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Tautomerism of histamine
Volume 34, number
3
CHEMICAL
1
PHYSICS LETTERS
ALlgIst 1975
TiwrdhiERlrshf OF HESTA~~~E Sungzong KANC and David CHOU DepaiTmeilt of Pharmacology. Mount Sinai School of hfedicine, City Univern’zy of Nerv York, NC& York.1Ve-s York 10029. USA Received 8 April 1975 Revised manuscript received 5 May 1973
Both ab initio and INDO molecular orbital calculations on histamine show tk the histamine N(3)H tautomer is preferred for the monocationic form, whereas in tie neutral state the N(l)H tautomer is favored. This implies that upon neutralization of the protoruted histamine which is predominant in the neutrzL aqueous solution the tautoaeric shift occurs from the N(3)H to the N(l)H form. Although the toti electronic energy term rxkes the N(l)W tzutomer of the manocation more favorable, it is the nuclear repukion term that results in the N(3)H tautomkr for the monocAtion being more stable. The tautomeric energy difference for both the neutral and protonated histamines is independent OPthe side chain confcrmations.
Potentiometric
titration
on histamine
pears to be more stable based on the above mentioned experirnefital resatts, it should be noted that tautomeric stability may depend on the nature of solvent. For example, one of us [!3] observed that uraci! monoanion exists exclusively as an N(3)H tautomer in solutions of Iow dielectric constant, where= the N(l)H
(I-IV)
(numbering scheme in fig. 1) showed that, in neutral buffer solutions, 80% of the molecule exists as an N(3)H iautomeric form (IV) [l] indicating the free energy difference of 0.82 kcaijmole. A similar tautomeric ratio wzs previously observed for histidine [2] . A carbon-l 3 nuclear magnetic resonance study of histidine in solution also showed the predominance of the N(3)H tautomer [3] _Examination of published X-ray crystalIogaphic data indicates that his&mine was found in a crystal 2s an N(I)H tautomer [4] , whereas histidine [5,6] , burimamide [7] and 6.histamine-purine dihydrate [S] were found as 2.n N(3)Htautomer. Although the N(3)H tautomcr ap-
tau’.omer
is favored
by solutions
of I$$
strength.
An alternative to the experimental approach is molecular orbital (MO) calculations. The most accurate calculation of thd tautomeric energy difkrence requires 2 complete search for an equilibrium geometry for each tautomer and each ionic species. The excessive amount of .comput.ing time necessary for this type of calculation, however, makes it imprzcticd.
H I0 H-Y-H
l-i :=
H-Y
H-N-H
H-6-H
H-6-H
H-h-H
H-C-H I
H-A-H
H-L
-c 4
H /
ionic
N/k’
N-
II
H. ;-
-Fig.?.
537
‘. .,
Volume 34, number. 3 Table 1 Ab inito and
C’HEMICAL
PHYSICS
LITTERS
1 AUEUSt
1975
INDO total enorGies of two histamine tautomers for the neutral and monocationic species
Geometry
MO method
Species
N(I)H tautomer (au)
N(3) tautomer (au)
Tautomeric difference
energy
dEN l)H-N(3)H (kc3.l I mole) Donohue-Caron
[ 121
-356.704820
-356.718240
ta.24
monocation neutral
-356.381785 - 75.152566 - 74.623578
-356.381921 - 75.159435 - 74.622401
+a.09 +4.31 -0.74
ab initio
monocation
-356.628656
-356.319056 - 75.085047 - 74.572207
-356.635504 -356.312471
+4.30 -4.13
INDO
neutral monocation neutral
- 75.077846 - 74.556735
-4.55 -9.71
monocation neutral monontion
-356.752134 -356.415334 - 75.166624 - 74.626677
-356.765001 -356.416196
+ 8.07 +0.54
-
75.175663
+ 5.67
- 74.627991
+ 0.82
monocation neutr;ll
ab initio INDO
Bennett-Ibers
[41
ab inito
standard [13]
INClO
neutral
The best alternative is to aerf0n-n the calculations on several different geometries of a given molecule. We, therefore, carried out the ab ititio [IO] and INDO [ 1 l] MO calculations on three different germetries of histamine; two from the X-ray crystallographic data (Bennett-Ibers [4] and DonohueCaron [12]), and one using standard geometry*. The conformation of the side chain was fiied at ~#(N-cr5) = 180” and $(0l-p-S-4) = 90”. This conformation is not only one of the most stable conformers, but also insures the maximum separation of the imidazole ring from the amino group where the protonation and deprotcaation occur. AU ab initio MO calculations ** were performed with bases of atomic optimized gaussian-type functions of Whitman and Hornback [I6]. The 5.~3~ seus were used for both the carbon and nitrogen atoms, whi!e a 2s set optimized in an ab initio methane calculation was used * The histamine
heavy atom
gectietry
WZGtaken from the
histidino
crystal structtue with standard C-H and N-H bond lengths [ 131 and averasd bond angles, because at the time this work bcgen no tistamine structure was reported. It has been shown that the imidazole rings of histamine and histidinc xe‘identical within the experimental errors. See ref. [ 141. ** The computer progxm POLYATOM used in this study was obtained form thk Quantum Chemistry Program Exchange (QCPE) of the Jkliana Utiversity. For further detailssesref. [is].
