J. Phys. Chem. 1995, 99, 5956-5960
5956
Theoretical Study of Tautomerism in the Reduced Forms of 1,4-Disubstituted Anthraquinones John 0. Morley Chemistry Department, University of Wales, Swansea, Singleton Park, Swansea SA2 8PP, U.K. Received: November 22, 1994; In Final Form: January 27, 1995@
Calculations are reported on the gas phase structures and tautomeric preferences of the reduced or leuco forms of lP-dihydroxy- and 1,4-diaminoanthraquinoneusing both the AM1 method and the 3-21G basis set. The results show that 2,3-dihydro-9,10-dihydroxy-1,4-anthraquinone is preferred in the former case and 1,4diamino-2,3-dihydro-9,lO-anthraquinone in the latter, in line with experimental data recorded in chloroform. The same pattern emerges when the calculations are simulated in water using the COSMO method, though the energy differences among the four possible tautomers of leuco- 1,4-dihydroxyanthraquinoneare reduced while those for leuco- 1,4-diaminoanthraquinoneincrease.
Introduction Substituted anthraquinonesbased on 1,4-dihydroxyanthraquinone (Ia) have occupied an unique place in the field of dyes and pigments because of their brightness and high chemical, photochemical, and thermal Increasingly, however, they are being replaced with azo-dyes such as the phenylazothiophenes, which have much larger extinction coefficients and are easier and considerably less expensive to man~facture.4~~ In contrast, in the pharmaceutical area there is growing interest in their properties, as recent work has shown that the N-alkyl derivatives of a number of closely related systems such as 1,4diaminoanthraquinone (Ib) and 1,4-diamino-5,8-dihydroxyanthraquinone (IC)are chemotherapeutically active as anticancer agents6-10 which act by intercalating with DNA.” For example, both ametantrone (Id) and mitoxantrone (Ie) are highly effective anticancer drugs with an efficacy and therapeutic index exceeding those of adriamycin, methotrexate, or 5-fluorouraci1.9,10.12,13 R1
0
R
A’
0
k
SCHEME 1: Numbering Convention Adopted for the Leucoanthraquinones
for the simpler 1,4-dihydroxyanthraquinone(IC), only one tautomer, 2,3-dihydro-9,1O-dihydroxy1,Canthraquinone (IIa), is found experimentally by NMR studies.I4 In contrast, the preferred tautomeric form of the corresponding leuco- 1,4diaminoanthraquinoneis thought to be 1,4-diamino-2,3-dihydo9,lO-anthraquinone (IIIb) on the basis of ‘H and 13C NMR studies on the closely related leuco derivative (IIIc) of the 1,4bis(buty1amino) derivative (If,) in CDCl3 solution. However, 13CNMR studies on leuco- 1,4-bis(hydrazino)anthraquinone(Ig) in dimethyl sulfoxide-d6 solution appear to show only the 2,3dihydro-9,lO-dihydroxy- 1P-diimine (IId).15 OH
X
0
XH
OH
XH
0
XH
(1)
a: R =OH; R1 = H b: R = NH2; R’ = H C: R = NHp; R’ = OH d: R = NH(CH2)pNH(CH&OH; R’ = H e: R = NH(CH2)2NH(CH2)20H;R1 = O H f: R = NHC4Hg; R’ = H 9: R = NHNHp; R’ = H
Synthetically, almost all of the active 1,4-diaminoanthraquinone drugs are prepared from the corresponding 1,4-dihydroxyanthraquinones by an initial reduction to give the so-called leuco derivatives, which are then reacted with the appropriate alkylamine. The resulting leuco-1,4-dialkylaminoanthraquinonesalso show anticancer activity in some cases,9 though this is less pronounced than that found for the corresponding anthraquinone obtained after ~ x i d a t i o n . ~ - ~ In principle, the technically important leuco derivatives can exist in several possible tautomeric forms, though in practice @Abstractpublished in Advance ACS Abstracts, April 1, 1995.
The relative stability of these tautomers has not been established, and the present studies have been carried out to theoretically explore the four possible structures of the leuco derivatives of both 1,4-dihydroxyanthraquinone(IIa-IVa) and 1,4-diaminoanthraquinone (IIb-IVb).
