J. Phys. Chem. 1994, 98, 11705-11713
11705
A Theoretical Study of Spin Trapping by Nitrone: Trapping of Hydrogen, Methyl, Hydroxyl, and Peroxyl Radicals Susan L. Boyd'J and Russell J. Boyd* Department of Chemistry, Mount Saint Vincent University, Halfm, Nova Scotia B3M 2J6, Canada, and Department of Chemistry, Dalhousie University, Halgm, Nova Scotia B3H 4J3, Canada Received: June 20, 1994; In Final Form: August 16, 1994@
The geometries and energetics of the spin trapping reaction of the nitrone function have been determined using a b initio methods at the Hartree-Fock and second-order Maller-Plesset levels with the 6-3 1G(d) and 6-31G(d,p) basis sets. Radicals ('H, 'CH3, 'OH, and 'OOH), the prototype nitrone spin trap (H2C=NHO), and the resultant spin adducts were examined to ascertain the most probable site of radical addition, the minimum-energy geometries of the adducts, and the energy changes involved in the addition reaction. The calculations show that addition clearly favors the C-site of the nitrone, with the 0-site being the second location when double spin adducts form; this supports experimental observations. Double spin adducts are energetically preferred over monoadducts. Addition at the C-site is highly exothermic, with no activation energy barrier for any of the radicals studied.
Introduction Electron paramagnetic resonance (epr) is a technique for detection and identification of relatively stable free radicals. But if a radical is short-lived, a method known as spin trapping1t2 allows its analysis by epr: spin trapping entails addition of the reactive radical to another reagent (the "spin trap") to produce a more stable radical (the "spin adduct"). In particular, since the pioneering work of Iwamura and Inamot0~9~ C-phenyl-Ntert-butylnitrone (PBN) has been used as a spin trap to add a variety of radicals, producing the corresponding nitroxide (also known as nitroxyl or aminoxyl) spin adducts: 0'R
+ CsHs -CH
=N -C(CH3)3
PBN
' 0 I
I
4
CsHS-CH -N-C(CH& I
R nitroxide adduct
where 'R = CEN-C(CH3)3, CH~O-C(O)-C(CH~)Z,~,~ methyl, ethyl, n-butyl, phenyl, b e n ~ y lfluoro, ,~ chloro? ~uccinimidyl,~ alkoxyl,*h y d r ~ x y land , ~ peroxyl1° radicals. In addition to PBN, many other nitrones have been used, including 5,5-dimethyl-l-pyrroline 1-oxide (DMPO)," tertb~tylnitrone,~(3,5-di-tert-butyl-4-hydroxyphenyl)tert-butylnitrone,12(2,4,6-trimethoxyphenyl)tert-butylnitrone, l3 and methyl-N-durylnitrone.lo In this project, we have used the simple unsubstituted nitrone (HzC=NHO) as a prototype for the more highly substituted spin traps, which are too large to be treated by ab initio methods. Although nitrone has not yet been observed e~perimentally'~ and is likely to be extremely reactive, its 1,3-dipolarnature has been the subject of many theoretical s t u d i e ~ , ' ~and - ~there ~ is considerable debate as to whether its behavior is best described by considering it as a zwitterion or as a singlet diradical, i.e.,
+ Mount Saint Vincent University. t Dalhousie University. @Abstractpublished in Advance ACS Abstracts, October 1, 1994.
Its exact nature is not critical to us, however, since it is the common "starting material" for all the addition reactions we are examining, and we focus on the relative energy changes for these additions. Thus we have assumed zwitterionic character and have optimized nitrone using the restricted Hartree-Fock function;17all energies are given relative to this optimized structure. Our work examines three aspects of the spin-trapping reaction by nitrone. Firstly, it is widely recognized that the reacting radical adds to the a-carbon on nitrones. Thus we consider the geometries and energetics of the addition reactions to the a-C, as well as to the 0- and N-sites of nitrone using the hydrogen atom, the methyl radical, and the hydroxyl radical. Secondly, double spin adducts have been observed for some nitrones,8 in which case the first addition is at the C-site and the second addition occurs at the oxygen atom of the nitroxide adduct. 0I
RCH=NR
+
+
Z'C(CH&CN
-
OC(CH&CN
I
RCHNR
I
C(CH&CN
In no case has addition to the N of the nitrone been observed. Mixed double spin adducts involving hydrogen, methyl, and hydroxyl radicals were therefore examined to ascertain if any preference exists regarding the site of addition for a given radical. Finally, peroxyl radicals appear to be trapped less readily than the corresponding hydroxyl radicals; in particular, PBN cannot be used in model membrane studies to trap peroxyl radicals and does not affect the inhibition of oxygen uptake? This may be due to the relative rate constants for spin-trapping, with the rate constant for peroxyl radicals lower than that for the corresponding alkoxyl radical. Comparison of the profiles for the reactions of hydrogen, methyl, hydroxyl, and peroxyl radicals with nitrone was therefore undertaken and is reported herein. In other systems, peroxyl spin adducts have been found to be very unstable and either to be replaced by the alkoxyl radical spin a d d u ~ t *or~ to . ~decompose ~ to benzoyl terr-butyl nitroxide and alkoxyl radicals.1° A theoretical investigation of the
0022-365419412098-11705$04.50/0 0 1994 American Chemical Society
Boyd and Boyd
11706 J. Phys. Chem., Vol. 98, No. 45, 1994
TABLE 1: Starting Materials Optimized Species’ Bond Lengths
(A> nitrone
Dipole Moment
Selected Pami eters
CN NO
1.269 1.254
Bond Angles (deg) CNO CNH, NCH,
128.3 116.5 118.9
Dihedral Angles (den) ON(C)H, + 180.0 ONCH, +180.0
(a.u.) C N 0
0.0 0.0 0.0
C (+0.216) N -0.016 0 -0.593 HI +0.393
1.073
HCH
-168.80921 -169.31426
SCF
-0.49823
0
SCF
-39.55899 -39.69270
0
-75.38228 -75.53192
1.89
-150.17053 - 150.50768
2.10
120.0
MP2
*OH
0 H h
OH
0102 0,H
0 +1.051 H -0.051
0.959
1.309 0.954
OOH
105.6
0,+0.920 0 2 +0.090 H -0.011
II
I1 EC SCF MP2
0 -0.444
H +0.444
0,-0.076 0 2 -0.392 H +0.468
4.47
SCF MP2
*H
CH
(D)
a S ~ c t u r e swere optimized at the HF/6-31G(d) level and have no imaginary frequencies; Le., they are in minimum energy conformations. Mulliken population analysis. The values for C are in parentheses as they include the values for attached H; i.e., the spin and charge populations for the H are summed to the C. e 1 au = 2625.5 kJ/mol. The MP2 energies are single point energies obtained with the 6-31G(d.p) basis set at the 6-31G(d) optimized geometry, Le., MW6-3 lG(d,p)//HF/6-31G(d).
