Mechanism of Methoxide Ion Substitution in the Z and E Isomers of O-Methylbenzohydroximoyl Halides

Article abstract of DOI:10.1021/jo030299e

Kinetics and stereochemical studies have been carried out on the reactions of the Z and E isomers of O-methylbenzohydroximoyl halides [1Z and 1E, ArC(X)= NOCH₃] with sodium methoxide in 9:1 DMSO-methanol. The reactions of methoxide ion with hydroximoyl fluorides (X = F) are stereospecific. The reaction with 1Z (X = F) gives only the Z substitution product (1Z, X = OCH ₃). The reaction of methoxide ion with 1E (X = F) is less selective, giving ca. 85% E substitution product. The Hammett ρ-values for the Z and E isomers (X = F) are +2.94 and +3.30, respectively. The element effects for 1Z (Ar = C₆H₅) are 2.21 (X = Br):1.00 (X = Cl):79.7 (X = F). The 1E element effects are (Ar = C₆H₅) 1.00 (X = Cl):8.3 (X = F) and (Ar = 4-CH₃OC₆H₄) 1.97 (X = Br):1.00 (X = Cl):12.1 (X = F). The entropies of activation for these reactions are negative (for example, ΔS? = - 15 eu for 1Z and ΔS? = - 14 eu for 1E, Ar = 4-CH₃OC₆H ₄, X = F). These experimental observations are consistent with a mechanism proceeding through a tetrahedral intermediate. Ab initio calculations were carried out to help explain the stereospecificity of these reactions. These calculations indicate that the tetrahedral intermediate from the Z isomer undergoes rapid elimination to the Z substitution product before stereomutation can take place. These calculations also show that the lowest barrier for rotation around the carbon-nitrogen single bond in the tetrahedral intermediate derived from 1E leads to an intermediate that eliminates fluoride ion to give E product.

Full text of DOI:10.1021/jo030299e

Mech a n ism of Meth oxid e Ion Su bstitu tion in th e Z a n d E Isom er s
of O-Meth ylben zoh yd r oxim oyl Ha lid es
J ames E. J ohnson,*,† Debra D. Dolliver,*,‡,§ Lonchun Yu,† Diana C. Canseco,†
Michael A. McAllister,‡,| and J effrey E. Rowe
Department of Chemistry and Physics, Texas Woman’s University, Denton, Texas 76204-5859,
Department of Chemistry, University of North Texas, Denton, Texas 76203, and School of Chemistry,
La Trobe University, Bundoora, Victoria 3086, Australia
jjohnson@twu.edu
Received October 6, 2003
Kinetics and stereochemical studies have been carried out on the reactions of the Z and E isomers
of O-methylbenzohydroximoyl halides [1Z and 1E, ArC(X)dNOCH3] with sodium methoxide in 9:1
DMSO-methanol. The reactions of methoxide ion with hydroximoyl fluorides (X ) F) are
stereospecific. The reaction with 1Z (X ) F) gives only the Z substitution product (1Z, X dOCH3).
The reaction of methoxide ion with 1E (X ) F) is less selective, giving ca. 85% E substitution product.
The Hammett F-values for the Z and E isomers (X ) F) are +2.94 and +3.30, respectively. The
element effects for 1Z (Ar ) C6H5) are 2.21 (X ) Br):1.00 (X ) Cl):79.7 (X ) F). The 1E element
effects are (Ar ) C6H5) 1.00 (X ) Cl):18.3 (X ) F) and (Ar ) 4-CH3OC6H4) 1.97 (X ) Br):1.00 (X )
Cl):12.1 (X ) F). The entropies of activation for these reactions are negative (for example, ∆Sq )
-15 eu for 1Z and ∆Sq ) -14 eu for 1E, Ar ) 4-CH3OC6H4, X ) F). These experimental observations
are consistent with a mechanism proceeding through a tetrahedral intermediate. Ab initio
calculations were carried out to help explain the stereospecificity of these reactions. These
calculations indicate that the tetrahedral intermediate from the Z isomer undergoes rapid
elimination to the Z substitution product before stereomutation can take place. These calculations
also show that the lowest barrier for rotation around the carbon-nitrogen single bond in the
tetrahedral intermediate derived from 1E leads to an intermediate that eliminates fluoride ion to
give E product.
In tr od u ction
elimination mechanism in which a significant hypercon-
jugative barrier prevents internal rotation of the result-
ing carbanionic intermediate (which could lead to partial
or complete inversion of configuration).1 Recent theoreti-
cal and experimental work has suggested that in unac-
tivated alkenyl systems concerted nucleophilic substitu-
tion by relatively weak nucleophiles (Cl- or Br-) would
preferentially occur by an in-plane, SN2-like mechanism,
resulting in complete inversion of configuration.6-9 How-
ever, it is indicated that in these substitutions with
stronger nucleophiles (OH- or SH-) an out-of-plane SN2
mechanism with retention of configuration might be
viable.7
The stereochemical outcome of a reaction can provide
valuable information about the reaction’s mechanism. In
the study of nucleophilic substitution at the sp2-hybrid-
ized carbons of alkenes (CdC), stereochemical outcomes
can be monitored relative to other groups attached to the
double bond. In nucleophilic substitution reactions on
vinylic systems with good nucleophiles, a predominant
retention of configuration in the product has been
observed.1,2 For some cases, it has been proposed that
this stereochemical outcome arises from a single-step
mechanism in which the leaving group departs on the
same side as the attack of the incoming nucleophile.3-5
Most, however, appear to react via a stepwise addition-
A single-step SN2-like mechanism has also been pro-
posed for some nucleophilic substitution reactions at the
sp2-hybridized carbon of the acyl group (CdO).10-18 While
the stereochemical outcome of these reactions cannot be
* To whom correspondence should be addressed. Phone: 940-898-
2567. Fax: 940-898-3198.
† Texas Woman’s University.
‡ University of North Texas.