Methods of Calculation The AM1 method16 of the MOPAC program at the ‘precise’ level17 and the 3-21G basis set18 of the GAMESS program19 were used to optimize the structures of the molecules considered
0022-3654/95/2099-5956$09.00/00 1995 American Chemical Society
J. Phys. Chem., Vol. 99, No. 16, 1995 5957
Reduced Forms of 1,4-Disubstituted Anthraquinones
TABLE 1: Calculated Bond Lengths of the Tautomeric Forms of Leuco-1,4-dihydroxyanthraquinone(Ha-IVa) and 1,4-Diaminoanthraquinone(IIb-IVb) Obtained Using the AM1 Methoda bond IIa IIIa IVa Va IIb IIIb IVb Vb Cl-C2 C2-C3 c3-c4 C4-Cl4 C1-C13 C2-H2 C3-H3 C10-C14 ClO-c11 C5-Cll C5-C6 C6-C7 C7-C8 C8-Cl2 Cll-c12 C9-Cl2 C9-Cl3 C13-Cl4 C9-09 c10-010 c1-x1 c4-x4 09-H 010-x X1-H X4-H
1.501 1.505 1.502 1.470 1.472 1.124 1.124 1.388 1.445 1.416 1.380 1.409 1.380 1.415 1.408 1.445 1.387 1.441 1.366 1.365 1.243 1.243 0.971 0.97 1
1.498 1.510 1.497 1.372 1.372 1.124 1.124 1.463 1.476 1.401 1.394 1.395 1.394 1.401 1.401 1.476 1.463 1.459 1.248 1.248 1.357 1.357
1.379 1.414 1.373 1.438 1.442 1.100 1.100 1.408 1.409 1.431 1.366 1.424 1.366 1.432 1.424 1.410 1.409 1.430 1.383 1.381 1.375 1.385 0.969 0.973 0.974 0.969 0.974 0.972
1.504 1.508 1.495 1.373 1.467 1.124 1.124 1.465 1.474 1.402 1.391 1.397 1.391 1.404 1.404 1.462 1.374 1.458 1.363 1.249 1.244 1.355 0.973 0.974
1.512 1.507 1.509 1.480 1.482 1.124 1.122 1.387 1.441 1.417 1.378 1.411 1.378 1.418 1.406 1.444 1.392 1.443 1.367 1.370 1.292 1.289 0.976 0.972
1.508 1.515 1.510 1.386 1.386 1.124 1.123 1.460 1.480 1.402 1.396 1.397 1.393 1.401 1.398 1.488 1.462 1.456 1.248 1.250 1.377 1.369
1.387 1.399 1.391 1.455 1.453 1.103 1.102 1.417 1.405 1.434 1.365 1.426 1.363 1.433 1.418 1.406 1.419 1.442 1.384 1.385 1.404 1.406 0.970 0.970 0.995 0.999 0.994 0.998
1.511 1.508 1.508 1.391 1.477 1.124 1.124 1.464 1.476 1.403 1.390 1.398 1.390 1.405 1.402 1.462 1.374 1.460 1.368 1.249 1.292 1.363 0.975 0.995
Bond lengths in angstroms. here using the usual gradient techniques. In the ab initio calculations, optimization was considered complete when the
largest component of the gradient was less than 0.001 hartree bohr-'. The numbering convention in Scheme 1 was used for each molecule.