536
.-
for each hydrogen atom. The ab initio results (table 1) using the DonohueCaron [12] and standard (131 geometries indicate that the N(3)Htautomer (IV) of _hLtamine monocation is 8 k&/mole more stable than the N(l)H tautomer (II). It is the monocation which predominates ti aqueous solution at pH = 7. Tnk results using the Bonnett-Ibers geometry [4] show that as the monocation the N(3jH tautomer (IV) is 4.3 k&/mole more stable than the N(l)H tautomer (II). The INDO results ussing the Donahue-Caron [12] and standard [13] geometries qualitatively confii
the ab initio results. For the monocationic form the N(3)H tautomer (IV) is more stable than the N(I)H tautomer (It). The energy difference is, however, only 4-5 kcal/mole. In contrast, wing the Bonnettlbers geometry, the INDO calculations show the N(3)H tautomer (IV) to be 4.5 kcal/mole less stable than the N( l)H tautomer (II) (table 1). The probable explanation for this finding is the fact that the Bonnett-Ibers crystal structure has the equilibrium geometry for the N( l)H tautomer, not for the N(3)H tautomer. In general, if MO calculations are carried out using the X-ray cliystallographic geometry measured in a crystal, the most stable conformers calculated by the theoretical methods will be the one existing in that crystz! [ 171. The same reasoning also accounts
for the fact that the ab initio
tautomeric
energy
Volume
34, number
3
C~lEhlICAL
PHYSICS LETTERS
difference of the histamine monocation (AEI1_l-v, in table 1) for the Bonnett-lbers geometry is 4.3 kcal/mole compared to 8 kcaI/mole for the other two geometries. The tautomeric energy difference of the neutral molecule (LAE,_~) of histamine substantially differs from that of the protonated form (A_!?,,_,) Both ab initio and INDO calculations on the DonohueCaron [12] and standard [ 131 geometries show no energy difference between the N(3)H (III) and N( l)H (I) tautomers. The ab initio results on the BonnettIbers geometry [4] show that for the neutral form of histamine the N(I)H tautomer (I) is 4.1 kcaI/mole more stable than the N(3)H form (III), the inverse of the results for the protonated species. Using the INDO method the N( l)H tautomer (I) is 9.7 kcal/ mole more stable than the N(3)H form (III). It appears that the pronouncedly high stability of the N( 1)H tautomer of the neutral form is due to the crystallographic geometry which is in the equilibrium state for the N(l)H neutral form as described above. Since the high stability of the neutral N(l)H tautomer over the monocationic N( 1)H tautomer for the Bonnett-Ibers geometry is parallel to those for the other two geometries (table I), the INDO result that the monocationic N(3)H tautomer (IV) of the BonnettIbers geometry is less stable than the corresponding N( 1)H tautomer is clearly attributed to the fact that the Bonnett-lbers geometry is the equilibrium state for the N(1)H tautomer. The results (table 1) on three different histamine geometries unambiguously indicate that, upon neu-
1 August 1975
tralization of the monocationlc species, the tautomeric shift (IV + I) occurs in favor of the N(l)H tautomer (I) by 8 k&/mole according to the ab initio c&htions and by 5 kcal/mole according to the INDO method! It is important to note that the calculated energy difference of the rautomeric shift (IV + I) upon neutralization of histamine monocation does not depend on the input geometry used in the calculations. These calculations are in agreement with the experimentai findings that, in aqueous solutions at neutral pH, 80% of histamine