O-alkylation of N-phenylhydroxylamine in dimethyl sulfoxide with methylarenesulfonates

Article abstract of DOI:10.1021/jo951448z

The methylation of N-phenylhydroxylamine (NPHA) with methylarenesulfonates in DMSO gives alkylation of the O atom in contrast to methylation in methanol where N alkylation occurs. The Hammett p values indicate that alkylations with N-methylanilines and NPHAs both involve the N atom. The NPHAs show "nominal α-effects" but involve comparison of N atoms with O atoms. The reactivity of the principle component, the zwitterion I, is examined with leaving group studies and comparison with benzyl alkoxide reactivity.

Full text of DOI:10.1021/jo951448z

9
434
J . Org. Chem. 1996, 61, 9434-9436
O-Alk yla tion of N-P h en ylh yd r oxyla m in e in Dim eth yl Su lfoxid e
w ith Meth yla r en esu lfon a tes
K. R. Fountain,* Robert D. White, Kamlesh D. Patel, Dallas G. New, YuBo Xu, and
Aaron J . Cassely
Truman State University, Kirksville, Missouri 63501
Received August 7, 1995X
The methylation of N-phenylhydroxylamine (NPHA) with methylarenesulfonates in DMSO gives
alkylation of the O atom in contrast to methylation in methanol where N alkylation occurs. The
Hammett F values indicate that alkylations with N-methylanilines and NPHAs both involve the N
atom. The NPHAs show “nominal R-effects” but involve comparison of N atoms with O atoms.
The reactivity of the principle component, the zwitterion I, is examined with leaving group studies
and comparison with benzyl alkoxide reactivity.
N-Phenylhydroxylamine (NPHA) exists largely as the
Ta ble 1. Su m m a r y of Ra te Da ta for Meth yla tion of
Su bstitu ted N-m eth ya n ilin es a n d Su bstitu ted
N-P h en ylh yd r oxyla m in es w ith Meth yla r en esu lfon a tes in
DMSO-d 6 a t 29.5 °C
zwitterion, 1, in DMSO.1 The evidence for this statement
consists of the finding that F values for the basicity of
NPHA change from -5.69 to -1.20 when the solvent is
changed from methanol to DMSO. The corresonding
5
pKlgMe
G1
G2
X
k × 10 (SD)
Me
change in the F value for the sterically similar N-
methylanilines is -4.70 to -4.83.1 Observation of the
4-Me
4-MeO
9.95(0.05)
13.4(0.08)
2.2(0.08)
0.66(0.01)
1.25(0.1)
9.1(0.3)
0.68
4
-MeO
4-MeO
4-MeO
4-MeO
4-MeO
4-Br
prototropic shift in the spectroscopy of the NPHA mol-
ecules is also reported.1 Alkylation studies also show that
the O atom is alkylated instead of the N atom, as is the
case in methanol.2 This functionality has not been
previously investigated, so this paper reports the initial
studies on its reactivity.
H
3-Cl
4
-Cl
4-Cl
-0.74
-2.36
0.00
4
4
-Cl
-Cl
4-NO2
H
40.1 (0.0)
3.5(0.5)
4-Cl
4-Me
1.7(0.2)
0.46
4
4
-Cl
-Cl
3-NO2
4-Me, 3-NO2
9.1(0.4)
25.7(0.3)
-2.15
-1.75
OH
H
H
H
H
H
4-MeO
4-Me
H
4-Br
4-F
4-MeO
4-MeO
4-MeO
6.2(0.1)
10.0(0.1)
15.6(0.3)
38.3(0.4)
32.5(0.3)
4.12(0.5)
17.6(0.5)
0.33(0.1)
-0.33
4
4
4
-Br
-Me
-NO2
Exp er im en ta l Section
When 504 mg (4.62 mmol) of freshly prepared N-phenyl-
hydroxylamine was treated with 5.13 mmol of methyl 4-ni-
trobenzenesulfonate (4-nosylate) in 75 mL of pure DMSO
overnight a pale yellow mixture was obtained. This solution
was added to 1 M cold hydrochloric acid and extracted three
times with dichloromethane to remove most of the DMSO.