possible mechanism for decomposition or rearrangement of the peroxylnitrone adduct will be described in a subsequent communication.
Computational Methods Calculations were performed at the unrestricted Hartree-Fock (denoted by HF throughout this paper) and second-order Mdler-Plesset (MP2) levels using the GAUSSIAN 9024 computer program. Standard 6-3 1G(d) basis sets25were used for all geometry optimizations, and single point energies were determined at the MP2/6-3 lG(d,p)//HF/6-31G(d) level. When appropriate, the existence of multiple stable rotamers was investigated. Spin contamination was observed to be fairly small ((S2) ranged from 0.761 to 0.766) and, therefore, no attempt was made to project out spin contamination. All optimized structures were checked by vibrational frequency analysis at the 6-31G(d) level to confirm that a minimum energy conformation had been located. Spin and charge populations were obtained by Mulliken population analyses.
Results and Discussion For convenient reference, the optimized structures and energies of all “starting materials” are presented in Table 1. The dipole moment (,u = 4.47 D) of the parent nitrone (H2C=N(O)H) results from the electronegative 0 (charge population = -0.593) withdrawing electron density from the N (charge population = -0.016), which in turn pulls electron density from the H atom and the CH2 group (charge population = +0.393 and +0.216, respectively). This high polarity might account in part for the instability of nitrone14 and also for the recognized tendency for polymerization of nitrones which have
small substituents. Indeed, as shown in Table 2, addition of substituents does appear to lower the polarity slightly: Nmethylnitrone has p = 4.46 D; C, N-dimethylnitrone has p = 4.35 D; and C-vinyl-N-methylnitronehas p = 4.32 D. a. Site for Radical Trapping. Data on the hydrogen radical adducts of nitrone are given in Table 3. It is interesting that while H+ addition (Le., protonation) of nitrone favors the O-site,14 ‘H addition clearly favors the C-site. (A&p2 for addition at the C-site is -244 kJ/mol, as compared to that for addition at the 0-site, - 149 kJ/mol, or the N-site, - 10 kJ/mol.) In the case of the ‘H radical addition to the C-site, the adduct has spin population associated primarily with the 0 (0.73) and to a lesser extent with the N (0.30), suggesting the following resonance contributors: 0
:0: H3C -N:
I
I
H -70%
-
0.
:0:-
I
H3C -NO+
I
H -30%
This localization of spin on the oxygen contradicts the polarizedneutron-diffraction result?6 which indicates almost equal distribution of the spin population between the N and the 0. Iterative configuration interaction methods with good quality basis sets have been found to predict the spin partitioning more a~curately;~’ however, although the actual distribution differs, the same trends are observed with Mulliken spin populations. The ‘H radical adduct is quite polar, but its dipole moment (p = 2.93 D) is much lower than that of the starting nitrone (,u = 4.47 D); the 0 is negatively charged (-0.332), as is the N (-0.279), leaving the H on the N, and also the methyl group, positive (4-0.365 and 4-0.247, respectively). When the ‘H radical adds to the 0, the spin population goes almost exclusively to the C (0.97),
J. Phys. Chem., Vol. 98, No. 45, 1994 11707
A Theoretical Study of Spin Trapping by Nitrone H I H-C-N:
t.6-H
0
a
I
=
I
H
-100
v
?