is the N(3)H tautomer [I] . They also explain the fact that the Bonnett-Ibers crystal had the N(l)K tautomer, since it is neutral histamine that was crystallized from dry benzene [1]. The tautomeric energy differences have been furtlrer separated into the nuclear repulsion term and total electronic energy in order to assess the amount of the contributions of these two terms. The results of the ab initio calculations on three different zeometries show that in terms of the total electronic energy alone the N( 1)l-l tautomer is about 1 A.5 au more stable than the N(3)H tautomer for both the neutral and protonated forms. Furthermore, the preference of the N(1)”
form
over the N(3)H
form
is more
pro-
nounced for the monocation (8-9 kcaI/mole for all three geometries) than for the neutral species (table 2). It is conceivable, therefore, that the stability of the N(3)H tautomer for the monocation is to be attributed to the nuclear repulsion energy. Contrxy to the contribution of the total electronic energy to the tautomeric energy difference, the nuclear repulsion energy difference between two monocationic tauto-
Table 2 Contribution [I-III]
of nuc1ea.r rep&ion
and for
the monocation
Geometry
and total
!II-IV]
electronic
_The
energies
Energy terms
energies
to th-, tactomeric
were calculated
form
[I-rrr1
[ 121
electronic nuclear repulsion
Bennett-Ibers standard
[13]
difference
both
for the neutral
specks
MO methods
Tautomeric energy difference [N(l)H-N(3)H] (au) neutral
Donohue-Qron
energy
by ab initio
-1.173725 1.173861
monocztion [II-IV] .
neutral-monoution
-1.188111 1.201532
9.03 -17.36
electronic nuclezr repLLl%ion
-1.092837 l.C!86252
1.113518
electronic nuclear repulsion
-1.132104 1.132’965
-1.145596 1.138462
-1.106665
(kQl/mole)
g-68 -17.11
8.47 -16.00 539
Volume
34, number 3
CHEMICAL
PHYSICS
LETTERS
1 Au_wst 1975
Table 3 Tautomeric energy difference for both the neutral md the ationic forms as a function Donahue-Caron geometry was used in these calculations C5) ar.d 3, (a-CP-C544). 30”
0”
0
N(l)H
60”
of the side chain rotations,
90”
120”
150”
180”
210”
240”
-1.45 -1.26 -0.93 -0.90 -1.06
-1.43 -1.21 -0.83 -0.80 -0.66
-1.39 -1.20 -0.85 -0.75 -0.79
-1.43 -1.25 -0.28 -0.72 -0.80
-
150”
22.07
-
0.05
-
3.26
-
1.52
-1.72
-0.46
-0.76
-0.85
-
180°
15.91
-
3.23
-
1.98
-
0.67
-0.34
-0.33
-0.80
-0.33
-
0.34
-
li60 1.06 0.58 0.31 0.85
N(l)H 0” 3o” 60’ 90” 120° 150’ 180”
-
-
1.15 1.01 0.61 056 0.16
cation
1.58
0.80 198 5.38 1132 41.36 59.76
270”
300”
330”
-
-
0.77 0.50 0.32
0.54 1.98
-
3.23
0.53 0.15 1.31 2.82 5.32 9.15 15.48
-
1.80 0.55 1.19 3.52 7.51 17.31 76.54
neutral - N(3)H neutral 1.45 1.28 0.86 0.73 0.83 0.57
0” 30” 60’ 9oa I?-0=
o(N-Cc
-
-
1.61
-
1.0s
-
0.92 0.95 1.75
-
1.58 1.22 0.95 ,I.01 1.41
-
0.46
-
-
0.67
-
1.58 1.24 0.84 0.72 0.80
1.61 1.45 0.84 0.68 0.70
1.60
1.55
3.46
- N(3)H cation 1.80 0.84
053 I .9a
1.32 2.62
1.83 2.90
2.24 2.97
2.41 2.76
3.45 7.29 14.06 36.79 76.54
4.53 8.15 14.02 26.62 15.46
4.83 7.42 9.82 10.81 10.11
4.55 6.18 7.56 8.72 9.34
4.07 5.13 6.24 7.58 7.68
3.49 4.32 5.36 6.47 6.87
2.24 2.27 2.85 3.68 4.77 6.13 7.68
1.83 1.7: 2.28 3.18 4.52 15.13 9.34
1.32 1.12 1.77 2.86 4.66 7.61 10.11
mers [II-N] is 16-I’i’ k&/mole greater than that between the neutral tautomers [I-III] in favor of the N(3)H tautomer. The fact that the N(3)H tautomer becomes 8 k&/mole more stable upon protonation of the side chain amino group results from the
ular hydrogen bonding for the N(3)H tautomer and from the electrostatic repuision for the N(l)H tautomer. It is less relevant to the aim of this paper.