Neutralization with sodium bicarbonate solution and 3-fold
extraction with dichloromethane gave, after drying and solvent
removal, a 34% yield of O-methyl N-phenylhydroxylamine,
1
, was measured by our published kinetic method on a Varian
2
,4
XL200 NMR.
DMSO-d6
G ArNHX + CH O SArG
2
8
1
3
3
+
+
-
G ArN HMe (a) or G ArNH OCH (b) + O SArG (1)
1
2
1
2
3
3
2
having a CH
3
O signal in DMSO-d
at 2820-2810 cm
at 1150 cm as well as NO at 1260 cm (twinned with N-C
6
at 3.78 ppm and IR bands
Table 1 summarizes the results. A Hammett plot of log knuc
for methylation with methylarenesulfonate ester in DMSO,
Figure 1, shows a F value of -1.70. The corresponding plot
for N-methylanilines, also in Figure 1, shows F ) -2.10 for
-
1 3
suitable for OCH
3
3
and an OCH stretch
-
1
-1
-
1
1
for aromatic amine at 1240 cm ). Additionally, the H NMR
spectrum was extremely simple when the reaction was done
Me
this “normal” nucleophile. Figure 2 shows âlg determina-
in DMSO-d
rearranged products associated with methylation of N in
methanol-d
The reactivity of substituted NPHA and N-methylanilines
vs. substituted methylarenesulfonates in DMSO-d , reaction
6
, showing only the OMe signal, with no trace of
5
tions for both nucleophiles in DMSO-d
6
.
The substituted benzyl alcohols were used as received or
were synthesized by sodium borohydride reduction of the
6
.
6
(4) Fountain, K. R.; Fountain, D. P.; Michaels, B.; Myers, D. B.;
Salmon, J . K.; Van Galen, D. A.; Yu., P. Can. J . Chem. 1990, 69, 798.
(
5) Hoffman, R. V.; Shankweiler, J . M. J . Am. Chem. Soc. 1986, 108,
*
To whom correspondence should be addressed. Tel.: (816) 785-
5536. McManus, S. P.; Smith, M. R.; Shankweiler, J . M.; Hoffman, R.
V. J . Org. Chem. 1988, 53, 141.
(6) Benoit, R. L.; Mackinnon, M. J .; Bergeron, L. Can. J . Chem. 1981,
59, 1501.
4
633. Fax: (816) 785-4045. E-mail: sc18@truman.edu.
X
Abstract published in Advance ACS Abstracts, December 1, 1996.
(1) Fountain, K. R.; Cassely, A. J .; New, D. G.; White, R. D.; Xu,
Y.-B. J . Phys. Org. Chem. 1995, 8, in press.
2) Fountain, K. R.; Hutchinson, L. K.; Mulhearn, D. C.; Xu, Y.-B.
J . Org. Chem. 1993, 58, 7883.
3) Bellamy, L. J . The Infra-red Spectra of Complex Molecules;
Chapman & Hall: London, 1975; p 17.
(7) (a) Decouzon, M.; Exner, O.; Gal, J . F.; Maria, P. C. J . Org. Chem.
1990, 55, 3980. (b) Bordwell, F. G.; Fried, H. E.; Hughes, D. L.; Lynch,
T.-Y.; Satish, A. V.; Whang, Y. E. J . Org. Chem. 1990, 55, 3330.
(8) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in
Organic Chemistry, 3rd ed.; Harper & Row: New York, 1987; p 146.
(
(
S0022-3263(95)01448-4 CCC: $12.00 © 1996 American Chemical Society

O-Alkylation of N-Phenylhydroxylamine
J . Org. Chem., Vol. 61, No. 26, 1996 9435
F igu r e 3. Hammett plot for g-BzONa in DMSO-d
SC OMe.
6 3
vs MeO -
F igu r e 1. Hammett plot for substituted N-phenylhydroxyl-
amines and N-methylanilines in DMSO-d at 29.5 °C.