Results and Discussion 1. Structural Aspects. There are no reported calculations on the structures and stabilities of the leucoanthraquinones discussed here though the electronic properties of both 1,4dihydroxy- (Ia) and 1,4-diaminoanthraquinone(Ib) have been calculated recently using a floating Gaussian basis setz0 and those of the latter with the STO-3G basis set.21 The calculated structures of the leuco derivatives reported here, however, are significantly different from those of the anthraquinones (Ia and Ib), as expected (Tables 1-4). In the 2,3-dihydro tautomers (IIa, IIb, IIIa, IIIb, Va, and Vb), the aliphatic carbons at the 2- and 3-positions of the ring are twisted from the central aromatic ring plane, with the former positioned approximately 6-15' below the molecular plane and the other 6-15' above, with the actual value dependent on the theoretical method adopted (Tables 2 and 4). While the bond lengths between the aliphatic carbons (C2C3) are broadly similar in each pair of tautomers for both leuco1,4-dihydroxy- (IIa, IIIa, and Va) and leuco-1P-diaminoanthraquinones (IIb, IIIb, and Vb) with values of 1.51 8, by the AM1 method (Table 1) and 1.53 8, using the 3-21G basis set (Table 3), other bond lengths in the alicyclic ring are markedly different. For example, the CI-Cl3 and C4-Cl4 bond len calculated at the 3-21G level change from 1.46 to 1.35 moving from the 1P-diketone (IIa) to the 1,4-diol (IIIa) and from 1.47 to 1.36 8, in moving from the 1,Cdiimine (IIb) to
TABLE 2: Calculated Angles of the Tautomeric Forms of Leuco-l,4-dihydroxyanthraquinone(IIa-IVa) and 1,4-Diaminoanthraquinone (IIb-IVb) Obtained Using the AM1 Methoda angle IIa IIIa IVa Va IIb IIIb IVb c2-c1 -c13 CI-C2-C3 c2-c3-c4 c3-c4-c14 C4-Cl4-Cl3 Cl-Cl3-Cl4 Cl-C2-H2 H2-C2-H2' C4-C3-H3 H3-C3 -H3' C14-C1O-C11 c1o-c14-c13 c1o-c11-c12 c5-cll-Cl2 C6-C5-Cll C5-C6-C7 C6-C7-C8 C7-C8-C12 C8-Cl2-Cll C9-Cl2-Cll C9-Cl3-Cl4 c12-c9-c13 C13-C9-09 C14-C10-010 c13-Cl-x1 c 14-c4-x4 C9-09-H C10-010-H C1-X1 -H C4-X4 -H Cll-C9-C14-C2 c 1l-C9-C14-C3 C13-C1-X1-H C14-C4-X4-H C13-C9-09-H C14-C10-010-H Angles in degrees.
117.3 111.4 111.1 118.1 119.8 119.5 108.8 107.5 108.7 107.4 121.5 119.3 119.1 119.2 120.4 120.3 120.2 120.2 119.7 118.8 119.7 121.5 125.9 126.1 123.0 122.7 111.2 111.4 --173.5
169.0 5.4 3.3
122.3 111.2 111.9 122.3 118.7 118.7 108.8 107.5 108.9 107.5 118.3 119.8 121.2 119.7 120.3 120.0 120.0 120.3 119.7 121.2 119.8 118.3 121.7 121.7 127.3 127.3 111.6 111.6 --168.5 173.1 0.9 0.8
121.6 120.4 119.7 121.9 118.6 117.8 119.9 120.6 122.0 119.5 118.8 119.2 120.6 120.3 120.5 120.8 118.5 119.2
121.1 122.7 119.5 107.3 107.3 109.1 106.5 --179.3 178.6 35.9 64.7 129.4 50.8
117.9 112.0 110.6 122.5 119.8 118.2 108.5 107.6 109.0 107.4 118.0 119.2 120.8 119.7 120.2 120.0 120.3 120.1 119.6 119.1 120.0 122.2 126.0 121.9 121.9 127.1 111.3 111.9 -170.2 172.0 1.o 2.2
116.5 110.7 107.6 113.2 119.4 120.1 109.6 107.3 110.5 107.6 121.7 119.9 118.7 119.6 120.3 120.2 120.3 120.3 119.3 119.2 118.6 121.8 126.6 126.0 121.6 122.3 110.6 110.3 --177.7
162.4 1.5 12.3
121.4 111.6 111.1 121.6 118.7 119.1 109.7 107.5 109.9 107.6 118.1 119.5 121.1 119.8 120.3 119.9 120.1 120.3 119.7 121.2 119.4 117.5 123.7 123.6 124.0 124.0 118.7 120.8 -165.6 174.0 -12.7 -6.4
118.4 122.2 121.5 119.1 118.6 119.6 120.5 120.6 122.0 118.8 119.3 118.5 121.2 120.1 120.1 121.1 118.8 119.1 117.9 122.3 119.8 120.7 122.8 123.0 107.1 106.6 114.8 115.1 175.8 -.179.0 39.2 34.7 128.1 120.5
Vb 114.5 110.6 109.3 118.6 120.9 118.3 109.8 107.4 110.2 107.5 117.4 118.5 120.5 119.7 120.2 120.0 120.2 120.1 119.7 118.9 119.5 122.2 126.7 123.3 122.3 124.9 110.4 120.3 -168.7 168.7 -8.1 1.7
Morley
5958 J. Phys. Chem., Vol. 99, No. 16,1995