predomizmt
stein
tern
contribution
of
the nuclear
repulsion
(table 2). The dependence of .Lhetautomeric energy difference cn the conformation has been studied by rotating $(C4-C5-Co-Ca) and @(CS-C&Cc-N) of the side chain (I). Iti the mDnocation the N(3)H tautomer is more stable than the N(I)H tautomer wivithjnthe allowed conformational range (table 3). In the case of the neutral molecule the N( l)H tautamer is condstently more stable tlzm the N(3)H tautomer. It is interesting to note that in both the monocation and the neutral form the N(3)H tautomer becomes more stable &hen 9 is rotated from 0 to 180”. This phenomenon is more pronounced for the monocation. For example, ai $J = 180” where the tide chain is fuliy extended, the stability of the N(3)H form increases by 0.6 kv! for the neutral forin -ivhen $J goes from 0 to IgO’, whereas for the monocation the change is 4.4 kcaI/moIe (table 3). The pronounced tautomeric energy differences f&tie mono&ion near @= 0” and $ - 1,80Qr&&s both from the strong intramolec-
We are grateful to Drs. J. Goldfarb and H. Weinfor
helpful
discussions,
and to Mr. C. Sabers
and
Ms. F. TeArnan of the City University of New York Computing Center for technical assistance. This work was supported by a grant (WI-17489) from the Na_ tional Institute of Mental Health.
References [l] C.R. Ganellin, J. Pharm. Pharmacol. 25 (1973) 787. [2] D.E. Hulquist, R.W. Moyer and P.D. Boyer, Biochemistry 5 (1966) 322. [3] W.F. Reynolds, I.R. Peat, h1.H. Freedman and J.R. Lyerla Jr., I. Am. Chem. Sot. 95 (1973) 328. [4] J.J. Bennett and J.A. Ibers, J. Am. Chem. Sot. 95 (1973) 4829. [5 ] J J, Madden, E.L. McGandy and N.C. Seeman, Acta Cryst. BZ8 (1972) 2377. [ 6) J J. hbdden, E.L. McGandy and N.C. Seeman, Acts Cryst. 928 (1972) 2382. [7] B. Kame~&, K. Frout and C.R. CzneUin,J. Chem. Sac. PerkinTrans. II (1973) 1734. (S] U. Thewalt and EC. Bw.
Acta Cryst. B28
(1972) 1767.
Volume 34, number
3
CHEMICAL
[V] R. Shapiro and S. Keng, Bioc-him. Biophys. Act2 232 (1971) 1. [lo] CC-I. Roothaan, Rev. Mod. Phys. 23 (1951) 69. [ 111 J.A. Pople and D.L. Baveridg, Approximate molecular orbital theory (McGraw-Hill Book, New York, 1970). [12] J. Donohue and A. Caron. Acta Cryst. I7 (1964) 1178. [13] J.A. Pople md M. Gordon, J. Am. Chem. Sot. S9 (1967) 4253.
PHYSkT.3 LETTERS
1 August 1975
[14] D. Carlstrom, R. Berger and G. Falkenberg, Quart. Rev. Biophys. 6 (1973) 257. [1.5] D.B. Newman et al., The POLYATOM (version 2) Systern of Programs for Quantitative Theoretical ChemWry. Part 1: Description of Programs, QCPE, Indiana University, Bloomington, Indiana.
