with the ring inversion
process that involves a relatively nonzwitterion ground state and
it is not merely corresponding to the participation of a zwitterion
and polar canonical structure like 9 (Scheme 2). Furthermore,
the barriers to ring inversion are similar to those of N-substituted
morpholines studied by Sandstrom and Lunazzi and other
6-membered rings containing external and internal double
bonding such as N-acyl morpholines, cyclohexenes, cyclohex-
anones, etc. In fact, the partial double bond character of the
exocyclic bond in the latter compounds proves to be much
higher than that in the compounds 1a-e studied. Indeed, if the
resonance structure 9 had been significant, not only high
rotational barriers about the N-S bond should be observed but
also the change of the solvent should remarkably affect the
height of the barrier to ring inversion in 1e (vide infra). Thus,
the decrease in free energy of activation of the ring inversion
in 1 can be attributed to the partial double bond character of
the N-S bond due to nN-σ*S-C anomeric interactions and/or
sulfur d-orbital participation [(nN-dS)-π] (cf. Scheme 2 and
TOC). The effect apparently increased progressively in related
systems in which the N-unsaturation substituent changed from
sulfonyl to aryl, vinyl, and carbonyl.
Another important result is given in Table 1: the barrier
differences observed in various solvents for 1e are almost
(47) Ohwada, T.; Okamoto, I.; Shudo, K.; Yamaguchi, K. Tetrahedron Lett.
1998, 39, 7877–7880, and references cited therein.
J. Org. Chem. Vol. 74, No. 13, 2009 4745

Modarresi-Alam et al.
similar to those described herein for sulfonamides 1. In
compounds 6 the S-N double bond character is a result of
(nN-dS)-π overlap along with considerable contribution of the
nN-σ*S-C bonding interaction, which accounts for the observed
exceptionally high rotational barriers in perfluorobutane-1-
sulfonamides 6.35 This negative hyperconjugative effect is well-
known to assist the stabilization of S- and Se-substituted
carbanions, the effect being subject to stereoelectronic control.35,36
Furthermore, it is evident that the symmetrically staggered
conformation 8a (see Scheme 2 and TOC) is optimal for this
kind of interaction, since the lone pair at the N-atom is disposed
in the same plane as the S-C bond. Finally, the energy of the
σ*S-C orbital is strongly reduced by the highly electron-
withdrawing perfluorinated substituent in sulfonamides 6,
thereby facilitating the nN-σ*S-C overlap.
The notable differences in the observed energy barriers to
N-S rotation between the sulfonamides 1a-d and perfluoro-
sulfonamides 6 remain to be rationalized. Since the electronic
effects described above would also operate in compounds 1,
the difference might be a consequence of the stronger electron-
withdrawing effect of the perfluorobutyl substituent compared
to methyl and aryl. This may result in the better leaving group
ability of a nonaflate group compared to methyl or aryl.
A stabilization of the negative charge of R-deprotonated
sulfones, which are isoelectronic to sulfonamides, is achieved
by overlap with d-orbitals of the SO2 S-atom.35,38 Obviously,
the geometry of the planar ground state conformation of
carboxylic acid amides, in which the lone pair of the N-atom
and the C-C bond adjacent to the carbonyl group are arranged
in perpendicular planes, a priori excludes simultaneous
(nN-PCdO)-π and nN-σ*C-C overlap. A remarkably fast
intermolecular halogen exchange in N,N-dialkyl halogeno-
sulfinylamides could be rationalized in terms of strong
nN-σ*S-X interaction leading to the equilibrium by dissociation:
R2NS(O)X h [R2NdSdO]+ X-.40
8a. However, all conformers 8a-c could exist in solution.
Therefore, the variation of the free energy of activation for ring
inversion of compounds 1 is attributed to the partial double bond
character of the S-N bond due to nN-σ*S-C weak anomeric
interactions or sulfur d-orbital participation [(nN-dS)-π] or a
combination of these factors (cf. Scheme 2 and the abstract
graphic).