TABLE 3: Calculated Bond Lengths of the Tautomeric Forms of Leuco-ly4-dihydroxyanthraquinone(Ha-IVa) and lY4-Diaminoanthraquinone (IIb-IVb) Obtained Using the 3-216 Basis Set! bond Cl-C2 C2-C3 C3-C4 C4-Cl4 C1-C13 C2-H2b C3-H3b C10-C14 C10-C11 C5-Cll C5-C6 C6-C7 C7-C8 C8-Cl2 Cll-C12 C9-Cl2 C9-Cl3 C13-Cl4 C9-09 C10-010 C1-XI C4-X4 09-H 010-H X1-H X4-H H-bond
IIa
IIIa
1.507 1.531 1.509 1.461 1.461 1.083 1.083 1.362 1.434 1.403 1.366 1.403 1.366 1.403 1.396 1.434 1.361 1.443 1.349 1.348 1.230 1.231 0.979 0.980
1.502 1.534 1.502 1.346 1.346 1.083 1.083 1.444 1.482 1.385 1.380 1.386 1.380 1.385 1.389 1.482 1.443 1.473 1.240 1.240 1.336 1.336
IVa
1.348 1.408 1.348 1.438 1.438 1.069 1.069 1.393 1.381 1.434 1.345 1.428 1.345 1.434 1.417 1.381 1.393 1.435 1.401 1.400 1.371 1.371 0.967 0.967 0.984 0.968 0.984 1.746 1.745 1.755
Va
IIb
IIIb
1.510 1.525 1.501 1.353 1.454 1.084 1.084 1.445 1.473 1.388 1.378 1.390 1.378 1.390 1.393 1.457 1.347 1.463 1.345 1.244 1.232 1.330 0.982
1.513 1.534 1.513 1.471 1.471 1.085 1.085 1.365 1.431 1.406 1.363 1.406 1.363 1.406 1.395 1.431 1.365 1.448 1.349 1.349 1.270 1.270 0.992 0.992
1.514 1.532 1.514 1.363 1.364 1.085 1.085 1.440 1.487 1.388 1.379 1.389 1.378 1.387 1.385 1.486 1.440 1.488 1.241 1.241 1.341 1.340
IVb
1.352 1.413 1.351 1.453 1.453 1.073 1.073 1.392 1.386 1.431 1.347 1.429 1.347 1.431 1.410 1.386 1.392 1.446 1.405 1.405 1.393 1.396 0.970 0.970 1.004 0.994 0.990 1.004 0.994 1.737 1.700 1.857 1.956 1.693
Vb
1J17 1.535 1.512 1.371 1.467 1.085 1.085 1.441 1.477 1.391 1.375 1.392 1.375 1.393 1.391 1.457 1.348 1.472 1.350 1.245 1.271 1.333 0.990 1.007 1.822 1.730
Bond lengths in angstroms. Distance between the acidic hydrogen at the hydroxyl or amino group and the adjacent oxygen or nitrogen atom; there are two different hydrogen-bonds in the unsymmetrical structures (Va and Vb). the 1P-diamine (IIIb) (Table 3). The corresponding bond lengths in the alternative tautomers (Va and Vb), however, show the expected values of 1.45 8, for the former (Cl-C13) and 1.35 A for the latter (C4-C14), in line with the formal written structure (Table 3). In the central ring, the C9-Cl3 and C10C14 bond lengths increase from around 1.36 to 1.44 8, in moving from the 1,4-diketone (IIa) or diimine (IIb) to the corresponding 1$-diol (IIIa) and 1,4-diamine (IIIb), respectively (Table 3). Similar trends are found using the AM1 method (Table 1). The hydrogen atoms of the hydroxyl groups in the reduced dihydroxyanthraquinones (IIIa, IIIa, and Va) clearly interact strongly with the carbonyl oxygens, resulting in a strong intramolecular hydrogen bond of around 1.75 8, in each case at the 3-21G level. A somewhat stronger hydrogen bond is formed in the 9,10-dihydroxy-l,4-diimine(IIb) with a value of 1.70 8, (Table 3). However, the hydrogen bond strength appears to be weaker in the 1,4-diamino-9,10-quinone(IIIb), as shown by the greater distance of 1.86 A (Table 3), probably because the acidity of a hydrogen atom at an amino group is less than that of a hydrogen atom at an hydroxy group (oxygen is more electronegative than nitrogen). This is reflected also in the mixed isomer (Vb), where the hydrogen bond distance between the hydroxyl hydrogen and the imine nitrogen is shorter at 1.73 8, than that between the amine hydrogen and the carbonyl oxygen at 1.82 8, (Table 3). The corresponding distances of the hydrogen bonds at the AM1 level are longer in all cases. In the fully aromatic structures, 1,4,9,1O-tetrahydroxyanthracene (IVa) and 1,4-diamino-9,1O-dihydroxyanthracene (IVb), the bond lengths between carbons in the substituted rings show less variation, but even here the C1-C13 and C4-Cl4 bond lengths of 1.44 %, in the former and 1.45 8, in the latter at the 3-21G level are much longer than those found between the C1-