and the charge is more evenly distributed (OH, -0.154 and CH2, +0.162); this adduct has a much lower dipole moment (p = 1.15 D), and the CN bond is shorter. The N adduct of 'H also concentrates the spin population on the C,
2-z
-200
-r I
?5 >
-300
P
W C
-400
I
H-$-N+-H
I
-500
I
0.80
1.20
1.60
2.00
H C-H Distance
while the charge population shifts to the 0 (0,-0.655 and CH2, +0.246), producing a highly polar species (,u = 4.86 D). In terms of planarity at the nitrogen?8 the C-site adduct is the most nearly planar of the three adducts considered: the ON(C)H dihedral angle is 146.1' for the C-site adduct (this would be 180" for a planar species and 120' for a tetrahedral or trigonal bipyramidal one), while for the 0- and N-sites it is 117.7" and 121.3", respectively. Most spin-trapping observations are made either in aqueous solution or in heterogeneous systems in contact with aqueous phases. Given the larger dipole moment of the C-adduct over that of the 0-adduct of 'H with nitrone, we expect that, were medium effects to be considered, the C-adduct would be even more energetically favored than suggested by our gas-phase data. The results for the addition of the 'CH3 radical to nitrone closely parallel those for addition of the 'H radical, as can be seen in Table 4. Thus, C-site addition is energetically favored ( A E m = -221 kJ/mol) compared to addition at the 0-site ( A E m = -84 kJ/mol) or the N-site (AEm= +9 kJ/mol). The C-adduct has spin population primarily at the 0, and most of the negative charge is on the 0 as well, making the adduct quite polar = 2.90 D). The 0-adduct has spin population concentrated on the C, fairly even charge distribution, and is a relatively nonpolar species (p = 0.97 D). The N-adduct with spin population almost exclusively on the C is highly polar (p = 4.67 D). Finally, an analogous study of the hydroxylnitrone adduct shows an even stronger relative preference for addition to the C-site ( A E m = -244 kJ/mol, Table 5). In fact, addition to either the 0- or N-site is endothermic: AE = +76 and +58 kJ/mol, respectively. N-Site addition is actually more favorable than 0-site addition, which contrasts with the situation in the 'H and 'CH3 spin adducts and is due to the unstable 0-0 bond formed when 0-site addition occurs. b. Double Spin Adducts. The properties of double spin adducts are listed in Table 6. Not surprisingly, diadduct formation is highly exothermic. In fact our calculations suggest that formation of a diadduct is favored over formation of two monoadducts; for example, A E m for 2'H H2C=N(O)H CH3--N(OH)H is -574 kJ/mol, whereas for 2'H 2H2C-N(O)H 2CH3-N('O)H it is -488 kJ/mol. It is unlikely that this is an artefact of the reactive prototype trap and radicals used. Nor should the significantly greater exothermicity of the reaction leading to the diadduct (-574 kJ/ mol - (-488 kJ/mol) = -86 kJ/mol) result from the fact that this reaction is not isogyric; exothermicity for nonisogyric reactions of the type R' R" R:R' appears to be either slightly overestimated by MP2/6-3lG(d,p)//HF/6-31G(d) calculations, e.g., A E m - Me,,* -10 kJ/mol for R' = R" = C,29or considerably underestimated, e.g., A E m - A&,, * +25 kJ/mol for R' = C, R" = H.25 Therefore, diadduct
+
-
+
-
b A
E
2.80
(A)
.............................
o -100
2.40
..*'".....*..t ...........
t A
t
h = -221 kJ/mol ...*e
: 2--
-200
2 . 7
E.
-300
2.
P C
-400
I
I
I
I
1.70
2.00
2.30
2.60
-500 I
1.40
2.90
c-c Distance (A)
c n
E
o -100
?
2- -200 2 . A
J -
E.
t
-300
>
....
l...-
P
......9,
c
-400
-500
1.20
1.40
1.60
2.00
1.80
2.20
C-0Distance (A)
d
E
0
Ahn= -141 -100
?
2=
2 . -. + -J
5
1
/-
kl/mol
....... ......w
*.......~.......4,**
-200
t
'.% "% y
-300
2.
....
P C
-400
......
.......
-500
1.20
1.40
1.60
1.80
2.00
2.20
c-0 Distance (A)
Figure 1. Reaction profile for the addition of various radicals to nitrone. The radicals are (a) 'H, (b) *CH3, (c) 'OH,and (d) QOH. Geometric changes as the radical approaches the equilibrium bond distance are shown.
Boyd and Boyd
11708 J. Phys. Chem., Vol. 98, No. 45, 1994
TABLE 2: Substituted NitronesO selected Parameters
Optimized
Charge Populations
Species
Moment
Dihedral Angles (dea)
Bond Angles
Dipole
Energy (a.u.)
@)
~~
methyl nitrone
CIN NO NC,
1.270 1.262 1.463
C,NO C,NC, NC,HI NClH2 NGH,
CIN NO NC, CIC3
1.271 1.272 1.459 1.492
CINO 123.8 C,NC, 122.0 NC,C, 120.0
CIN NO NC, C1C3 C,C,
1.277 1.269 1.460 1.456 1.323
CINO C,NC, NCIC3 C,C,C4
125.0 121.2 120.0 117.8 111.4
ON(CI)C2 ONC,H, ONC2H,
+ 180.0 + 180.0 + 180.0
0 -0.615 N +0.103 CI (+0.204) C2 (+0.308)
SCF
-207.84853
4.46
0 -0.633 N +0.061 CI (+0.192)
SCF
-246.89324
4.35
SCF
-284.74064
4.32
H3 ~~
dimethyl nitrone
methyl vinyl nitrone
ON(C,)C, + 180.0 ONC,C, 0.0 NC,C,H, + 180.0 ONC,H:, +180.0
125.0 121.2 121.9 122.3
ON(C,)C, ONC,C, NC,C,C,
+ 180.0 0.0
+ 180.0
C, (+0.300) C, (+0.081)
0 -0.623 N +0.028 C, (+0.217)
C, +0.303
c,(+O.W) c, (-0.022)
d
See footnotes for Table 1. TABLE 3: *€ Nitrone I Spin Adducts: Hydrogen Radical Optimized Adduct
+ Nitrone - Adduct"
selected parameters
Spin Populations
Charge Populations
EnerlcJ
Moment (a.u.)