(5) Dodd, D.; J ohnson, M. D.; Meeks, B. S.; Titchmarsh, D. M.; Van
Duong, K. N.; Gaudemer, A. J . Chem. Soc., Perkin Trans. 2 1976,
1261-1267.
§ Current address: Southeastern Louisiana University, Department
of Chemistry and Physics, Hammond, LA 70402.
| Current address: Agouron Pharmaceuticals, Alanex Division, San
Diego, CA 92121-1194.
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1994, 116, 5961-5962.
La Trobe University.
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10.1021/jo030299e CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/17/2004
J . Org. Chem. 2004, 69, 2741-2749
2741

J ohnson et al.
SCHEME 1
monitored, this type of mechanism has been proposed on
the basis of Brønsted correlations,11-14 correlation of the
reaction with solvent ionizing power and nucleophilic-
ity,15,16 and isotope effects.17,18 Calculations demonstrate
that in a concerted gas-phase substitution of formyl
chloride by chloride ion the barrier for in-plane attack
(SNσ) of the chloride ion is higher than for an out-of-plane
attack (SNπ) in the mode thought to account for retained
stereochemistry in the concerted substitution reactions
of alkenes.8,9
Nucleophilic substitution at the sp2-hybridized carbon
of an imine (CdN) has not received the same degree of
attention as the CdC or CdO bonds, and to our knowl-
edge, there has been no experimental evidence support-
ing a concerted type of mechanism of substitution with
this moiety. It appears that only two mechanistic path-
ways for nucleophilic substitution at the carbon-nitrogen
double bond have been experimentally identified: an
ionization pathway (DN + AN)19-21 and an addition-
elimination pathway (AN + DN).21-28 Recent theoretical
work, however, demonstrates that concerted nucleophilic
substitution at an imine carbon may either be mecha-
nistically similar to that of the carbonyl (SNπ resulting
in retained stereochemistry) or that of an alkene (SNσ
resulting in inverted stereochemistry).9 It seems reason-
able that the possibility of a concerted mechanism
involving this bonding system should be considered,
especially in cases where the stereochemical outcome is
suggestive.
SCHEME 2
One such case is the nucleophilic substitution of
methoxide ion on O-methylbenzohydroximoyl chlorides
(1Za and 1Ea ) in 90:10 DMSO/MeOH (Scheme 1).28 The
reaction of the Z isomer (1Za ) yields completely retained
stereochemistry in the substitution product, while the E
isomer (1Ea ) yields preferential retention of stereochem-
istry (77% retention and 23% inversion). This unusual
stereochemical outcome could not be readily explained
in view of the proposed stepwise addition-elimination
mechanism in which the addition step was found to be
q
rate determining (AN + DN) (Scheme 2).
(11) Castro, E. A.; Cubillos, M.; Santos, J . G. J . Org. Chem. 1998,
63, 6820-6823.
(12) Castro, E. A.; Pavez, P.; Santos, J . G. J . Org. Chem. 1999, 64,
2310-2313.
Resu lts a n d Discu ssion
(13) Stefanidis, D.; Cho, S.; Dhe-Paganon, S.; J encks, W. P. J . Am.
Chem. Soc. 1993, 115, 1650-1656.
Our previous study28 of the reaction of 1Z included a
Hammett correlation with σ (F ) 1.90) and a rate
comparison of the substitution of (Z)-O-methylbenzohy-
droximoyl bromide (1Zc) to (Z)-O-methylbenzohydrox-
imoyl chloride (1Za ) (Br/Cl ) 2.2:1.0). This paper expands
these findings by including kinetic data on selected (Z)-
and (E)-hydroximoyl fluorides (1Ze-i and 1Ee-i), bro-
mides (1Zd and 1Ed ), and chlorides (1Zb and 1Eb)
(Chart 1) to provide full element effect data for this
substitution reaction.
An investigation of the rate of (Z)- and (E)-hydroximoyl
halides (1Ze-i, 1Ee-i, 1Zd , 1Ed , 1Zb, and 1Eb) and
sodium methoxide reactions showed each to be first-order
in both hydroximoyl halide and methoxide ion (see Table
1S in the Supporting Information). With the hydroximoyl
fluorides, the rate constant (Table 1) for substitution of
the Z isomer (1Ze-i) in all cases was found to be larger
than that for the E isomer (1Ee-i) (at 26.06 ( 0.04 °C;
k1Ze/k1Ee ) 4.78:1.00, k1Zf/k1Ef ) 6.44:1.00, k1Zg/k1Eg ) 2.69:
1.00, k1Zh /k1Eh ) 7.33:1.00, k1Zi/k1Ei ) 1.87:1.00). Product
distributions for the hydroximoyl fluorides were very
similar to those seen for substitution reactions done on
(14) Ba-Saif, S. A.; Colthurst, M.; Waring, M. A.; Williams, A. J .
Chem. Soc., Perkin Trans. 2 1991, 1901-1908.