C2 and C3-C4 carbons (Table 3). Furthermore, the hydrogen atoms of the hydroxyl groups at the 9- and 10-positions of 1,4,9,10-tetrahydroxyanthracene(IVa) are twisted from the ring plane by around 50" with one hydrogen above the plane and the other below (Table 4). Both oxygens at the 9- and 10-positions are hydrogen bonded to the hydrogen atoms of the adjacent almost planar hydroxyl groups at the l- and 4-positions of the ring, as shown by the 0-H distance of 1.76 8, in each case. The twist predicted for the substituents and the hydroxyl groups at the 9- and 10-positions is more extreme using the AM1 method (Table 2). A similar pattern emerges in 1,4-diamino-9,lo-tetrahydroxyanthracene (IVb), where the hydrogen atoms of the hydroxyl groups at the 9- and 10-positions are twisted from the ring plane by around 85" in this case with one hydrogen above the plane and the other below. Both oxygens at the 9- and 10-positions are also hydrogen bonded to the hydrogen atoms of the adjacent amino groups at the 1- and 4-positions of the ring, but the bond is even weaker than that found in the previous cases of the diaminoquinones (IIIb and Vb) with an 0-H distance here of 1.95 8, (Table 3). This increase in distance appears to arise because the amino groups are partly sp3 hybridized with the near hydrogen of the amino group at the 1-position, positioned above the ring plane at 26", hydrogen bonded to the oxygen of the hydroxyl group at the 9-position, which is twisted in such a way that its hydrogen atom is below the ring plane. The inverse is calculated for the hydrogen atom of the amino group at the 4-position, which is positioned below the plane and hydrogen bonded to the oxygen at the 10-position (Table 4). This molecular arrangement appears to ensure that the lone pairs of electrons on the oxygen atoms are available for bonding to the amino hydrogen atoms. 2. Relative Stabilities. There seems to be little doubt that the reduced form of 1,4-dihydroxyanthraquinoneexists solely as 2,3-dihydro-9,1O-dihydroxy-l,4-anthraquinone (IIa). However, there is conflicting data over the preferred tautomer of leuco-l,4-diaminoanthraquinone,which is predicted to exist either as 2,3-dihydro-9,10-anthraquinone (IIIb) on the basis of the structure of the corresponding leuco derivative (IIIc) of the 1,4-bis(butylamino) derivative (If)'4 or 2,3-dihydro-9,10-dihydroxy-1,Cdiimine (IIb) on the basis of the structure of the corresponding leuco derivative (IId) of the 1,4-bis(hydrazino) derivative (Ig).15 On balance, structure IIIb is more likely, as it shows a closer resemblance to the leuco-1,4-bis(butylamino) derivative (IIId) than to the leuco- 1,4-bis(hydrazino)derivative (IId), which contains an additional stabilizing electronegative nitrogen atom at the imino nitrogen. However, the relative stability of the different tautomers has not been established, and it has been suggested that an equilibrium mixture may exist, particularly in different solvents.22 The gas phase results obtained here at the 3-21G level on the reduced form of 1,4-dihydroxyanthraquinone,which approximate the trends expected in nonpolar solvents, show that 2,3-dihydro-9,1O-dihydroxy1,4-anthraquinone(IIa) is preferred by 7.1 kcal mol-' over the unsymmetrical 2,3-dihydro-4,9dihydroxy- 1,lo-anthraquinone (Va), with 2,3-dihydro-1,4-dihydroxy-9,lO-anthraquinone(ma) some 10.3 kcal mol-' higher in energy (Table 5). The fully aromatic structure, 1,4,9,10tetrahydroxyanthracene (IVb) is predicted to be much higher in energy than any of the other tautomers (Table 5). The AM1 results show exactly the same trends with similar energy gaps between the 2,3-dihydro derivatives (IIa and Va and IIa and IIIa), but the heat of formation of 1,4,9,10-tetrahydroxyanthracene (IVb) is predicted to be closer to those of the other tautomers. Both methods appear to mirror the experimental results with IIa dominant.