3
CHEMICAL
1
PHYSICS LETTERS
ALlgIst 1975
TiwrdhiERlrshf OF HESTA~~~E Sungzong KANC and David CHOU DepaiTmeilt of Pharmacology. Mount Sinai School of hfedicine, City Univern’zy of Nerv York, NC& York.1Ve-s York 10029. USA Received 8 April 1975 Revised manuscript received 5 May 1973
Both ab initio and INDO molecular orbital calculations on histamine show tk the histamine N(3)H tautomer is preferred for the monocationic form, whereas in tie neutral state the N(l)H tautomer is favored. This implies that upon neutralization of the protoruted histamine which is predominant in the neutrzL aqueous solution the tautoaeric shift occurs from the N(3)H to the N(l)H form. Although the toti electronic energy term rxkes the N(l)W tzutomer of the manocation more favorable, it is the nuclear repukion term that results in the N(3)H tautomkr for the monocAtion being more stable. The tautomeric energy difference for both the neutral and protonated histamines is independent OPthe side chain confcrmations.
Potentiometric
titration
on histamine
pears to be more stable based on the above mentioned experirnefital resatts, it should be noted that tautomeric stability may depend on the nature of solvent. For example, one of us [!3] observed that uraci! monoanion exists exclusively as an N(3)H tautomer in solutions of Iow dielectric constant, where= the N(l)H
(I-IV)
(numbering scheme in fig. 1) showed that, in neutral buffer solutions, 80% of the molecule exists as an N(3)H iautomeric form (IV) [l] indicating the free energy difference of 0.82 kcaijmole. A similar tautomeric ratio wzs previously observed for histidine [2] . A carbon-l 3 nuclear magnetic resonance study of histidine in solution also showed the predominance of the N(3)H tautomer [3] _Examination of published X-ray crystalIogaphic data indicates that his&mine was found in a crystal 2s an N(I)H tautomer [4] , whereas histidine [5,6] , burimamide [7] and 6.histamine-purine dihydrate [S] were found as 2.n N(3)Htautomer. Although the N(3)H tautomcr ap-
tau’.omer
is favored
by solutions
of I$$
strength.
An alternative to the experimental approach is molecular orbital (MO) calculations. The most accurate calculation of thd tautomeric energy difkrence requires 2 complete search for an equilibrium geometry for each tautomer and each ionic species. The excessive amount of .comput.ing time necessary for this type of calculation, however, makes it imprzcticd.
H I0 H-Y-H
l-i :=
H-Y
H-N-H
H-6-H
H-6-H
H-h-H
H-C-H I
H-A-H
H-L
-c 4
H /
ionic
N/k’
N-
II
H. ;-
-Fig.?.
537
‘. .,
Volume 34, number. 3 Table 1 Ab inito and
C’HEMICAL
PHYSICS
LITTERS
1 AUEUSt
1975
INDO total enorGies of two histamine tautomers for the neutral and monocationic species
Geometry
MO method
Species
N(I)H tautomer (au)
N(3) tautomer (au)
Tautomeric difference
energy
dEN l)H-N(3)H (kc3.l I mole) Donohue-Caron
[ 121
-356.704820
-356.718240
ta.24
monocation neutral
-356.381785 - 75.152566 - 74.623578
-356.381921 - 75.159435 - 74.622401
+a.09 +4.31 -0.74
ab initio
monocation
-356.628656
-356.319056 - 75.085047 - 74.572207
-356.635504 -356.312471
+4.30 -4.13
INDO
neutral monocation neutral
- 75.077846 - 74.556735
-4.55 -9.71
monocation neutral monontion
-356.752134 -356.415334 - 75.166624 - 74.626677
-356.765001 -356.416196
+ 8.07 +0.54
-
75.175663
+ 5.67
- 74.627991
+ 0.82
monocation neutr;ll
ab initio INDO
Bennett-Ibers
[41
ab inito
standard [13]
INClO
neutral
The best alternative is to aerf0n-n the calculations on several different geometries of a given molecule. We, therefore, carried out the ab ititio [IO] and INDO [ 1 l] MO calculations on three different germetries of histamine; two from the X-ray crystallographic data (Bennett-Ibers [4] and DonohueCaron [12]), and one using standard geometry*. The conformation of the side chain was fiied at ~#(N-cr5) = 180” and $(0l-p-S-4) = 90”. This conformation is not only one of the most stable conformers, but also insures the maximum separation of the imidazole ring from the amino group where the protonation and deprotcaation occur. AU ab initio MO calculations ** were performed with bases of atomic optimized gaussian-type functions of Whitman and Hornback [I6]. The 5.~3~ seus were used for both the carbon and nitrogen atoms, whi!e a 2s set optimized in an ab initio methane calculation was used * The histamine
heavy atom
gectietry
WZGtaken from the
histidino
crystal structtue with standard C-H and N-H bond lengths [ 131 and averasd bond angles, because at the time this work bcgen no tistamine structure was reported. It has been shown that the imidazole rings of histamine and histidinc xe‘identical within the experimental errors. See ref. [ 141. ** The computer progxm POLYATOM used in this study was obtained form thk Quantum Chemistry Program Exchange (QCPE) of the Jkliana Utiversity. For further detailssesref. [is].