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2742 J . Org. Chem., Vol. 69, No. 8, 2004

Methoxide Ion Substitution in O-Methylbenzohydroximoyl Halides
TABLE 1. Secon d -Or d er Ra te Con sta n ts for th e
CHART 1
Rea ction of Meth yl Ben zoh yd r oxim oyl Ha lid es w ith
Sod iu m Meth oxid e in 9:1 DMSO-Meth a n ol Solu tion a ,b
hydroximoyl halide
T, °C
102k, M-1 s-1
1Ze
1Ze
1Ze
1Ze
1Ze
1Ee
1Ee
1Ee
1Ee
1Ee
1Zf
1Ef
1Zg
1Eg
1Zh
1Zh
1Zh
1Eh
1Eh
1Eh
1Zi
1Ei
1Zb
1Zb
1Zb
1Zb
1Zb
1Eb
1Eb
1Eb
1Eb
1Zd
1Zd
1Zd
1Zd
1Ed
1Ed
1Ed
1Ed
20.25
26.06
30.08
35.55
39.22
20.25
26.06
30.08
37.30
40.67
26.06
26.06
26.06
26.06
26.06
36.60
44.60
26.06
36.06
44.60
26.06
26.06
44.60
48.83
51.63
54.48
57.25
44.60
48.83
51.63
54.48
44.60
48.83
51.63
54.48
44.60
48.83
52.89
54.48
11.4 ( 0.6
23.4 ( 1.0
32.4 ( 1.8
47.0 ( 2.2
61.1 ( 2.3
2.63 ( 0.38
4.90 ( 0.32
8.45 ( 0.60
12.6 ( 1.3
18.4 ( 2.0
121 ( 14
18.8 ( 2.2
6.36 ( 0.51
2.36 ( 0.32
7.26 ( 0.58
15.3 ( 1.1
32.6 ( 1.9
0.990 ( 0.104
2.37 ( 0.22
5.27 ( 0.16
10600 ( 700
5680 ( 1020
0.446 ( 0.017
0.684 ( 0.063
0.956 ( 0.035
1.18 ( 0.04
1.52 ( 0.06
0.436 ( 0.013
0.684 ( 0.033
0.894 ( 0.060
1.13 ( 0.11
1.24 ( 0.01
1.98 ( 0.11
2.53 ( 0.07
3.33 ( 0.019
0.858 ( 0.037
1.32 ( 0.07
1.92 ( 0.06
2.25 ( 0.04
the hydroximoyl chlorides and bromides. The Z-hydrox-
imoyl fluorides (1Ze-i) gave only the Z-hydroximate
(1Zj-n ) and the E-hydroximoyl fluorides (1Ee-i) gave
mixtures of the E- and Z-hydroximates with the E-
hydroximate predominating (ca. 85% E, Table 2).
Activation parameters for the hydroximoyl fluorides
(1Ze, 1Ee, 1Zh , and 1Eh ), hydroximoyl chlorides (1Zb
and 1Eb), and hydroximoyl bromides (1Zd and 1Ed )
were measured and are compared to the previously
acquired values for (Z)- and (E)-O-methylbenzohydrox-
imoyl chlorides (1Za , 1Zb, and 1Ea )28 (Table 3). All
entropies of activation (∆Sq) are negative, consistent with
an associative process occurring in the rate-determining
step in all the reactions.
The effect of substituents attached to the phenyl ring
of the (Z)- and (E)-hydroximoyl fluorides was also inves-
tigated for this reaction. Reasonably good Hammett
correlations were obtained with σ for the Z isomer with
a F value of 2.94 (r ) 0.995) and for the E isomer with a
F value of 3.30 (r ) 0.993) (Figure 1).
With the measurement of the rates of methoxide
substitution on the O-methylbenzohydroximoyl fluorides,
a full element effect rate comparison could be made for
this reaction. Rates for substitution of the hydroximoyl
chlorides and bromides had been measured previously28
at 44.60 °C. At this temperature, the substitution of the
hydroximoyl fluorides occurred too quickly to be ac-
curately measured by the technique utilized in this study.
Therefore, the rate constants for substitution of the
hydroximoyl fluorides were extrapolated to 44.60 °C
using the slope from a plot of ln k vs 1/T. The element
effects at 44.6 °C for 1Z are 2.21 (X ) Br, 1Zc28):1.00
(X ) Cl, 1Za 28):79.7 (X ) F, 1Ze). The 1E element effects
at 44.6 °C are 1.00 (X ) Cl, 1Ea ):18.3 (X ) F, 1Ee) and
1.97 (X) Br, 1Ed ):1.00 (X ) Cl, 1Eb):12.1 (X ) F, 1Eh ).
a
In most cases, the rate constants are an average of at least
two measurements (see Table 1 in the Supporting Information).
b
Errors were calculated from standard deviations at the 95%
confidence level.
TABLE 2. P r od u ct Distr ibu tion s in th e Rea ction of
(E)-Hyd r oxim oyl F lu or id es w ith Sod iu m Meth oxid e in 9:1
DMSO-Meth a n ol Solu tion a ,b
(E)-hydroximoyl fluoride
T, °C
% E product
1Ee
1Ee
1Ee
1Ee
1Ee
1Ef
1Eg
1Eh
1Eh
1Eh
20.25
26.06
30.08
37.30
40.67
26.06
26.06
26.06
36.06
40.60
83
85
85
85
85
88
86
81
84
85
a
Product distributions were determined by HPLC analysis.
The error in the measurement of the product distribution is
b
approximately 5%.
enhancement due to the halogen in the Z isomer of these
compounds than in the E isomer.
In all situations, the hydroximoyl fluoride reacts
significantly faster than either the hydroximoyl chloride
or hydroximoyl bromide. This would be expected if the
(29) Rappoport, Z.; Topol, A. J . Chem. Soc., Perkin Trans. 2 1975,
863-874.
(30) Bunnett, J . F.; Garbisch, E. W., J r.; Pruitt, K. M. J . Am. Chem.
Soc. 1957, 79, 385-391.
reaction proceeded by an addition-elimination mecha-
q
nism in which the addition step was rate limiting (AN
+
DN).28-34 There appears to be a much stronger rate
J . Org. Chem, Vol. 69, No. 8, 2004 2743

J ohnson et al.