Reduced Forms of 1,4-Disubstituted Anthraquinones
. I . Phys. Chem., Vol. 99, No. 16, 1995 5959
TABLE 4: Calculated Angles of the Tautomeric Forms of Leuco-1,4-dihydroxyanthraquinone(IIa-IVa) and 1,4-Diaminoanthraquinone(IIb-IVb) Obtained Using the 3-21G Basis SeP angle C2-Cl-Cl3 Cl-C2-C3 c2-c3-c4 c3-c4-c14 C4-Cl4-Cl3 Cl-Cl3-Cl4 Cl-C2-H2 H2-C2-H2' C4-C3-H3 H3-C3-H3' C14-C1O-C11 c1o-c14-c13 c1o-c11-c12 c 5-c11 -c 12 C6-C5-Cll C5-C6-C7 C6-C7-C8 C7-C8-C12 C8-Cl2-Cll C9-Cl2-Cll C9-Cl3-Cl4 c12-c9-c13 C13-C9-09 c13-c1-XI C9-09-H C10-010-H C1-X1 -H C4- X4-H c 1 l-C9-C14-C2 c 1I-C9-C14-C3 C13-C1-X1-H C14-C4-X4-H C13-C9-09-H C14-C10-010-H a
IIa
IIIa
IVa
Va
IIb
IIIb
IVb
Vb
116.4 111.5 111.8 117.0 120.7 120.6 107.9 108.2 107.8 108.0 120.1 120.2 119.7 119.7 119.9 120.4 120.4 119.9 119.7 119.6 120.3 120.1 124.2 122.4 111.2 111.2
120.4 111.1 111.1 120.4 120.0 120.0 108.3 107.9 108.3 107.8 117.4 120.6 121.7 119.8 120.2 120.2 120.0 120.2 119.8 121.7 120.6 117.9 122.4 125.0
119.3 121.7 121.7 119.3 119.0 119.0 118.0
116.1 112.1 110.9 121.1 120.7 119.9 107.7 108.5 108.4 107.8 116.7 120.3 121.0 119.9 120.2 119.9 120.4 120.0 119.7 120.2 120.7 120.8 124.3 122.7 110.7
116.0 110.8 110.8 116.0 120.6 120.6 109.0 108.3 109.0 108.4 120.2 120.0 119.7 119.6 120.0 120.4 120.4 120.0 119.6 119.7 120.0 120.2 124.0 120.6 110.0 110.0
118.5 110.6 110.6 118.3 120.2 120.2 109.1 108.4 109.2 108.3 117.2 120.5 121.9 119.8 120.2 120.0 120.0 120.2 119.8 121.9 120.5 117.2 123.9 124.9
118.0 122.6 122.6 118.0 119.4 119.3 119.2
115.3 109.5 109.5 119.0 120.4 119.3 109.5 108.6 109.5 108.4 116.3 120.3 121.3 119.9 120.2 119.8 120.4 120.0 119.6 120.2 120.5 120.7 124.6 121.0 109.9
-170.1 172.8
111.0 111.0 -169.4 172.1 -1.5 -1.6
2.9 1.2
118.0 122.4 118.4 119.1 118.6 120.9 120.4 120.4 120.9 118.6 119.1 118.4 122.4 118.5 122.7 112.7 112.8 111.5 111.5 178.7 179.4 6.6 6.9 133.5 131.1
110.7 -170.8 171.1 -0.7 0.7
-170.3 171.4 -178.4 -178.4 -3.3 -3.2
119.2 122.5 118.3 119.2 119.0 120.4 120.5 120.5 120.4 119.0 119.2 118.2 122.5 121.6 121.4 111.1 111.1 118.3 118.1 179.3 179.2 25.5 27.6 88.8 85.9
117.5 117.5 -167.3 172.1 -2.0 -1.3
117.1 -170.2 167.8 -1.1 0.8
Angles in degrees.