536
.-
for each hydrogen atom. The ab initio results (table 1) using the DonohueCaron [12] and standard (131 geometries indicate that the N(3)Htautomer (IV) of _hLtamine monocation is 8 k&/mole more stable than the N(l)H tautomer (II). It is the monocation which predominates ti aqueous solution at pH = 7. Tnk results using the Bonnett-Ibers geometry [4] show that as the monocation the N(3jH tautomer (IV) is 4.3 k&/mole more stable than the N(l)H tautomer (II). The INDO results ussing the Donahue-Caron [12] and standard [13] geometries qualitatively confii
the ab initio results. For the monocationic form the N(3)H tautomer (IV) is more stable than the N(I)H tautomer (It). The energy difference is, however, only 4-5 kcal/mole. In contrast, wing the Bonnettlbers geometry, the INDO calculations show the N(3)H tautomer (IV) to be 4.5 kcal/mole less stable than the N( l)H tautomer (II) (table 1). The probable explanation for this finding is the fact that the Bonnett-Ibers crystal structure has the equilibrium geometry for the N( l)H tautomer, not for the N(3)H tautomer. In general, if MO calculations are carried out using the X-ray cliystallographic geometry measured in a crystal, the most stable conformers calculated by the theoretical methods will be the one existing in that crystz! [ 171. The same reasoning also accounts
for the fact that the ab initio
tautomeric
energy
Volume
34, number
3
C~lEhlICAL
PHYSICS LETTERS
difference of the histamine monocation (AEI1_l-v, in table 1) for the Bonnett-lbers geometry is 4.3 kcal/mole compared to 8 kcaI/mole for the other two geometries. The tautomeric energy difference of the neutral molecule (LAE,_~) of histamine substantially differs from that of the protonated form (A_!?,,_,) Both ab initio and INDO calculations on the DonohueCaron [12] and standard [ 131 geometries show no energy difference between the N(3)H (III) and N( l)H (I) tautomers. The ab initio results on the BonnettIbers geometry [4] show that for the neutral form of histamine the N(I)H tautomer (I) is 4.1 kcaI/mole more stable than the N(3)H form (III), the inverse of the results for the protonated species. Using the INDO method the N( l)H tautomer (I) is 9.7 kcal/ mole more stable than the N(3)H form (III). It appears that the pronouncedly high stability of the N( 1)H tautomer of the neutral form is due to the crystallographic geometry which is in the equilibrium state for the N(l)H neutral form as described above. Since the high stability of the neutral N(l)H tautomer over the monocationic N( 1)H tautomer for the Bonnett-Ibers geometry is parallel to those for the other two geometries (table I), the INDO result that the monocationic N(3)H tautomer (IV) of the BonnettIbers geometry is less stable than the corresponding N( 1)H tautomer is clearly attributed to the fact that the Bonnett-lbers geometry is the equilibrium state for the N(1)H tautomer. The results (table 1) on three different histamine geometries unambiguously indicate that, upon neu-
1 August 1975
tralization of the monocationlc species, the tautomeric shift (IV + I) occurs in favor of the N(l)H tautomer (I) by 8 k&/mole according to the ab initio c&htions and by 5 kcal/mole according to the INDO method! It is important to note that the calculated energy difference of the rautomeric shift (IV + I) upon neutralization of histamine monocation does not depend on the input geometry used in the calculations. These calculations are in agreement with the experimentai findings that, in aqueous solutions at neutral pH, 80% of histamine