CH,N(O)H
CN NO
1.445 1.267
118.4 118.2
ON(C)H, + 146.1 ONCH, -70.4 ONCH, +50.0 ONCH, +168.7
c (-0.006)
SNO
C
H4
CNO CNH, NCH, NCH, NCH,
H3
108.3 109.0
0
+ 0.298 + 0.728
HI -0.020
- 169.42499
- 169.90526
SCF -309 MP2 -244
2.93
SCF MP2
- 169.38330 - 169.86943
SCF -199 MP2 -149
1.15
SCF MP2
4.86
110.7 111.5 115.5 114.4 104.5
ON(C)H, + 117.7 ONCH, +47.2 ONCH, +190.4 CNOH, -123.6
C (+0.967) N +0.009 0 +0.020 H, +O.m H2 -0.003
C (+0.162) N -0.373
OH,
CNO CNH, NCH, NCH, NOH,
CN NO
1.437 1.387
CNO CNH, NCH,
109.6 110.2 113.8
ON(C)H, + 121.3 ONCH, +70.4
c (+l.OIl)
c (+0.246)
N -0.116 0 +0.094 HI +0.005
N -0.374 0 -0.655
p.
qNo
@)
SCF MP2
1.402 1.397 0.947
CN
(kJ/mol)
C (+0.247) N -0.279 0 -0.332 HI +0.365
HZ NO
CH,N(OH)H
0
112.0
N
Dipole
AE
0 -0.609 HI +0.364 HZ +0.455
SCF MP2
- 169.33643 -169.81645
-76 -10
H, +0.392
C
(I
See footnotes for Table 1. AE = energy change for gas-phase species at equilibrium bond lengths, 0 K, Le., AE = Eau* - [Enit"
+
Ehydrogrnl~
formation is probably energetically favored in general. It certainly occurs e~perimentally.~.~ While diadducts go unde-
tected in epr studies since they are epr-inactive, they have been observed using liquid chromatography and mass spectrometry.8
A Theoretical Study of Spin Trapping by Nitrone
TABLE 4: 'CHJ Nitrone Spin Adducts: Methyl Radical Optimized Adduct
+ Nitrone - AdducP
selected Parameters
Bond Lenpths (A) ClN CIC2 NO
1.450 1.526 1.267
J. Phys. Chem., Vol. 98, No. 45, I994 11709
Spin Populations
Bond Angles (dq)
Dihedral Angles (deg)
CINO 118.5 NCIC2 113.4 C,NH, 118.2
ONC,C2 -70.6 ON(C,)H, + 146.6 NC,C,H, + 179.0 ONCIH2 +51.5
AE
Charge Populations
C, (-0.030) N +0.306 0 +0.723 HI -0.021
C, (+0.229) N -0.279 0 -0.337 C, (+0.024) HI +0.363
c, (+0.021)
SCF -208.46311 MP2 -209.09101
Dipole Moments
(kJ/mol)
@)
SCF -249 MP2 -221
2.90
SCF -115 MP2 -84
0.98
SCF -18 MP2 +9
4.67
C, CH2N(OCHy)H
CHZN(O)HCH,
H4
I CIN
1.402
C,N NO NC,
1.439 1.377 1.469
I CINO
C,NO C,NC, NC,H2 NCHy NCH,
CINOCZ - 127.6 ONCIH, + 189.7 ONC,H, +46.5 NOC2H4 + 179.0 ON(Cl)Hl + 117.9
C (+0.965) N +0.011 0 +0.019 C,( -0.004) HI +0.007
C, (+0.162) N -0.359 0 -0.497 C, (+0.333) HI +0.362
108.2 113.3 113.7 113.9 111.1
ON(C)H, + 118.0 ONCIH, +70.7 ON(C,)C, - 122.2 ONC,H, +178.8 ONCIHy -70.2
c, ( + l . O I l )
c, (+0.252)
N
N -0.273 0 -0.655 C, (+0.285) HI +0.391
TABLE 5: 'OH Nitrone Spin Adducts: Hydroxyl Radical Optimized
selected Parameters
(A) HOCH,N(O)H
CN NO, CO,
1.438 1.273 1.389
CN NO, 0102
1.399 1.364 1.397
CN NO, NO2
1.443 1.324 1.395
Bond Angles (dq) CNO,
-
-0.111
0 +0.093 c, (+0.002) HI +0.005
Spin Populations
-75.4 0, NCO2 O,N(C)H, + 142.8 +66.5 NCOZH,
C (+0.018) N +0.264 0, +0.758 0 2 +0.016 HI -0.017 H4 -0.004
CNO, NO102 0,02H, CNH,
113.8 109.9 103.2 114.2
CNOIO, +70.9 N0,02H4 -94.6 O,N(C)H, + 124.8 0,NCH2 +48.4 OINCHy + 191.2
N +0.025 C (+0.964) 0, -0.021 0 2 +0.038 HI +O.OOO H, -0.003
CNO, CNH, CNO,
111.5
O,N(C)O2 122.3 O,N(C)H, +124.0 OINOZH2 +2.9 OINCHy +70.4 OINCH, -72.7
NCO, CO2H2 109.2
~
CH,N(OOH)H
CHZN(0)HOH
110.3 108.4
SCF -208.37505 MP2 -209.00367
Charge Populations
EWY
AEb
Moment.. Dipole
(a.u.)
