Introduction
Experimental
Discussion
Removal of the C 7 - C 8 Double Bond
Author: G. O. JOLLIFFE, M. M. AHMAD
Pages: 37 to 40
Creation Date: 1971/01/01
Since the early attempts ( [ 1] -3) to determine ionization constants of morphine, numerous workers ( [ 4] -13 and [ 21] ) have reported values of morphine and related compounds under varying conditions of temperature and concentration. It was, therefore, considered pertinent for comparison purposes to determine ionization constants for morphine and a number of morphine-like compounds under identical conditions.
Alterations in the chemical structure of a molecule are usually accompanied by changes in reactivity. A substituent or a conformation which stabilises the ion more than the uncharged molecule will favour ionisation and vice versa, this effect being reflected by changes in ionization constant. To aid comparative studies this paper reports, for several morphine-like compounds, ionization constants obtained under identical conditions.
Ionization constants were determined potentiometrically at 37 °C in an aqueous medium under nitrogen. The pH values were measured with a Beckman Research pH meter using a screened glass electrode (Beckman AS7LB) and a sintered plug type saturated calomel electrode. Three forms of titration cell (fig. 1) were used, depending on the volume of solution available, the titrant being added from an "Agla" micrometer syringe (Burroughs Wellcome and Co.). The titrant and buffer solutions were freshly prepared in boiled and cooled distilled water and stored in a carbon dioxide free atmosphere. The sodium hydroxide solution was freed from carbon dioxide by the method of Davies and Nancollas ( [ 14] ) using Amberlite-IRA 400. resin. The compounds, recrystallized from suitable solvents ( [ 15] ) and tested for purity by thin layer chromatography ( [ 16] ), were dissolved in carbon dioxide free distilled water. A suitable aliquot (2 - 30ml) of each solution was titrated with a suitable titrant, the pH being recorded after each increment as soon as equilibrium conditions were established (0.5-2min). The stirring mechanism was turned off during each measurement. The equivalence point was located from a graph of ΔpH/ΔV against V (the mean volume of titrant). However, amphoteric compounds were accurately weighed and dissolved in sufficient water to give 2mM solutions. The titrant, in such cases, was added in 20 equal parts (each one-tenth of an equivalent) and the pH values recorded as before.
* Submitted by M. M. Ahmad in partial fulfilment of the requirements for the degree of Ph.D. in the University of London (1968). Present address c/o Sandoz (Pakistan) Ltd., Jamshoro, Hyderabad, Sind, West Pakistan.
The pH meter was standardized and the electrode linearity checked, by using two standard buffer solutions, immediately before and after each titration. If the pH value was not reproduced to within ±0.02, the titration was rejected. The pKa values of the monoacidic bases were calculated from the following form of Henderson's equation:
pKa = pH + log([Protonated base]/[Unchanged base])
The pKa values of amphoteric compounds were calculated by the method of Noyes ( [ 17] ), a suitable form of which is given by Albert and Serjeant ( [ 18] ). It was found unnecessary to correct the pH values for a change in volume by the addition of titrant, which was usually 50-100 times stronger than the solution of the base. Activity corrections were also neglected because the concentrations of the bases were less than 5mM ( [ 18] ). The results are recorded in the table, p. 39.
In the present work the difference in the ionization constants of the morphine-like compounds examined can, in most cases, be accounted for by inductive and field effects from those portions of the molecule proximal to the ionizable group. The compounds can be arranged in a series of groups, the members within a group differing only in the nature of the substituent at a given position in the molecule (A).
The replacement of the 3 hydroxyl group by methoxy, ethoxy, etc. does not appear to have an appreciable effect on the ionization of the tertiary nitrogen (compounds XXIII, V, XI, III and XV). This can be due to the very similar values for the inductive and field effects of these substituents.
The change of the hydroxyl group to methoxy, ethoxy or acetyl at the C 6 position does not appear to have any direct effect on the ionization of the tertiary nitrogen (compounds XXIII, XXI, XXIV and XVII). This may be due either to the considerable distance (five carbon atoms) between C 6 and the basic centre or to the effects of these groups being counter balanced by the effect of the substituents on the phenolic hydroxyl group at C 3. The change of the hydroxyl group to methoxy, ethoxy or acetyl at C 6 is accompanied by a decrease in the dissociation of the phenolic hydroxyl group at C 3. This is due to the inductive effects of these groups being transmitted through two paths, viz.-C 6-C 5-C 0- and-C 6-C 5-C 13-, to the aromatic ring. The C 6-OH group is slightly more powerful than the other substituents in its ability to attract electrons so that the electron density on the phenolic oxygen will be slightly greater in the case of the substituted compounds which hinders the dissociative process of the phenolic -OH group (i.e. increases the pKa 2values). The acetyl group (in the case of compounds XVII and XVI) being a still less powerful electron attractor than alkoxy group, results in a further lowering of the acidic strength of the phenolic -OH. The keto group (as in compound XX) is a more powerful electron attractor than an -OH group and hence its introduction at C 6 results in an increased dissociation of the phenolic -OH group (lowering of the pKa 2 value).