Conclusions
We described herein the ring inversion in morpholine
sulfonamides, easily detectable by low-temperature NMR spec-
troscopy. The determined barriers to ring inversion of the
morpholine sulfonamides 1 are 9.2-10.3 kcal mol-1 and
decrease with increasing conjugation along the series studied
where substituents have different electron-withdrawing power
but similar steric properties. These energy barriers proved to
be comparable to those well-known for a saturated six-
membered ring. The effect is rationalized as a result of the partial
double bond character adopted by the S-N bond due to
(nN-dS)-π and nN-σ*S-C interactions that are amplified by
the electron-withdrawing nature of the substituents. The partial
double bond character of the N-S bond is due to nN-σ*S-C
weak anomeric interactions and sulfur d-orbital participation
or a combination of these factors. This implies that the strong
electronic and steric effects can increase the barrier to rotation
about the N-S bond in this particular case.
Experimental Section
General. Variable-temperature 1H NMR spectra were calibrated
with a standard methanol sample.13 The temperature was measured
at the probe ((0.1 °C). Samples were allowed to equilibrate for
10 min at each temperature before the spectrum was recorded.
Chemicals. All starting materials and solvents were purified with
appropriate purification techniques before use, when necessary.49
N-(aryl-alkylsulfonyl) morpholines 1a-d are known compounds
Thenitrogenatomof1b(θ)∠S1-N1-C8+∠S1-N1-C11
+ ∠C8-N1-C11 ) 344.07°) is more pyramidalized than that
of 1d (θ ) ∠S1-N1-C7 + ∠S1-N1-C10 + ∠C7-N1-C10
) 344.7°) (Table 1), while the nitrogen atom in 6 is planar (θ
) 359.26° ≈ 360°). The pyramidal angles for NH3, NF3, and
(CH3)3N are (3 × 107.3° ) 321.9°), (3 × 102.5° ) 307.5°),
and (3 × 108.0° ) 324°), respectively.48 Thus, the nitrogen
atom in 1 is the flattened pyramids (θ ≈ 344°) due to
conjugation with the aryl sulfonyl group. The higher ring
inversion barrier for 1 can thus be linked to the poorer
conjugative effect of arylsulfonyl substituent compared to any
substituted phenyl group and/or acyl group in N-arylmorpholines
and N-acylmorpholines.
1
and identified by comparison of some their spectral data (IR, H
and 13C NMR) and physical properties with those of authentic
samples and were prepared from morpholine and sulfonylchlorides
according to literature procedures.5,30,31,50
Acknowledgement. The University of Sistan & Baluchestan
Graduate Council supported this research. Ali Reza Modarresi-
Alam thanks DAAD and University of Potsdam.
Supporting Information Available: Variable-temperature 1H
NMR spectra of 1b-e in different solvents. This material is
available free of charge via the Internet at http://pubs.acs.org.
The N-S bond in 1b (1.6461(16) Å) is elongated as
compared with that in 1d (1.644(9) Å) and, on the other hand,
the bond length of C(aryl)-S in 1b (1.7693(17) Å) is shorter
than that in 1d (1.789(8) Å), both in the crystalline state.
The dynamic NMR study and X-ray data of the N-sulfonyl
morpholines 1 confirms the exocyclic conjugation (partial double
bond character), which is due to nN-σ*S-C anomeric interactions
and that the preferred conformer in the solid state proves to be
JO900454A
(48) Weast R. C.; Lide, D. R., Ed. CRC Handbook of Chemistry and Physics,
70th ed.; CRC Press: Boca Raton, FL, 1989-1990; ppF-190 and F-192.
(49) (a) Casey, M.; Leonard, J.; Lygo, B.; Procter, G. AdVanced Practical
Organic Chemistry; Chapman & Hall, Int.: New York, 1990. (b) Armarego,
W. L. F.; Perrin, D. D. Purification of Laboratory Chemicals; Butterworth-
Heinmam: Oxford, UK, 1996.
(50) Weast, R. C.; Grasselli, J. G. Handbook of Data on Organic Compounds,
2nd ed.; CRC Press: Boca Raton, FL, 1989.
4746 J. Org. Chem. Vol. 74, No. 13, 2009