(kJ/mol)
@)
Dihedral Angles (dd
117.2 117.7 113.5
CNH,
SCF -208.41 198 MP2 -209.03913
+ Nitrone - AdducP
Adduct
Bond Lengths
-
110.6
-
During epr monitoring of spin trapping in biological systems, diadduct formation may be relatively infrequent due to low collision probabilities; Le., the higher concentration of the spin trap over that of the free radical may favor monoaddition. For the mixed 'H and 'CH3 double adduct, double addition is again energetically favored over monoaddition; compare -465
N
c
C (+0.522) N +0.297 0,-0.324 0 2 -0.723 HI +0.373 H, +0.450
SCF -244.28165 MP2 -244.93908
SCF -237 MP2 -244
1.08
N -0.298 C (+0.148) 0,-0.225 0, -0.453 HI +0.370 H2 +0.457
SCF -244.14788 MP2 -244.81722
SCF +I14 MP2 +76
2.44
N +0.069 C (+0.298) 0,-0.657 0 2 -0.589 HI +0.406 H, +0.473
SCF -244.15818 MP2 -244.82396
SCF +87 MP2 +58
2.73
~~
-0.098 (+1.025)
0, +0.068 0 2 +0.004 HI +0.004 H, -0.004
+
kJ/mol (i.e., -221 kJ/mol -244 kJ/mol) for formation of two monoadducts with -55 1kJ/mol for formation of the mixed diadduct. There is regiospecificity as well, since T H 3 addition to the C-site with 'H addition to the 0-site (AE = -551 kT/ mol) is energetically preferred over the reverse (AE = -509 kJ/mol).
Boyd and Boyd
11710 J. Phys. Chem., Vol. 98, No. 45, 1994
+ Radical 2 + Nitrone - DiadductO
TABLE 6: Nitrone Double Adducts: Radical 1
selected Parameters
Optimized
Charge Populations
Adduct
Bond Length!
(A,
Bond Angles (de)
Dihedral Angles
Energy
AEb
Dipole
Moments (a.u.)
(kJlmol)
@I
(de)
di He 0.74
NO CN OH,
1.403 1.448 0.947
ZNO ZNH, VOH2
107.8 109.1 104.4
CNOH2 -123.3 ON(C)H, + 112.4 ONCH, +187.0
2 (+0.207) V -0.385 3 -0.627 HI +0.351 H, +0.454
iCF -170.01 158 uIP2 - 170.52934
SCF -541
C,N NO C,C,
1.453 1.404 1.521
C,NO NC,C, C,C,H, NOH, C,NH,
108.3 111.5 110.5 104.6 108.9
ONC,C, +73.6 C,NOH, 124.4 ON(C,)H, + 112.4 NC,C,H, + 177.7
C, (+0.196)
SCF -209.04954 MP2 -209.71493
SCF -481 MP2 -551
0.70
SCF -209.04015 MP2 -209.69901
SCF -456 MP2 -509
0.56
SCF -248.07781 MP2 -248.88465
SCF -395 MP2 -486
0.57
SCF -244.87139 MP2 -245.56806
SCF -477 MP2 -587
1.64
SCF -244.77507 MP2 -245.47650
SCF -224 MP2 -347
2.58
MP2 -574
H3
+
He
CH.0
CH,CH,N(OH)H
-
C, (+0.014) N -0.389 0 HI
-0.629 +0.353 +0.454
H,
H3
CH,N(OCH,)H
C,N NO
OC,
1.449 1.398 1.398
C,NO NOC, C,NHi NC,H,
107.7 110.1 109.1 108.1
C,NOC, -126.8 ON(C,)H, + 112.4 ONC,H, + 186.5 NOCH, +178.6
C, (+0.208) N -0.373
1.454 1.400 1.398 1.521
C,NO NOC, NC,C, C,C,H, OC,H, C,NH,
107.9 110.2 111.6 110.4 106.4 108.6
C,NOG -135.4 ONC,C, +73.5 NOC,H3 +178.8 NC,C,H, + 177.9 ON(C,)H, + 112.3
C, (+0.196)
0
-0.513 (+0.328) HI +0.350
C,
di CHp
H3
CH,CH,N(OCH,)H
C,N NO
OC, C,C,
HOCH,N(OH)H
H
l
0
C, HI
1.437 1.406 1.391 0.949 0.947
C,NO, NCO, C02H2 CNH, NO,H,
107.3 114.0 108.3 108.7 104.6
CNO,H, - 123.7 0,NC02 -59.0 NCO,H, +61.0 O,N(C)H, + 112.0
0, -0.644 C (+0.494) N -0.387
CN NO,
1.448 1.367 1.404 0.950
CNO, 112.3 Nolo2 110.0 O,O,H, 102.6
CN0,02 +66.9 O,N(C)H, + 119.6 N0,02H2 - 115.4 O,NCH, -181.9
0, -0.230
O,H,
V
N
(+0.019) -0.376 -0.516 (+0.328) +0.349
CN NO, CO, 02H, 0,H3
O,O,
c
C,
0, HI H, H,
c
-0.740 +0.359 +0.457 +0.461
(+0.204) N -0.318 0, -0.470 HI +0.357 H, +0.457
A Theoretical Study of Spin Trapping by Nitrone
J. Phys. Chem., Vol. 98, No. 45, 1994 11711
TABLE 6 (Continued)
I
I
~~
CH,NH(O)OH
HOCH,N(OCH,)H
CNO, 112.9 CNO? 107.5 N0,H2 10C.2
O,N(C)O, - 122.8 O,N(C)H, + 124.8 0 , N 0 , H 2 +2.3
0, -0.666 C (+0.318) N +0.077 0, -0.599
SCF -244.79802 MP2 -245.49950
SCF -284 MP 2 -407
1.67
C,NO, 107.2 NO,C, 110.2 NC,O, 114.0
C,NO,C, - 127.3 O,N(C,)H, + 112.2 OlNC,O2 -59.8 NC,O,H, +60.4
0, -0.533 C, (+0.497) N -0.375 0, -0.741 HI +0.357 H, +0.456 C, (+0.343)
SCF -283.89994 MP2 -284.73778
SCF -392 MP2 -522
1.67
C,N NO,
1.457 1.368 O,O, 1.405 C,C, 1.521
C,NO, NC,C, Nolo2 0,02H,
112.0 111.2 109.8 101.6
C,NO,O, +66.9 O,N(C,)H, + 119.2 NO,O,H, + 118.3 O,NC,C, +67.5
0, -0.236 C, (+0.197) N -0.327 0, -0.472 HI +0.345 H, +0.458 C, (+0.035)
SCF -283.81269 MP2 -284.66160
SCF -163 MP2 -322
2.06
CN NO, CO,
CNO, NO,O, O,O,H, NCOz CO,H,
112.9 110.7 102.5 115.4 109.1