TABLE 3. Rela tive Ra tes a n d Activa tion P a r a m eter s
rel rate of methoxide Ea
∆Hq ∆Sq
methoxide, all staggered and eclipsed conformers of the
tetrahedral intermediate formed by the AN + DN mech-
anism, transition states for elimination of fluoride ion,
and products. These structures are graphically repre-
sented in Chart 2.
q
compd substitution at 44.60 °C (kcal/mol) (kcal/mol) (eu)
1Ze
227
59.6
2.84
3.26
74.8
12.1
1.02
1.00
2.84
1.97
15.7
17.0
13.4
16.3
18
-17
1Ee
1Za 27
1Ea 27
1Zh
1Eh
1Zb
1Eb
1Zd
1Ed
-9.9
-10
In these calculations, the phenyl group has been
replaced by a hydrogen for computational expediency and
will be referred to as the “simplified system.” The phenyl
group was included in certain structures to better define
the reaction coordinate in calculations that will be
discussed later. The Cartesian coordinates and total
energies for all structures are included in the Supporting
Information. Calculations were performed using Gauss-
ian 9436 and Gaussian 9837 at the HF/6-31+G(d), MP2/
6-31+G(d)//HF/6-31+G(d), and B3LYP/6-31+G(d)//HF/
6-31+G(d) levels of theory.38,39 In addition, to account for
solvent polarity effects, single-point calculations per-
formed using the self-consistent iterative polarizable
continuum method (SCIPCM)40 on the geometry opti-
mized at the HF/6-31+G(d) level with a dielectric con-
stant (∈ ) 47.0) to reflect that of dimethyl sulfoxide
[HF(scrf)/6-31+G(d), and B3LYP(scrf)/6-31+G(D)//HF/
6-31+G(d)] were also performed. All calculations include
a single methanol molecule to mimic minimal immediate
solvation effects and to stabilize the intermediate struc-
tures. The data for these calculations are also included
in the Supporting Information. Qualitatively, there is
little difference between the reaction coordinates derived
from the different computational levels. Therefore, all
discussion referring to the simplified system will refer
to calculations done at the HF/6-31+G(d) level keeping
in mind that other theory levels provide the same picture
of the reaction.
15.1
17.0
20.7
19.5
20.5
20.2
14.5
16.2
20.4
19.9
19.9
18.9
-15
-14
-5.0
-9.2
-4.7
-8.5
F IGURE 1. Hammett plots (σ) for methoxide substitution of
1Ze-i and 1Ee-I in 90:10 DMSO-MeOH at 26.06 °C. Note:
For illustrative purposes, the 1E plot is ofset by the addition
of one log unit to the log (k/ko) values.
Nucleophilic attack of methoxide ion on O-methylhy-
droximoyl fluoride (the simplified system) would form a
tetrahedral intermediate with single bond character
between carbon and nitrogen. There are three staggered
Interestingly, the hydroximoyl bromides in all in-
stances react approximately 2-3 times faster than the
hydroximoyl chlorides. Ab initio molecular orbital calcu-
lations have indicated that stabilization of a carbon-
carbon double bond by chloride exceeds that by bromide.35
This might also be true of the carbon-nitrogen double
bond, and the difference in rates between the bromide
and chloride may reflect a greater stabilization of the
double bond of the starting material in the hydroximoyl
chloride relative to the hydroximoyl bromide.
(36) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.;
J ohnson, B. G.; Robb, M. A.; Cheeseman, J . R.; Keith, T. A.; Petersson,
G. A.; Montgomery, J . A.; Raghavachari, K.; Al-Laham, M. A.;
Zakzewski, V. G.; Ortiz, J . V.; Foresman, J . B.; Cioslowski, J .; Stefanov,
B. B.; Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala, P. Y.;
Chen, W.; Wong, M. W.; Andres, J . L.; Repogle, E. S.; Gomperts, R.;
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Gordon, S. M.; Gonzalez, C.; Pople, J . A. Gaussian 94, Revision D.3;
Gaussian: Pittsburgh, PA, 1996.
A positive correlation with Hammett σ values, a
measured negative entropy of activation, and an element
effect study that shows rate trends of F . Cl or Br for
the reaction of O-methylbenzohydroximoyl halides with
methoxide in 90:10 DMSO/methanol all support the
proposed addition-elimination mechanism. Although we
previously28 have given possible explanations for the
stereospecificity of these reactions, it seemed worthwhile
to try to obtain a better understanding of these reactions
through theoretical calculations.
(37) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakzewski, V. G.; Montgomery, J . A.,
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Challacombe, M.; Gill, P. M. W.; J ohnson, B.; Chen, W.; Wong, M. W.;
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Ab initio calculations were performed on starting
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2744 J . Org. Chem., Vol. 69, No. 8, 2004

Methoxide Ion Substitution in O-Methylbenzohydroximoyl Halides
CHART 2a
a
Key for structure numbers in Chart 2: Z and E, configuration of hydroximoyl fluoride or hydroximate; SM, starting materials; PROD,
products; TS, transition state; I, tetrahedral intermediate.
conformations (around the C-N bond) for this tetrahe-
dral intermediate that presumably could interconvert by
rotation around the carbon-nitrogen single bond. There
are two other internal rotors within the intermediates
J . Org. Chem, Vol. 69, No. 8, 2004 2745

J ohnson et al.
SCHEME 3
F IGUR E 2. Reaction coordinate for the Z isomer (HF/
6-31+G(d) + ZPVE).
(the oxygen-carbon bond of the C-O-C-N attachment
and the oxygen-nitrogen bond of the C-O-N-C attach-
ment). Conformations were investigated by rotation
around these rotors also. All conformations reported in
this paper resulting from rotation around the C-N bond
represent the structures with the most stable arrange-
ment around the other two internal rotors. The confor-
mations I-A, I-B, and I-C represent the lowest energy
staggered conformations around the C-N bond with the
methanol solvent molecule positioned on the left when
facing down the nitrogen-carbon single bond and I-D,
I-E, and I-F with the methanol molecule on the right.
The tetrahedral intermediate first formed by methox-
ide attack on (Z)-O-methylhydroximoyl fluoride would be
I-C (Scheme 3 and Chart 2). The tetrahedral intermedi-
ate first formed by methoxide attack on (E)-O-methyl-
hydroximoyl fluoride would be I-B (Scheme 3 and Chart
2). Intermediate I-C has a lone pair of electrons on
nitrogen in an antiperiplanar relationship to fluorine. It
is assumed that these electrons in this arrangement could
assist in the departure of fluoride ion from the molecule.