is the N(3)H tautomer [I] . They also explain the fact that the Bonnett-Ibers crystal had the N(l)K tautomer, since it is neutral histamine that was crystallized from dry benzene [1]. The tautomeric energy differences have been furtlrer separated into the nuclear repulsion term and total electronic energy in order to assess the amount of the contributions of these two terms. The results of the ab initio calculations on three different zeometries show that in terms of the total electronic energy alone the N( 1)l-l tautomer is about 1 A.5 au more stable than the N(3)H tautomer for both the neutral and protonated forms. Furthermore, the preference of the N(1)”
form
over the N(3)H
form
is more
pro-
nounced for the monocation (8-9 kcaI/mole for all three geometries) than for the neutral species (table 2). It is conceivable, therefore, that the stability of the N(3)H tautomer for the monocation is to be attributed to the nuclear repulsion energy. Contrxy to the contribution of the total electronic energy to the tautomeric energy difference, the nuclear repulsion energy difference between two monocationic tauto-
Table 2 Contribution [I-III]
of nuc1ea.r rep&ion
and for
the monocation
Geometry
and total
!II-IV]
electronic
_The
energies
Energy terms
energies
to th-, tactomeric
were calculated
form
[I-rrr1
[ 121
electronic nuclear repulsion
Bennett-Ibers standard
[13]
difference
both
for the neutral
specks
MO methods
Tautomeric energy difference [N(l)H-N(3)H] (au) neutral
Donohue-Qron
energy
by ab initio
-1.173725 1.173861
monocztion [II-IV] .
neutral-monoution
-1.188111 1.201532
9.03 -17.36
electronic nuclezr repLLl%ion
-1.092837 l.C!86252
1.113518
electronic nuclear repulsion
-1.132104 1.132’965
-1.145596 1.138462
-1.106665
(kQl/mole)
g-68 -17.11
8.47 -16.00 539
Volume
34, number 3
CHEMICAL
PHYSICS
LETTERS
1 Au_wst 1975
Table 3 Tautomeric energy difference for both the neutral md the ationic forms as a function Donahue-Caron geometry was used in these calculations C5) ar.d 3, (a-CP-C544). 30”
0”
0
N(l)H
60”
of the side chain rotations,
90”
120”
150”
180”
210”
240”
-1.45 -1.26 -0.93 -0.90 -1.06
-1.43 -1.21 -0.83 -0.80 -0.66
-1.39 -1.20 -0.85 -0.75 -0.79
-1.43 -1.25 -0.28 -0.72 -0.80
-
150”
22.07
-
0.05
-
3.26
-
1.52
-1.72
-0.46
-0.76
-0.85
-
180°
15.91
-
3.23
-
1.98
-
0.67
-0.34
-0.33
-0.80
-0.33
-
0.34
-
li60 1.06 0.58 0.31 0.85
N(l)H 0” 3o” 60’ 90” 120° 150’ 180”
-
-
1.15 1.01 0.61 056 0.16
cation
1.58
0.80 198 5.38 1132 41.36 59.76
270”
300”
330”
-
-
0.77 0.50 0.32
0.54 1.98
-
3.23
0.53 0.15 1.31 2.82 5.32 9.15 15.48
-
1.80 0.55 1.19 3.52 7.51 17.31 76.54
neutral - N(3)H neutral 1.45 1.28 0.86 0.73 0.83 0.57
0” 30” 60’ 9oa I?-0=
o(N-Cc
-
-
1.61
-
1.0s
-
0.92 0.95 1.75
-
1.58 1.22 0.95 ,I.01 1.41
-
0.46
-
-
0.67
-
1.58 1.24 0.84 0.72 0.80
1.61 1.45 0.84 0.68 0.70
1.60
1.55
3.46
- N(3)H cation 1.80 0.84
053 I .9a
1.32 2.62
1.83 2.90
2.24 2.97
2.41 2.76
3.45 7.29 14.06 36.79 76.54
4.53 8.15 14.02 26.62 15.46
4.83 7.42 9.82 10.81 10.11
4.55 6.18 7.56 8.72 9.34
4.07 5.13 6.24 7.58 7.68
3.49 4.32 5.36 6.47 6.87
2.24 2.27 2.85 3.68 4.77 6.13 7.68
1.83 1.7: 2.28 3.18 4.52 15.13 9.34
1.32 1.12 1.77 2.86 4.66 7.61 10.11
mers [II-N] is 16-I’i’ k&/mole greater than that between the neutral tautomers [I-III] in favor of the N(3)H tautomer. The fact that the N(3)H tautomer becomes 8 k&/mole more stable upon protonation of the side chain amino group results from the
ular hydrogen bonding for the N(3)H tautomer and from the electrostatic repuision for the N(l)H tautomer. It is less relevant to the aim of this paper.