TABLE 5: Calculated Energies and Electronic Properties of the Tautomeric Forms of Leuco-1,4-dihydroxyanthraquinone (IIa-Va) and 1,4-Diaminoanthraquinone(IIb-Vby AM1 method tautomer
Hf
IIa IIIa IVa Va IIb IIIb
-118.30 -111.12 - 107.25 - 112.42 -8.89 -22.99 -18.41 -14.16
IVb
RE 0.00 7.18 11.05 5.88 14.10 0.00 4.58 8.83
COSMO
3-21G basis set
P
Hr
RE
P
0.88 0.12 2.22 0.54 3.39 4.38 1.29 4.11
- 134.10
0.00 6.53 10.23 4.74 26.04 0.00 10.50 13.10
1.31 0.56 3.28 0.93 3.99 9.17 2.18 8.30
-127.57 -123.87 -129.36 -22.13 -48.17 -37.67 -35.07
E -830.822 -830.806 -830.777 -830.811 -791.346 -791.366 -791.329 -791.353
553 179 537 258 700 629 519 285
RE 0.00 10.29 28.25 7.09 12.51 0.00 23.29 8.37
P
0.22 0.47 6.72 0.17 5.27 5.38 0.13 5.58
Vb Hfis the heat of formation (in kcal mol-'); E is the molecular energy (in au); p is the dipole moment (in D); RE is the energy of each tautomer relative to the lowest energy form (in kcal mol-I). The corresponding results obtained at the 3-21G level on the reduced form of 1,4-diaminoanthraquinoneshow that, in this (IIIb)is now case, 1,4-diamino-2,3-dihydro-9,1O-anthraquinone preferred by 8.4 kcal mol-' over the unsymmetrical 4-amino2,3-dihydro-9-hydroxy-1-iminoanthracen-9-one(Vb), with 2,3dihydro-9,10-dihydroxy-9,10-anthraquinoneimine(IIb) some 12.5 kcal mol-' higher in energy (Table 5). Again, the fully aromatic structure, 1,4-diamino-9,10-dihydroxyanthracene (IVb), is predicted to be much higher in energy (Table 5 ) . The AM1 method also identifies the 1A-diamino derivative (IIIb) as the lowest energy structure, with the unsymmetrical tautomer (Vb) and the dimine (IIb) 8.8 and 14.1 kcal mol-' higher in energy, respectively, in line with the 3-21G results. However, the tetrasubstituted anthracene (IVb) is predicted to lie between the favored structure (IIIb) and the unsymmetrical tautomer (Vb) for reasons which are not entirely clear (Table 5 ) . As in the previous case, both methods therefore appear to correctly identify the tautomer (IIIb) expected experimentally.
Although the gas phase model explored here gives a good correlation with experimental data in CDC13, it is unable to predict the effect of polar solvents on the tautomer preferences, which may possibly change in moving from CDC13 to say water or dimethyl sulfoxide. The accurate calculation of the free energy of solvation of polar molecules is difficult, but to simplify the problem, the entropy contribution is usually assumed to be reasonably constant, as each tautomer of the two series is roughly the same size and contains the same number of functional groups. The COSMO method23(implemented in the MOPAC program17 at the AM1 level16), which is based on a continuum approach where the solute is embedded in a dielectric continuum of permittivity E, was adopted to calculate the effect of solvation on the tautomer preferences. Using water as the continuum (E = 78.4, and adopting the recommended number of segments per atom on the solvent accessible surface23),the results obtained for the reduced form of 1,4-dihydroxyanthraquinone show heats of formation which
5960 J. Phys. Chem., Vol. 99, No. 16, 1995 are lower than those obtained for the gas phase calculations, but the same trends are apparent with the 1,4-quinone (IIa) again preferred (Table 5 ) . However, the energy barrier between the tautomers is reduced and the unsymmetrical 1,lO-quinone (Va) and 9,lO-quinone (IIIa) are now only 4.7 and 6.5 kcal mol-' higher in energy, respectively, than the preferred structure (IIa). Surprisingly, the application of the COSMO technique appears to have very little effect on the molecular geometries with the ring geometries unchanged and only a slight increase found in the C=O bond lengths. Furthermore, the intramolecular hydrogen bond is conserved in all cases again with little if any change to the surrounding geometry. Similar calculations on the reduced form of 1,4-diaminoanthraquinonein water show heats of formation which are substantially lower than those obtained in the gas phase, but here the energy barrier between pairs of tautomers increases so that 1,4-diamino-2,3-dihydro9,lO-anthraquinone (IIIb) is now preferred by 13.1 and 26.0 kcal mol-' over tautomers Vb and IIb, respectively. The fully aromatic structure, 1,4-diamino-9,10-dihydroxyanthracene(IVb) is predicted to be 10.5 kcal mol-' higher in energy (Table 5 ) . Again the geometry of these structures appears to be largely unaffected by the inclusion of solvent. While the geometry of the hydrophobic aromatic ring would not be expected to change markedly with the inclusion of solvent, it is puzzling that the geometry of the polar groups appears to be largely unaffected by the solvent. Because the calculated screening energy is very sensitive to the distance of the solvent accessible surface from the atoms, one possible explanation for the results obtained here may be that the van der Waals radii used to define the solvent accessible surface are too large. An ab initio study using a similar dielectric continuum approach would clearly be beneficial in helping to understand the effects of solvent on these large molecules, but this was beyond the scope of the present studies.