This would result in the Z-isomer of the product (retained
stereochemistry). In I-B, the lone pair electrons are not
in an antiperiplanar relationship, and the barrier to
expulsion of fluoride from this intermediate would be
prohibitively high. I-B must undergo rotation to a
conformation in which lone pair electrons on nitrogen fall
in an antiperiplanar relationship to fluorine before
elimination of fluoride may proceed [either to I-C (leading
to the Z isomer of the product) or I-A (leading to the E
isomer of the product)].
With nucleophilic attack by methoxide on the (E)-O-
methylhydroximoyl fluoride (ESM), intermediate I-B is
formed (Figure 3). This intermediate must undergo
rotation to an intermediate in which lone pair electrons
on nitrogen are in an antiperiplanar orientation to
fluorine. The barrier to rotate to form I-A (through TS-
A, leading to the E isomer of the product and retained
stereochemistry) is only 1.5 kcal. The barrier to rotate
to form I-C (through TS-B, leading to the Z isomer of
the product and inverted stereochemistry) is 9.8 kcal.
These numbers too look qualitatively the same with
solvation by methanol on the other side of the molecule
(0.4 kcal to rotate to the intermediate leading to retained
stereochemistry and 8.9 kcal to rotate to the intermediate
leading to inverted stereochemistry).
By these values, one would anticipate sole formation
of the E isomer of the product. This is not what is seen
experimentally with approximately 15% of the product
exhibiting inverted stereochemistry (Z isomer of the
product). It is likely that the phenyl group that had been
eliminated from these calculations might affect the
relative heights of these rotational barriers (TS-A and
TS-B). In TS-A, the replacement of phenyl by hydrogen
possibly artificially lowers that barrier relative to TS-B.
As seen in Figure 4, there is likely to be steric and
electron-electron repulsive interaction present in TS-A
with a phenyl group (TS-A-P h ) that would destabilize
this transition state. In TS-B-P h , the effect of the phenyl
group would not be as dramatic.
It appears that upon formation of I-C by nucleophilic
attack of methoxide on the Z isomer of the starting
material, the barriers to convert (going through TS-B
leading to I-B or through TS-C leading to I-A) to the
other conformations are relatively high (10.9 and 11.7
kcal, respectively) (Figure 2). This is qualitatively the
same with solvation by methanol on the other lobe of
nitrogen (10.4 and 9.4 kcal, Chart 2). The barrier to
elimination of fluoride from I-C is only 2.8 kcal. It
appears that after nucleophilic attack by methoxide on
(Z)-O-methylhydroximoyl fluoride (ZSM) forming I-C,
elimination of fluoride would proceed at a much faster
rate than would rotation around the C-N bond. This
would lead to completely retained stereochemistry in the
product and helps to explain the experimental observa-
tions.
Calculations with the phenyl in place were carried out
for TS-A, TS-B, I-B, and TS-ESM but only done at the
HF/3-21G level because of the complexity of the struc-
tures (titled TS-A-P h , TS-B-P h , I-B-P h , and TS-ESM-
P h in the Supporting Information). Here, TS-A (barrier
height ) 7.5 kcal) turns out to be only 3.3 kcal lower in
energy than TS-B (barrier height ) 10.8 kcal) as opposed
to an 8.3 kcal difference between these two transition
states with the phenyl replaced by hydrogen (Figure 3).
This barrier difference qualitatively better accounts for
the experimental findings of approximately 85:15 E/Z
product distribution.
The calculated barriers for nucleophilic attack of
methoxide in the simplified system showed the barrier
for attack of methoxide on the E isomer of the starting
material to be 2.7 kcal lower than that for the Z isomer
2746 J . Org. Chem., Vol. 69, No. 8, 2004

Methoxide Ion Substitution in O-Methylbenzohydroximoyl Halides
F IGURE 3. Reaction coordinate for the E isomer (HF/6-31+G(d) + ZPVE).
sentially no back reaction, these numbers would also
predict essentially no formation of the Z product. It is
felt that the low level of theory, the lack of electron
correlation, and the neglect for the full solvent effects in
these calculations force one to view the data strictly in a
qualitative sense. If one looks at this reaction surface
qualitatively, it appears that I-B sits at the bottom of a
rather deep well, and it does appear that back reaction
of I-B to form starting material could occur a small
percentage of the time. Therefore, despite a lower barrier
to nucleophilic attack in the E isomer, back reaction could
slow the rate of final product formation. This argument
could also account for the smaller experimental element
effect found for the E isomer relative to the Z isomer. In
other words, back reaction of the E isomer could negate
to a degree the influence of the halogen in increasing the
rate of the addition step of the mechanism. With this
interpretation, the experimental and computational find-
ings would be in complete agreement.
In summary, upon nucleophilic attack of methoxide on
the Z-hydroximoyl fluoride, the tetrahedral intermediate
that is formed is oriented such that fluoride ion can be
readily expelled (Figure 2). The barrier for elimination
of fluoride from the simplified intermediate is approxi-
mately 7 kcal lower in energy than either barrier to
rotation. Therefore, the elimination step is so much faster
than the rotation that the reaction proceeds with com-
plete retention of stereochemistry.
F IGURE 4. Effect of the phenyl group on transition state A
vs transition state B.
of the starting material. This does not appear to support
experimental findings as the Z isomer was found to react
faster than the E isomer in all cases. Calculations with
the phenyl group in place, however, appear to help
explain this discrepancy.
As noted before, it appears that once the E isomer
undergoes nucleophilic attack to form the tetrahedral
intermediate (I-B), it faces sizable barriers to rotation
to form product (10.8 kcal to the Z product and 7.5 kcal
to the E product). Interestingly, the barrier for loss of
the attacking nucleophile (back reaction of I-B to ESM)
is 13.1 kcal. This is only 2.2 kcal higher than the barrier
to rotation to the conformation that leads to Z product.