CNO,O, NO,O,H O,NCO, NCO,H, O,N(C)H,
+64.6
0, -0.226
SCF -319.63363 MP2 -320.51431
SCF -157 MP2 -358
1.89
-80.0 +62.8 + 122.1
C (+0.516) N -0.336 0,-0.746 0,-0.488
CN NO,
1.469 1.314
-1 C,N NO, C,Oz O,C,
I CH,CH,N(OOH)H 1-
1.437 1.401 1.392 1.400
di *OH HOCH,N(OOH)H H2
1.441 1.366 1.390 O,O, 1.406
+ 102.4
0 2
The di 'CH3 adduct is also favored ( A E M= ~ ~-486 kJ/mol) over the formation of two monoadducts (2 x -221 kJ/mol = -442 kJ/mol). For the mixed 'H and 'OH adduct, there is a strong preference for the 'OH to add to the C-site and the 'H to the 0-site (-587 kJ/mol) rather than vice versa (-347 kJ/mol); not surprisingly in view of the observation above that N-site addition is favored over 0-site addition for the 'OH radical, double addition involving the 'H on the C- and the 'OH on the N-site (-407 kJ/mol) is preferred over that with the 'H on the C- and the 'OH on the 0-site (-347 kJ/mol). Again, diadduct formation (hE~p2 = -587 kJ/mol) is favored over monoadduct formation (A&p2 = -244 kJ/mol -244 kJ/mol = -488 kJ/mol). By contrast, formation of the di 'OH adduct (A&p2 = -358 kJ/mol), while still very exothermic overall, is not favored over that for two mono 'OH adducts ( A E M= ~ 2~ x -244 kJ/mol = -488 kJ/mol). As noted above, 'OH addition to either the 0-site or the N-site is endothermic, and therefore it is highly unlikely that a second addition will occur unless concentration conditions greatly favor the reaction. This suggests that detection of hydroxyl adducts by epr should be more sensitive than that of hydrocarbon radicals, since the monoadduct concentration is not reduced by competing diadduct formation. For the mixed 'OH and 'CH3 adduct, the hydroxyl radical adds to the C-site and the methyl radical to the 0-site preferentially (AEME= -522 kJ/mol). The reverse is much less energetically favored (AEMR = -322 kJ/mol), which
+
supports the experimental observation that double adducts with a cyanopropyloxyl group (OC(CH&CN) on the C and a cyanopropyl group (C(CH&CN) on the 0 have been detected whereas the reverse has not been found.* c. Reaction Profiles for 'H, 'CH3, 'OH, and 'OOH Addition. One of the aims of this study was to consider why peroxyl radicals are not trapped by nitrones during model membrane studies.*l The three radical series, Le., 'H, 'CH3, and 'OH addition to nitrone, clearly confirm the experimental observation that C-site addition is favored over 0- or N-site addition. Therefore, in our investigation of the nitrone-peroxyl adduct, only C-site addition was investigated. Twenty-seven starting conformations were considered, and eight stationary points were located. These are depicted in Table 7. The energies of these conformers differ only slightly, ranging from A&p2 = -141 kJ/mol to A E m = -123 kJ/mol, and all indicate that the formation of the peroxyl adduct with nitrone is exothermic; peroxyl adduct formation ( A E M= ~ ~-141 kJ/ mol) is, however, less exothermic than the corresponding hydroxyl adduct formation (AEm= -244 kJ/mol). It is notable that the dipole moments for the eight minimum energy conformers vary tremendously (from 1.51 to 3.76 D) because of the highly polar bonds within this adduct; the actual dipole moment for the peroxyl radical should be a weighted average of these and is expected to be high. Since peroxyl radical addition to the C-site of nitrones is energetically favored overall, the question of whether an
11712 J. Phys. Chem., Vol. 98, No. 45, 1994
Boyd and Boyd
TABLE 7: 'OOH Nitrone Spin Adducts: Peroxyl Radical
+ Nitrone -.Adduct"
Optimized Adduct HOOCWO
Spin Populations
Charge Populations
Energy
(kJ/mol)
@)
SCF -155 MP2 -141
2.27
MP2 -319.87553
SCF -319.03968
SCF -157
1.70
MP2 -319.87482
MP2 -139
SCF -319.03878
SCF -155 MP2 -135
3.68
SCF -319.03553
SCF -146
2.79
MP2 -319.87284
MP2 -134
SCF -319.03752 MP2 -319.87265
SCF -152 MP2 -133
2.62
SCF -319.03513
SCF -145 MP2 -132
3.47
MP2 -319.87228
SCF -319.03641 MP2 -319.8701 1
SCF -149 MP2 -126
1.51
SCF -319.03519 MP2 -319.86867
SCF -145
3.76
(a.u.)