6
6
H
4
3
steric freedom for the O atom to approach the CH group
of the methylarenesulfonate. Alternatively, the slightly
greater value of F for the N-methylaniline series may
indicate greater resonance stabilization of the lone pair
on N. The enhanced reactivity of the O atom could also
be due to internal base catalysis provided by the “R-effect”
of the lone pair of electrons on N, but this is unlikely
because data show that the principle species is 1.
The nominal “R-effect” in this experiment matches N
atoms on substituted N-methylanilines with the O atoms
on substituted NPHA, “R-nucleophiles”, so no real R-effect
can be determined. (Although the pKNucH+ values of the
two nucleophiles are matched, they refer to different
ionization sites from different atoms.) The mechanism
-
must not involve OH, but the O , so the nucleophilicity
F igu r e 2. Determination of âlgMe for 3-ClNPHA (+) and
N-methylaniline (4) in DMSO-d at 29.5 °C.
might be expected to be more than the N atom on the
normal nucleophile. The fact that the reactivity is higher
than the uncharged N atom is thus not surprising.
The alkylation of the functional group -NH O has
2
not previously been studied, so this kind of reactivity may
6
Ta ble 2. Su m m a r y of Ra te Da ta for Meth yla tion of
Su bstitu ted Ben zyl Alk oxid e An ion s in DMSO-d 6 a t 30.3
+
-
°
C, Eq 2
be normal for this group. The krel values are 2.84-4.17
(for G
1
) H, G ) 4-Br) compared to the N-methylaniline.
1
Comparing Tables 1 and 2 shows that the benzyl alkoxide
ions are much more reactive than the zwitterion, 1. This
is probably due to the expected greater basicity of the
alkoxides. The two normal nucleophile series bracket the
reactivity of the zwitterion, 1, and serve to indicate the
kind of reactivity to be expected of these species.
2
2
G
k × 10 (SD)
G
k × 10 (SD)
4
4
-Me
-Cl
5.2(0.3)
3.4(1.0)
4-NO2
4-MeO
2.3(0.1)
6.2(0.5)
To ascertain the degree of transmission of the sub-
-
stituent effects to the O atom in 1 we compare the
Hammett plots of reaction 1 with the sterically and
structurally similar benzylalkoxide anions, eq 2 (Table
corresponding aldehydes in ethanol. All physical properties
measured were consistent with the literature values of these
compounds.
2
). The Hammett plot shows that transmission of
electronic effects through the CH group (F ) 0.41) is
substantially less than through the -NH
2
The sodium salts were generated in situ by addition of a
+
- group (F )
standardized solution of deuterated dimsyl ion in DMSO-d
and dilution to give 0.20 molar solutions in DMSO-d . Kinetics
of eq 2 were determined, with the internal standard being the
DMSO-d formed. Table 2 summarizes the data, with the
6
2
1.74). The maximum F possible from the data, by
6
neglecting the 4-Cl point, is 0.61, still only ca. 35% of
+
5
that for the -NH2 group F value.
Hammett plot shown in Figure 3. The F value for alkylation
of the deprotonated alcohols of 0.41 is much smaller than for
either N-methylaniline or NPHA.
It is possible that these F values indicate that the
+
-NH
2
group transmits electronic information in solution
-
chemistry better than the CH
2
group to the O center.
That this cannot be the case for this apparently improved
Discu ssion
+
transmission of electronic information for the -NH
2
group was obtained from consideration of the results of
computational chemistry. Structures for the substituted
zwitterions, 1, and substituted benzyl alkoxides were
optimized with the AM1 Hamiltonian (HyperChem). The
Any mechanism for this reaction must account for the
involvement of N atoms on both nucleophiles to nearly
the same extent from the signs and magnitudes of the F
values. The negative signs indicate that both alkylations
are hindered by electron withdrawal.9 The O atom on
the NPHA is more reactive than the N atom on N-
methylaniline. This last fact may indicate a greater
(9) Hehre, W. J .; Radom, L.; Schleyer, P v. R.; Pople, J . A. Ab Initio
Molecular Orbital Theory; J ohn Wiley & Sons: New York, 1986; pp
120-123.