While these numbers quantitatively would predict es-
In the E isomer, the tetrahedral intermediate initially
formed from methoxide attack must rotate into a con-
formation from which fluoride ion can be eliminated. The
calculated barriers including the phenyl indicate that the
first-formed tetrahedral intermediate sits in a fairly deep
well. There is competition at this point between rotation
to the intermediate that leads to E product, rotation to
the intermediate that leads to Z product, and loss of
J . Org. Chem, Vol. 69, No. 8, 2004 2747

J ohnson et al.
from the oven, quickly capped, and brought to room temper-
ature. The hydroximoyl halide was weighed into this 50 mL
flask. The previously prepared DMSO (38 mL) was added to
this 50 mL flask by gently blowing nitrogen into the sealed
DMSO container as DMSO was being removed with volumetric
pipets. The 10 and 25 mL volumetric flasks were removed from
the oven and quickly capped. Standardized sodium methoxide
solution (7 mL) was placed in the 10 mL volumetric flask, and
dry DMSO (10 mL) was placed in the 25 mL volumetric flask
under nitrogen.
All three volumetric flasks were thermally equilibrated for
15 min in a water bath regulated to (0.04 °C which was
checked with a quartz thermometer. The sodium methoxide
solution (5 mL) was pipetted into the 50 mL volumetric flask
containing the hydroximoyl halide and DMSO. Upon emptying
of the pipet, timing was started. The 50 mL volumetric flask
was quickly shaken and filled to the mark with the thermo-
stated DMSO.
Aliquots were taken at regular intervals and were quenched
with an approximately equal volume of an HCl solution of
approximately the same molarity as the sodium methoxide
solution in the 50 mL volumetric flask. A 20 µL portion of each
aliquot was injected onto an octadecyl HPLC column for all
reactions except those involving (E)-O-methylbenzohydroxim-
oyl fluorides. For these reactions, two octadecyl HPLC columns
linked in sequence were necessary to get baseline separation
of the compounds in the reaction mixture. The mobile phase
for each reaction was made of various acetonitrile and water
mixtures. Compounds were detected by a UV-vis detector set
at 254 nm. Normalization factors for peak areas were previ-
ously determined by analysis of samples containing known
amounts of reactants and products. Errors were calculated
from standard deviations at the 95% confidence level. In most
cases, rate constants correspond to an average of a least two
measurements. The errors reported in Table 1 correspond to
the highest error of the averaged measurements.
D. Kin etic Meth od for Rea ction of Sod iu m Meth oxid e
w ith 1Zi a n d 1Ei. The rates of reaction of the bis-trifluoro-
methyl compounds 1Zi and 1Ei with methoxide ion were too
fast to follow using the method described in part C. The rate
constants for 1Zi and 1Ei were obtained by competition
experiments with (Z)- or (E)-O-methyl-4-chlorobenzohydrox-
imoyl fluoride (1Zf or 1Ef). The following equation43 was used
to calculate the rate constants for 1Zi:
methoxide to reform starting material. The lowest barrier
to rotation is the route that leads to the E product, and
this is the product that is preferentially formed experi-
mentally. The competing back reaction to starting mate-
rial slows the reaction down and diminishes the rate
enhancement of replacing the leaving group from chlorine
(or bromine) to fluorine.
Exp er im en ta l Section
A. Gen er a l P r oced u r es. All chemicals used in this re-
search are reagent grade except as noted. (Z)-O-Methyl-4-
methoxybenzohydroximoyl bromide (1Zd ) and (Z)- and (E)-O-
methyl-4-methoxybenzohydroximoyl chloride (1Eb) were syn-
thesized by procedures described by J ohnson et al.19 Isomer-
ization of the hydroximoyl bromide 1Zd and separation of the
isomers to prepare 1Ed were performed by procedures de-
scribed by Sakamoto et al.41 Isomerization of the hydroximoyl
chloride 1Zb to form 1Eb was performed as outlined by
J ohnson et al.,19 substituting hexane for the solvent. The
hydroximoyl fluorides 1Ze, 1Ee, 1Zf, 1Ef, 1Zg, 1Eg, 1Zh , and
1Eh were synthesized as previously published.42 The benzo-
hydroximates 1Zj-m and 1Ej-l were prepared according to
literature procedures (1Zj,44 1Ej,44 1Zk ,45 1Ek ,45 1Zl,44 1El,44
and 1Zm 45). Compounds 1Zi, 1Ei, 1Em , 1Zn , and 1En have
not been previously prepared and are described below. One of
the isomers of methyl O-methyl-p-methoxybenzohydroximate
was prepared by Beart and Ward45 from the reaction of
diazomethane with p-methoxybenzohydroxamic acid. Although
Beart and Ward did not assign the configuration of their
product (1Zm or 1Em ), it is likely to be the Z isomer since a
recent report by Liguori et al.46 (who did not cite the work of
Beart and Ward) has shown that the reaction of diazomethane
with benzohydroxamic acids gives Z-hydroximates (such as
1Zk ). The configurational assignments for 1Zm and 1Em
prepared in this work were made by comparing the chemical
shifts of the hydroximate methoxy groups (further downfield
in the Z isomer)47 and the ortho hydrogens of the aromatic
ring (further downfield in the E isomer) of the two isomers.
Photochemical isomerizations of hydroximoyl chlorides and
fluorides were carried out in quartz tubes placed in a photo-
chemical reactor fitted with low-pressure lamps (254 nm).
Melting points are uncorrected.
B. P r ep a r a t ion of Solu t ion s a n d Solven t s Used for
Kin etics. Dimethyl sulfoxide (HPLC grade) was stored over
k1Zf/k1Zi ) log of fraction of 1Zf remaining/
log of fraction of 1Zi remaining
dried 4A molecular sieves in
a dried three-neck round-
bottomed flask fitted with a CaCl2 drying tube (which was
sealed to the outside environment when solvent was not being
transferred) and two greased ground glass stoppers.