Angles (dq)
I
I
CN
2 1
1.433 1.395 1.390
CN 1.428 NO, 1.274 CO, 1.395 0201 1.396
I
I CN
I
n - a
CNO, 119.1 NCO, 113.7 C0203 108.9 0203H2103.5
D,NCO, -82.0 NCO,O, +78.7 C0,03H2 -93.8 D,N(C)H,+ 148.4
C (-0.019) V +0.264
CNO, NCO, CO,O, 020,H2
D,NC02 +69.6 NCO,O, +67.3 CO,O,H, + 126.3 D,N(C)H,+ 146.3
c
118.2 114.4 107.2 101.8
0, +0.767 D, D,
+0.020 -0.001
C (+0.582) N -0.311 0, -0.311
SCF -319.03869
0 2 -0.358 0, -0.440
(+0.021) N +0.237 0, +0.783 0, -0.016 0, -0.003
C (+0.582) N -0.316 0, -0.298 0, -0.351 0 3 -0.466
~~
CNO, NCO, CO,O, O,O,H,
117.6 114.1 107.1 101.8
0,NC02 -75.2 NC0203 -67.9 C0,O1H, - 126.2 O,N(C)H,+ 143.0
c
(-0.017) +0.222 0, +0.7% 0, -0.016 0, -0.003
C (+0.568) N -0.310
O,O,
1.427 1.277 1.397 1.397
CN NO,
1.438 1.264
CNO, 118.4 NCO, 110.9 C0201 108.6 0203H2101.6
D,NCO, + 156.9 NC0203 -69.6 C0,03H, - 121.1 O,N(C)H,+ 151.5
C (-0.014) N +0.311 0, +0.725 0, +0.001
C (+0.580) N -0.284
NO, C02
Dipole
Moment
Dihedral
-A..
AEb
N
MP2 -319.87335
0, -0.291 O2 -0.353 0, -0.465
~~
0201 1.395
I
03 +O.ooO
0, -0.330 0, -0.372 0, -0.437
c
CN NO, CO,
1.429 1.275 1.396 0203 1.393
CNO, 118.6 NCO, 114.0 COzOl 108.6 0203H2102.0
0,NC02 -94.2 NC0203 +66.8 C0203H2+ 115.7 O,N(C)H,+ 145.2
c
CN NO, CO,
CNO, NC02 CO,O, 0,0,H2
O,NCO, + 155.9 NCO,O, +70.24 CO,O,H, + 121.2 O,N(C)H, + 148.6
c
1.441 1.266 1.389 0203 1.397
117.6 110.9 107.3 102.1
(-0.021)
N +0.234 0, +0.789 0, +0.019 0, -0.004
(-0.012)
N +0.305 0, +0.726 0, +0.001 Os +0.001
CN NO, CO,
1.423 1.276 1.407 0203 1.393
CNO, 117.9 NC02 108.4 C020, 106.6 0203H2102.1
0,NC02 -78.4 NC020, - 175.8 C0,0,H2 - 116.8 O,N(C)H,+ 144.2
~
CN NO, CO,
1.423 1.276 1.407 0201 1.394
a
See footnotes for Table 1.
CNO, NCO, CO,O, 0,0,H2
118.1 108.5 106.3 102.0
C (-0.019) N +0.225 0, +0.796 0, +0.010 0, +0.004
(+0.566)
N -0.304 0, -0.292 0, -0.367 0 3 -0.442
C (+0.582) N -0.293 0, -0.330 0, -0.354 0, -0.427
C (+0.582) N -0.321 0, -0.288 0, -0.368 0 3 -0.452
~~
0,NC02 -79.1 NC020, + 179.4 C0203H2+ 124.8 O,N(C)H,+ 144.6
c
(-0.021)
N +0.220 0, +0.800 0, +0.008 0 3 +0.006
C (+0.586) N -0.323 0,-0.283 0, -0.370
4
MP2 -123
-0.451
AE = E a u a - [Enitrone + EmXyl].