Conc. (mM) (approx.) |
Number of |
Average |
||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Compound |
Alkaloid |
Salt used |
R 1 |
R 2 |
Nuclear substitution |
Titration cell used |
Compd. |
Titrant |
Titrations |
pKa 1 values |
pKa 2values |
pKa 1 |
pKa 2 |
References to reported ionization constants |
I
|
Acetyl-codeine
|
Hydro-chloride
|
CH
3O-
|
-OH
|
a
|
1.5 | 50 | 5 | 36 |
-
|
7.72 ± 0.05
|
-
|
||
II
|
Benzyl-dihydro-morphine
|
Hydro-chloridea
|
C
6H
5CH
2O-
|
-OH
|
b
|
b
|
1.0 | 50 | 3 | 21 |
-
|
8.49 ±0.04
|
||
III
|
Benzyl-morphine
|
Methane-sulpho-nate
|
C
6H
5CH
2O-
|
-OH
|
a
|
1.0 | 50 | 3 | 19 |
-
|
7.81 ±0.02
|
-
|
||
IV
|
Benzyl-morphine-methyl-ether
|
Sulphate
|
C
6H
5CH
2O-
|
CH
3O-
|
a
|
0.5 | 20 | 3 | 21 |
-
|
7.70 ±0.03
|
-
|
||
V
|
Codeine
|
Hydro-chloridea
|
CH
3O-
|
-OH
|
b
|
2.0 | 100 | 3 | 23 |
-
|
7.86 ±0.03
|
-
|
4, 5, 9, 10, 12, 13, 21 | |
VI
|
Codeine-methyl-ether
|
Hydro-chloride
|
CH
3O-
|
CH
3O-
|
a
|
1.0 | 50 | 3 | 21 |
-
|
7.77 ±0.03
|
-
|
||
VII
|
Diacetyl-morphine
|
Hydro-chloride
|
CH
3CO.O
|
CH
3CO.O
|
a
|
3.0 | 200 | 3 | 24 |
-
|
7.63 ±0.05
|
-
|
7 | |
VIII
|
Dihydro-codeine
|
Hydro-chloride
|
CH
3O-
|
-OH
|
b
|
c
|
5.0 | 500 | 3 | 26 |
-
|
8.60 ±0.04
|
-
|
9 |
IX
|
Dihydro-codeinone
|
Hydro-chloride
|
CH
3O-
|
=O
|
b
|
c
|
5.0 | 600 | 3 | 27 |
-
|
8.00 ±0.05
|
-
|
7 |
X
|
Dihydro-hydroxy-codeinone
|
Hydro-chloride
|
CH
3O-
|
=O
|
14-OHb
|
c
|
1.5 | 250 | 4 | 29 |
-
|
8.53 ±0.03
|
-
|
7 |
XI
|
Ethyl-morphine
|
Hydro-chloride
|
C
2H
5O-
|
-OH
|
b
|
5.0 | 500 | 3 | 24 |
-
|
7.96 ±0.02
|
-
|
4, 13 | |
XII
|
Methoxy-methyl-dihydro-morphine
|
Hydro-chloride
|
CH
3OH
2O-
|
-OH
|
b
|
a
|
2.0 | 100 | 3 | 20 |
-
|
8.50 ±0.03
|
-
|
|
XIII
|
Methyl-dihydro-codeinone
|
Hydro-chloride
|
CH
3O-
|
=O
|
5-CH
3b
|
a
|
2.0 | 100 | 3 | 21 |
-
|
8.60 ±0.03
|
-
|
|
XIV
|
Pethidinec
|
Hydro-chloride
|
-
|
-
|
a
|
3.0 | 500 | 3 | 25 |
-
|
8.42 ±0.04
|
-
|
||
XV
|
Pholcodine
|
Hydro-chloridea
|
-OH
|
OC
4H
4NC
2H
4O-
|
c
|
5.0 | 500 | 3 | 21 | 21 |
7.96 ±0.04
|
9.27 ±0.04
|
||
XVI
|
Acetyl-dihydro-morphine
|
Hydro-chloridea
|
-OH
|
CH
3CO.O
|
b
|
c
|
2.0 | 0.2 | 9 | 7 |
8.43 ±0.02
|
9.61 ±0.066
|
||
XVII
|
Acetyl-morphine
|
Hydro-chloride
|
-OH
|
CH
3CO.O-
|
c
|
2.0 | 0.2 | 9 | 7 |
7.90±0.03
|
9.53 ±0.03
|
|||
XVIII
|
Dihydro-hetero-codeine
|
Hydro-chloride
|
-OH
|
CH
3O-
|
b
|
c
|
2.0 | 0.2 | 9 | 7 |
8.41 ±0.04
|
9.53 ±0.06
|
||
XIX
|
Dihydro-morphine
|
Hydro-chloride
|
-OH
|
-OH
|
b
|
c
|
2.0 | 0.2 | 9 | 7 |
8.33 ±0.03
|
9.41 ±0.04
|
21 | |
XX
|
Dihydro-morphinone
|
Hydro-chloride
|
-OH
|
=O
|
b
|
c
|
2.0 | 0.2 | 9 | 7 |
7.86 ±0.04
|
9.16 ±0.04
|
7 | |
XXI
|
Hetero-codeine
|
Hydro-chloride
|
-OH
|
CH
3O-
|
c
|
2.0 | 0.2 | 9 | 7 |
7.91 ±0.03
|
9.43 ±0.05
|
|||
XXII
|
Methyl-dihydro-morphinone
|
Hydro-chloride
|
-OH
|
=O
|
5-CH
3b
|
c
|
2.0 | 0.2 | 9 | 7 |
7.97 ±0.03
|
9.40 ±0.03
|
||
XXIII
|
Morphine
|
Hydro-chloride
|
-OH
|
-OH
|
c
|
2.0 | 0.2 | 9 | 7 |
7.91 ±0.04
|
9.19 ±0.04
|
4, 6, 10, 12, 13, 21 | ||
XXIV
|
Morphine-6-ethylether