The sodium methoxide solutions were prepared by reaction
of sodium with methanol (distilled from magnesium metal).
The sodium methoxide solutions were titrated with standard-
ized HCl solutions.
C. Kin etic Meth od . This method was used for all runs
except those measured on either (Z)- or (E)-(3,5)-bistrifluo-
romethyl-O-methylbenzohydroximoyl fluoride.
A similar equation was used to calculate the rate constant
for 1Ei.
E. P r ep a r a tion of New Com p ou n d s. (Z)-O-Meth yl-3,5-
b ist r iflu or om et h ylb en zoh yd r oxim oyl Ch lor id e (1Zo).
Methyl 3,5-bistrifluoromethylbenzohydroxamate (4.00 g, pre-
pared from 3,5-bistrifluoromethylbenzoyl chloride and meth-
oxylamine) was placed in a 50-mL three-neck round-bottomed
flask fitted with a condenser, a calcium chloride drying tube,
and a solid addition funnel. Phosphorus pentachloride (3.12
g) was added through the solid addition funnel with stirring.
The mixture was stirred and heated at 100 °C for 3 h. After
the mixture was allowed to cool to room temperature, it was
poured into cold water (50 mL). The solution was extracted
with chloroform (3 × 150 mL). The chloroform extracts were
dried, and the chloroform was removed. The residual oil was
vacuum distilled to give a clear liquid (1.02 g, 23%): 1H NMR
(90 MHz, CDCl3) δ 4.15 (s, 3H), δ 7.85 (s, 1H), δ 8.30 (s, 2H);
IR (neat) 1619 cm-1; Anal. Calcd for C10H6NOF6Cl: C, 39.30;
H, 1.98; N, 4.58; F, 37.30; Cl, 11.60. Found: C, 39.38; H, 1.89;
N, 4.37; F, 37.08; Cl, 11.90.
One 50 mL, one 25 mL, and one 10 mL volumetric flask
were dried in a 100 °C oven. The 50 mL flask was removed
(41) Sakamoto, T.; Okamoto, K.; Kikugawa, Y. J . Org. Chem. 1992,
57, 3245-3248.
(42) Rowe, J . E.; Lee, K.; Dolliver, D. D.; J ohnson, J . E. Aust. J .
Chem. 1999, 52, 807-811.
(43) Gould, E. S. Mechanism and Structure in Organic Chemistry;
Holt, Rinehart, and Winston: Chicago, 1959; p 173.
(44) J ohnson, J . E.; Nalley, E. A.; Kunz, Y. K.; Springfield, J . R. J .
Org. Chem. 1976, 41, 252-259.
(45) Beart, P. M.; Ward, A. D. Aust. J . Chem. 1974, 27, 1341-1349.
(46) Leggio, A.; Liguori, A.; Sicilliano, C.; Sindona, G. J . Org. Chem.
2001, 66, 2246-2250.
(47) J ohnson, J . E.; Springfield, J . R.; Hwang, J . S.; Hayes, L. J .;
Cunningham, W. C.; McClaugherty, D. L. J . Org. Chem. 1971, 36, 284-
294.
(Z)-O-Meth yl-3,5-bistr iflu or om eth ylben zoh yd r oxim o-
yl Br om id e (1Zp ). Methyl 3,5-bistrifluoromethylbenzohy-
droxamate (10.02 g) was placed in a 250-mL three-neck round-
bottomed flask fitted with a condenser, a calcium chloride
2748 J . Org. Chem., Vol. 69, No. 8, 2004

Methoxide Ion Substitution in O-Methylbenzohydroximoyl Halides
drying tube, and a solid addition funnel. The solid was stirred
as phosphorus pentabromide (15.08 g) was added through the
solid addition funnel. The mixture was stirred and heated at
80 °C for 3 h. After the mixture was allowed to cool to room
temperature it was poured into cold water (100 mL). The
solution was extracted with ether. The ether extracts were
dried, and the ether was removed. The residual oil was vacuum
distilled to give a clear liquid (7.40 g, 60%): 1H NMR (90 MHz,
CDCl3) δ 4.19 (s, 3H), 7.92 (s, 1H), 8.30 (s, 2H); IR (neat), 1618
cm-1. Anal. Calcd for C10H6NOF6Br: C, 34.31; H, 1.73; N, 4.00;
F, 32.56; Br, 22.83. Found: C, 34.28; H, 1.74; N, 3.95; F, 32.19;
Br, 22.91.
(Z)-O-Meth yl-3,5-bistr iflu or om eth ylben zoh yd r oxim o-
yl F lu or id e (1Zi). (Z)-O-Methyl-3,5-bistrifluoromethylbenzo-
hydroximoyl bromide (3.01 g) was dissolved in 20 mL of DMSO.
Potassium fluoride (2.00 g) was dissolved in DMSO (60 mL)
and placed in a 250-mL three-neck round-bottomed flask fitted
with a condenser and a calcium chloride drying tube. The
hydroximoyl bromide was then added into the reaction flask.
The mixture was stirred and heated at 100 °C for 22 h under
a slow nitrogen purge. After the reaction was complete, 80 mL
of saturated sodium chloride solution was added into the flask.
The solution was extracted with ether. The ether extracts were
dried, and the diethyl ether was removed. The residual oil was
vacuum distilled to give a clear liquid (2.41 g, 97%): 1H NMR
(90 MHz, CDCl3) δ 4.03 (s, 3H), 7.95 (s,1H), 8.20 (s, 2H); IR
(neat) 1648 cm-1. Anal. Calcd for C10H6NOF7: C, 41.54; H,
2.09; N, 4.84; F, 45.90. Found: C, 41.36; H, 2.18; N, 4.84; F,
45.80.
4.00 (s, 3H), 7.72 (s,1H), 8.10 (s, 2H); IR (neat) 1632 cm-1. Anal.