activation-energy barrier reduces the relative rate of addition of the peroxyl radical to nitrones was considered. For comparison, similar studies were done for 'H, 'CH3, and 'OH addition. Plots of the reaction profiles for addition of these
radicals to nitrone, with energies determined at the 6-31G(d) level, are given in Figure la-d and include selected geometries of the adduct during its formation. Geometry changes during the addition are as anticipated in all cases, with the planar nitrone
J. Phys. Chem., Vol. 98, No. 45, 1994 11713
A Theoretical Study of Spin Trapping by Nitrone
(2) Janzen, E. G.; Haire, D. L. Two Decades of Spin Trapping. In accepting the incoming radical and becoming nonplanar both Advances in Free Radical Chemistry; Tanner, D., Ed.; JAI Press: Greenat the C (which becomes tetrahedral) and the N (which becomes wich, CT, 1990; Vol. 1, p 253. approximatelytrigonal pyramidal). In no case was an activation (3) Iwamura, M.; Inamoto, N. Bull. Chem. SOC.Jpn. 1967, 40, 702, energy barrier detected; in particular, the theoretical reaction 703. (4) Iwamura, M.; Inamoto, N. Bull. Chem. SOC.Jpn. 1970, 43, 856, profile for addition of 'OOH does not appear significantly 860. different from that of the other adducts. ( 5 ) Janzen, E. B.; Blackbum, B. J. J. Am. Chem. SOC. 1969,91, 5909. These studies suggest that the failure of PBN to affect the (6) Janzen, E. G.; Knauer, B. R.; Williams, L. T.; Harrison, W. B. J. Phys. Chem. 1970, 74, 3025. inhibition of oxygen uptake during model membrane studies is (7) Chalfont, G. R.; Perkins, M. J.; Horsfield, A. J. Chem. SOC. 1970, not due to either inability of nitrones to trap peroxyl radicals or 401. to low spin-trapping rate constants. Indeed, trapping of peroxyl (8) Janzen, E. G.; Krygsman, P. H.; Lindsay, D. A,; Haire, D. L. J. radicals by nitrones has been observed in other systems,l0 Am. Chem. SOC. 1990, 112, 8279. (9) Kotake, Y.; Janzen, E. G. J. Am. Chem. SOC.1991, 113, 9503. although the adduct appears to be u n ~ t a b l e . We ~ ~ hypoth~~~,~~ (10) Niki, E.; Yokoi, S.; Tsuchiya, J.; Kamiya, Y. J. Am. Chem. SOC. esize, therefore, that the peroxyl radical and the PBN must be 1983, 105, 1498. physically separated by the medium in the model-membrane ( 1 1 ) Kim, K. S.; Lim, S. C.; Hoshino, M.; Kim, Y. H. J. Phys. Org. Chem. 1990, 3, 482. systems such that they do not contact one another; possibly the (12) Pacifici, J. G.; Browning, H. L., Jr. J. Am. Chem. SOC.1970, 92, spin trap embeds its hydrophobic C- end inside the membrane 523 1. with its hydrophilic NO- end at the surface, so that the C(13) Janzen, E. G.; DuBose, C. M.; Kotake, Y. Tetrahedron Lett. 1990, site is not accessible for binding with the peroxyl radical.30 31, 7395. (14) Strautmanis, J. R.; Peterson, M. R.; Csizmadia, I. G. J. Mol. Struct.
Conclusions In the formation of nitrone adducts, ab initio studies indicate that there is a strong preference for radicals to add to the C of the nitrone spin trap. If a second addition occurs, it is to the 0 of the nitrone. Double adducts are in general energetically preferred over monoadducts, except when formation of the double adduct requires creation of an 0-0 bond, as in the addition of an alkoxy1 radical to the 0 of nitrone. Adduct formation in all cases is highly exothermic and occurs with no activation energy barrier, so that the inability of nitrones to trap peroxyl radicals during model-membrane studies cannot be due to either thermodynamic or kinetic effects; it must instead simply result from physical separation of the nitrone molecules and the peroxyl radicals within the model-membrane system. Acknowledgment. The financial support of the Natural Sciences and Engineering Research Council of Canada (to R.J.B.) and the Research Fund of MSVU (to S.L.B.) is gratefully acknowledged. References and Notes (1) Janzen, E. G. Acc. Chem. Res. 1971, 4, 31.
(THEOCHEM) 1988, 170, 75. (15) Houk, K. N.; Yamaguchi, K. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A,, Ed.; Wiley: New York, 1985; Vol. 2, p 407. (16) (a) McDouall, J. J. W.; Robb, M. A. Chem. Phys. Lett. 1986, 132, 319. (b) McDouall, J. J. W.; Robb, M. A. Chem. Phys. Lett. 1987, 142, 131.
(17) Kahn, S. D.; Hehre, W. J.; Pople, J. A. J. Am. Chem. SOC.1987, 109, 1871. (18) Ohanessian, G.; Hiberty, P. C. Chem. Phys. Lett. 1987, 137, 437. (19) Cooper, D. L.; Gerratt, J.; Raimondi, M.; Wright, S. C. Chem. Phys. Lett. 1987, 138, 296. (20) Steinke, T.; Hansele, E.; Clark, T. J. Am. Chem. SOC.1989, 111, 9107. (21) Barclay, L. R. C. Personal communication. (22) Memtt, M. V.; Johnson, R. A. J. Am. Chem. SOC. 1977, 99, 3713. (23) Howard, J. A.; Tait, J. C. Can. J. Chem. 1978, 56, 176. (24) Frisch, M. J.; Head-Gordon, M.; Trucks, G . W.; Foresman, J. B.; Schlegel, H. B.; Raghavachari, K.; Robb, M. A.; Binkley, J. S.; Gonzalez, C.; DeFrees, D. J.; Fox, D. J.; Whiteside, R. A,; Seeger, R.; Melius, C. F.; Baker, J.; Martin, R. L.; Kahn, L. R.; Stewart, J. J. P.; Topiol, S.; Pople, J. A. GAUSSIAN 90, Revision H; Gaussian, Inc.: Pittsburgh, PA, 1990. (25) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio Molecular Orbital Theory; Wiley: New York, 1986. (26) Brown, P. J.; Capiomont, A,; Gillon, B.; Schweizer, J. Mol. Phys. 1983, 48, 753. (27) Wang, J.; Smith, V. H., Jr. Z. Naturforsch. 1993, 48 a, 109 (28) Boyd, S . L.; Boyd, R. J. J. Phys. Chem. 1994, 98, 1856. (29) Martell, J. M.; Boyd, R. J. J. Phys. Chem. 1992, 96, 6287. (30) Eriksson, L. A. Personal communication.