predomizmt
stein
tern
contribution
of
the nuclear
repulsion
(table 2). The dependence of .Lhetautomeric energy difference cn the conformation has been studied by rotating $(C4-C5-Co-Ca) and @(CS-C&Cc-N) of the side chain (I). Iti the mDnocation the N(3)H tautomer is more stable than the N(I)H tautomer wivithjnthe allowed conformational range (table 3). In the case of the neutral molecule the N( l)H tautamer is condstently more stable tlzm the N(3)H tautomer. It is interesting to note that in both the monocation and the neutral form the N(3)H tautomer becomes more stable &hen 9 is rotated from 0 to 180”. This phenomenon is more pronounced for the monocation. For example, ai $J = 180” where the tide chain is fuliy extended, the stability of the N(3)H form increases by 0.6 kv! for the neutral forin -ivhen $J goes from 0 to IgO’, whereas for the monocation the change is 4.4 kcaI/moIe (table 3). The pronounced tautomeric energy differences f&tie mono&ion near @= 0” and $ - 1,80Qr&&s both from the strong intramolec-
We are grateful to Drs. J. Goldfarb and H. Weinfor
helpful
discussions,
and to Mr. C. Sabers
and
Ms. F. TeArnan of the City University of New York Computing Center for technical assistance. This work was supported by a grant (WI-17489) from the Na_ tional Institute of Mental Health.
References [l] C.R. Ganellin, J. Pharm. Pharmacol. 25 (1973) 787. [2] D.E. Hulquist, R.W. Moyer and P.D. Boyer, Biochemistry 5 (1966) 322. [3] W.F. Reynolds, I.R. Peat, h1.H. Freedman and J.R. Lyerla Jr., I. Am. Chem. Sot. 95 (1973) 328. [4] J.J. Bennett and J.A. Ibers, J. Am. Chem. Sot. 95 (1973) 4829. [5 ] J J, Madden, E.L. McGandy and N.C. Seeman, Acta Cryst. BZ8 (1972) 2377. [ 6) J J. hbdden, E.L. McGandy and N.C. Seeman, Acts Cryst. 928 (1972) 2382. [7] B. Kame~&, K. Frout and C.R. CzneUin,J. Chem. Sac. PerkinTrans. II (1973) 1734. (S] U. Thewalt and EC. Bw.
Acta Cryst. B28
(1972) 1767.
Volume 34, number
3
CHEMICAL
[V] R. Shapiro and S. Keng, Bioc-him. Biophys. Act2 232 (1971) 1. [lo] CC-I. Roothaan, Rev. Mod. Phys. 23 (1951) 69. [ 111 J.A. Pople and D.L. Baveridg, Approximate molecular orbital theory (McGraw-Hill Book, New York, 1970). [12] J. Donohue and A. Caron. Acta Cryst. I7 (1964) 1178. [13] J.A. Pople md M. Gordon, J. Am. Chem. Sot. S9 (1967) 4253.
PHYSkT.3 LETTERS
1 August 1975
[14] D. Carlstrom, R. Berger and G. Falkenberg, Quart. Rev. Biophys. 6 (1973) 257. [1.5] D.B. Newman et al., The POLYATOM (version 2) Systern of Programs for Quantitative Theoretical ChemWry. Part 1: Description of Programs, QCPE, Indiana University, Bloomington, Indiana.