Calcd for C11H9NO2F6: C, 43.87; H, 3.01; N, 4.65; F, 37.85.
Found: C, 43.73; H, 3.04; N, 4.57; F, 37.69.
Meth yl (E)-O-Meth yl-3,5-bistr iflu or om eth ylben zoh y-
d r oxim a te (1En ). The E-hydroximate 1Zn (1.50 g) was
dissolved in glacial acetic acid (30 mL) and placed in a 50 mL
round-bottomed flask. The reaction solution was stirred and
heated at 80 °C for 4 h. After reaction was complete, the
reaction solution was neutralized with 6 N sodium hydroxide
in an ice-water bath. The solution was then extracted with
ether. The ether extract was dried, and the ether was removed.
An analysis of the mixture by GC-MS showed that it was a
mixture of 1Zn and 1En in a 50:50 ratio. The E isomer (1En )
was separated from the mixture by column chromatography
(silica gel, 70-130 mesh) using 1:6 chloroform/hexane as the
mobile phase. After column chromatography, the solvent was
removed, and the residual oil was vacuum distilled to give a
clear liquid (0.64 g, 42%): 1H NMR (90 MHz, CDCl3) δ 3.88
(s, 6H), 7.90 (s, 1H), 8.26 (s, 2H); IR (neat) 1613 cm-1. Anal.
Calcd for C11H9NO2F6: C, 43.87; H, 3.01; N, 4.65; F, 37.85.
Found: C, 43.82; H, 3.09; N, 4.68; F, 37.76.
Met h yl (Z)-O-Met h yl-4-m et h oxyb en zoh yd r oxim a t e
(1Zm ). Reaction of (Z)-O-methyl-4-methoxybenzohydroximoyl
bromide with sodium methoxide in DMSO/methanol solution
gave 1Zm 46 as a colorless liquid (purified by column chroma-
tography): 1H NMR (300 MHz, CDCl3) δ 3.815, 3.898 (two s,
6H), 3.903 (s, 3H), 6.89 (d, 2H, J ) 9.1 Hz), 7.58 (d, 2H, J )
9.1 Hz); 13C NMR (300 MHz, CDCl3) δ 55.16, 59.14, 62.13,
113.67, 122.47, 155.32, 160.93); IR (Nujol) 1609 cm-1
.
(E)-O-Meth yl-3,5-bistr iflu or om eth ylben zoh yd r oxim o-
yl F lu or id e (1Ei). (Z)-O-Methyl-3,5-bistrifluoromethylben-
zohydroximoyl fluoride (2.00 g) was dissolved in benzene (80
mL) and placed in six 20-mL quartz test tubes. The test tubes
were irradiated at 254 nm for 6 h. Immediately after irradia-
tion, the benzene solution was extracted with a saturated
solution of sodium carbonate (2 × 100 mL). The benzene
extract was dried, and the benzene was removed. A GC-MS
analysis showed that it was a mixture of 1Zi and 1Ei in a
ratio of 60:40, respectively. The E isomer (1Ei) was separated
from the mixture by preparative GC.44 A clear liquid product
was collected (0.51 g, 26%): 1H NMR (90 MHz, CDCl3) δ 4.00
(s, 3H), 8.00 (s,1H), 8.45 (s, 2H); IR (neat), 1737 cm-1. Anal.
Calcd for C10H6NOF7: C, 41.54; H, 2.09; N, 4.84; F, 45.90.
Found: C, 41.39; H, 2.10; N, 4.81; F, 45.41.
Meth yl (Z)-O-Meth yl-3,5-bistr iflu or om eth ylben zoh y-
d r oxim a te (1Zn ). Sodium metal (0.88 g) was dissolved in
methanol (30 mL) in a 250-mL three-neck round-bottomed
flask fitted with a condenser and a calcium chloride drying
tube. The hydroximoyl chloride 1Zo (1.15 g) was dissolved in
DMSO (30 mL) and added to the reaction flask. The mixture
was stirred and heated for 2 h at 50 °C under a slow purge of
nitrogen gas. After the reaction was complete, ice-water (60
mL) was added into the flask, and the mixture was extracted
with ether. The ether extract was dried, and the ether was
removed. The residual oil was vacuum distilled to give a clear
liquid (0.86 g, 76%): 1H NMR (90 MHz, CDCl3) δ 3.78 (s, 3H),
Met h yl (E)-O-Met h yl-4-m et h oxyb en zoh yd r oxim a t e
(1Em ). Isomerization of 1Zm in glacial acetic acid gave a
mixture of 1Zm and 1Em . Separation of the isomers by column
chromatography gave 1Em as a colorless liquid: 1H NMR (300
MHz, CDCl3) δ 3.806, 3.812, 3.815 (three s, 9H), 6.90 (d, 2H,
J ) 8.9 Hz), 7.76 (d, 2H, J ) 8.9 Hz); 13C NMR (300 MHz,
CDCl3) δ 54.45, 55.20, 62.05, 113.15, 121.84, 130.54, 158.45,
160.71; IR (neat) 1609 cm-1. Anal. Calcd for C10H13NO3: C,
61.53; H, 6.71; N, 7.17. Found: C, 61.70; H, 6.79; N, 7.13.
Ack n ow led gm en t is made to the Minority Biomedi-
cal Research Support Program of the National Institutes
of Health (NIH-MBRS Grant No. GM08256), The Robert
A. Welch Foundation, and the Texas Woman’s Univer-
sity Research Enhancement Program for support of this
work. J .E.R. thanks the Texas Woman’s University for
hospitality during the completion of part of this work.
Su p p or tin g In for m a tion Ava ila ble: Rate constants for
reactions of sodium methoxide with O-methylbenzohydroxim-
oyl halides. Coordinates of all optimized HF/6-31+G(d) and
HF/3-21G structures (ground states and transition states) and
their energies. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O030299E
J . Org. Chem, Vol. 69, No. 8, 2004 2749