Conclusions Calculations on the gas phase structures and tautomeric preferences of the reduced or leuco forms of 1,Cdihydroxyand 1,4-diaminoanthraquinoneusing both the AM 1 method and the 3-21G basis set show that 2,3-dihydro-9,1O-dihydroxy-1,4anthraquinone is preferred in the former case and 1,Cdiamino2,3-dihydro-9,lO-anthraquinone in the latter. The same pattern
Morley emerges when the calculations are simulated in water using the COSMO method, but while the energy differences among the tautomers of leuco- 1,4-dihydroxyanthraquinoneare reduced, the reverse trend is found for leuco- 1,4-diaminoanthraquinone.
References and Notes (1) Houben, J. Das Anthracen und der Anthrachinonen; Thieme: Liepzig, 1929. (2) Stilmar, F. B.; Perkins, M. A. In The Chemistry of Synthetic Dyes and Pigments; Lubs, H. A., Ed.; Reinhold: New York, 1955; pp 335390. ( 3 ) Encyclopedia of Chemical Technology, 2nd 4.;Kirk, R. E., Othmer, D. F, Eds.; Interscience: New York, 1963; Vol. 2, pp 431-500. (4) Gordon, P. F.; Gregory, P. Organic Chemistry in Colour; Springer-Verlag: Heidelberg, 1983. (5) AnnenrO.; Egli, R.;Hasler, R.; Henzi, B.; Jakob, H.; Matzinger, P. Rev. Pron. Color. 1987, 17, 72. (6) USPatent 4138415/1979 (to American Cyanamid). (7) Zee-Cheng, R. K.-Y.; Cheng, C. C. J . Med. Chem. 1978,21,291. (8) Zee-Cheng, R. K.-Y.; Podrebarac, E. G.; Menon, C. S.; Cheng, C. C. J . Med. Chem. 1979, 22, 501. (9) Murdock, K. C.; Child, R. G.; Fabio, P. F.;Angier, R. B.; Wallace, R. E.; Durr, F. E.; Citarella, R. V. J . Med. Chem. 1979, 22, 1024. (10) Cheng, C. C.; Zee-Cheng, R. K.-Y. Prog. Med. Chem. 1983, 20, 83. (11) Denny, W. A,; Wakelin, L. P. G. Anti-Cancer Drug Des. 1990,5, 189. (12) Shenkenberg, T. D.; Von Hoff, D. D. Ann. Int. Med. 1986, 105, 67. (13) Faulds, D.; Balfour, J. A,; Chrisp, P.; Lanky, H. D. Drugs 1991, 41, 400. (14) Kikuchi, M.; Yamagishi, T.; Hida, M. Dyes Pigments 1981,2, 143. (15) Krapcho, A. P.; Avery, K. L., Jr.; Shaw, K. J.; Andrews, J. D. J . Org. Chem. 1990, 55, 4960. (16) Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P. J. Am. Chem. SOC. 1985, 107, 3902. (17) QCPE Program 455 Version 6.0, Department of Chemistry, Indiana University, Bloomington, IN 47405. (18) See for example: Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio Molecular Orbital Theory; John Wiley and Sons: New York, 1986. (19) Guest, M. F.; Shenvood, P. GAMES, an ab initio program; The Daresburv Laboratorv: Wanineton. U.K. (20) Petke, J. D.;-Butler, P.IMaggiora, G. M. Int. J. Quantum Chem. 1985, 27, 71. (21) Hartman, R. S.; Alavi, D. S.; Waldeck, D. H. J. Phys. Chem. 1991, 95, 7872. ( 2 2 ) 'Greenhalgh, C. W. Endeavour 1976, 35, 134. (23) Klamt, A.; Schuurmann, G. J . Chem. SOC., Perkin Trans. 2 1993, 799. JP9431191