9
436 J . Org. Chem., Vol. 61, No. 26, 1996
Fountain et al.
Ch a r t 1
occurs in both cases. As the O atom becomes alkylated
the negative charge on O, which should actually help
stabilize the formal charge on the NH portion (which
2
are always positively charged in these species at all levels
of theory) decreases, Chart 1. At the end of the reaction
formal charge on NH
2
-
is no longer balanced by this
negative charge on O . The process of concentrating
formal positive charge next to the benzene ring is thus
similar in both N-methylaniline and N-phenylhydroxyl-
amine zwitterion. The susceptibility parameter, F, is
thus expected to be similar in the two species, which is
observed.
6 4
F igu r e 4. Hammett plot of O charge (Mulliken) for G-C H -
-
2
NH O zwitterions (b) and for G-BzO anions (4).
Hammett plots for the computed charges (Mulliken
A second interpretation, suggested by a reviewer, is
that the similarity of the F values is difficult to interpret
in detail. One important factor must be the progress of
bond formation between the nucleophilic atom and the
methyl group at the transition state; this degree of bond
formation could be similar or different in the two cases.
-
charges) on the O atom appear in Figure 4. The F values
(0.016 and 0.019) are small, and nearly the same, with a
slight advantage for transmission of the substituent effect
for the CH group. If these F values can be accepted as
2
-
indicators of gas-phase susceptibility of the O atoms to
the substituent effects for the two species, then the larger
F value for alkylation of NPHA must have a different
explanation than transmission of electronic information
Departure of the leaving group is, however, very nearly
Me
the same (â
lg
) 0.53 vs. 0.52).
Me
The âlg values for N-methylaniline and 3-ClNPHA
zwitterion, Figure 2, are very similar (0.53 and 0.52,
respectively). This fact indicates a transition state (TS)
that produces nearly the same degree of bond cleavage
-
through the respective groups to the O center.
The most probable reason for the similarity in F values
between N-methylaniline and NPHA on alkylation, in
spite of alkylation at sites differing in distance from the
benzene ring, is that charge development around the
region of the two N atoms of each species is similar. In
the alkylation of N-methylaniline a formal positive
charge develops on the N atom, although high-level ab
initio computations indicate it is more likely that this
charge is not entirely localized on N in either case, but
between the CH
group. The -NH
normal” nucleophile from the standpoint of pushing out
3
and the arenesulfonate anion leaving
+
-
2
O
group is thus behaving like a
“
Me
the leaving group. Interestingly, the âlg
N-methylaniline in DMSO-d is nearly the same as for
methanol-d (2) (0.53), whereas the value for the NPHA
changes from 0.47 in methanol-d (2) to DMSO-d , 0.52,
value for
6
4
4
6
3
also involves the H atom and the CH . In 1 a formal
indicating a lesser nucleophilic push for the zwitterion
than for the normal NPHA. These changes are small,
charge already exists on N but is formally neutralized
-
by the oppositely charged O . This is shown in ammonia
but similar changes are claimed to be real and signifi-
9
oxide, where the N atom is actually negative at the 6-31*
cant.5 This finding is consistent with the reported
level of theory but the overall NH
3
group is positive. Also,
2
R-effect for NPHA in methanol-d
reactivity occurs in DMSO-d
6
, but shows no special
trimethylammonium ion shows a positive charge on N
at this same level of theory.10 Formal charge on N is not
fully descriptive of the situation. Both species show a
major portion of positive charge on the H atoms. In
either case, the positive charges develop around the NH,
6
.
Ack n ow led gm en t. We thank the National Science
Foundation for supporting this work through NSF-RUI
9
214994. We also thank reviewer 2 for his remarks,
2
and the NH groups are greatly increased as alkylation
which stimulated the comparison work with substituted
benzyl alkoxides.
(10) Besler, B. H.; Merz, K. M., J r.; Kollman, P. A. J . Comp. Chem.
1
990, 11, 431.
J O951448Z