|
Per-chlorate
|
-OH
|
C
2H
5O-
|
c
|
2.0 | 0.2 | 9 | 7 |
7.95 ±0.02
|
9.34 ±0.05
|
NOTES:
a The free bases of these compounds were dissolved in excess of hydrochloric acid.
b The 7-8 position is saturated.
c The ionisation constant of Pethidine (XIV) is given for comparison purposes only.
pKa 1 = ionisation constant for the loss of a proton by the conjugate acid of a basic nitrogen.
pKa 2 = ionization constant for the loss of a proton by the phenolic hydroxyl group at carbon atom 3 (except XV).
The pKa values of the amphoteric compounds XVI-XXIV required Noyes' calculations.
In compounds V, VI and I the phenolic -OH has been masked by the -CH 3 group which prevents the loss of a proton through ionization. The change from -OH to less electronegative groups, such as CH 3O- or CH 3CO.O-, at C 6 is accompanied by base weakening effects. These changes may not have a direct effect on the ionization of the tertiary nitrogen because of the distance between C 6 and N. However, these changes can affect the electron density in the aromatic ring whose inductive effects are then transmitted to the tertiary nitrogen through C 10 and C 9 or through the field of solvent molecules. The -I effect of the acetoxy and methoxy groups is less than that of the -OH group, therefore it follows that the electron density on the aromatic ring of the acetoxy compound is also lower and leads, by induction, to a lower pKa value for this compound. Such effects are not observed in the series of compounds (XXIII, XXI, XXIV and XVII) and (XX, XIX, XVII and XVI).
In the series of compounds (XXI, VI and IV) and (XVII, I and VII) a change from -OH to other groups at C3 appears to have some base weakening effects when compared with the series of compounds XXIII, V, XI, III and XV. The electron withdrawing effects of those groups are in the order CH 3CO.O- > -OH > CH 3O and hence the lowest electron density will occur on the aromatic ring of the acetoxy compound which should be the weakest base.
Introduction of a methyl group in the nucleus at C 5 or C 7 [ref. 15 p. 264] is accompanied by base strengthening effects. The methyl group causes an increase in the electron density in the lone pair orbital of nitrogen which facilitates its protonation.
Although a hydroxyl group is base weakening through the inductive effects (-I), it has some base strengthening effect in the case of dihydro ( -14- ) hydroxycodeinone (compound X). This may be due to intramolecular hydrogen bonding between the lone pair orbital of nitrogen and hydroxyl groups, both of which have cis-configuration ( [ 19] ). The hydrogen bonding is probably greater to the ion than to the free base and hence a base strengthening effect is observed. A similar phenomenon was observed in the case of cis-10-hydroxydihydrodesoxycodeine by Rapoport and Masamune ( [ 20] ).
The removal of the C7 - C8 double bond is accompanied by an increase in the basic strength of the tertiary nitrogen (compare the series of compounds XXIII, V, III, XXI and XVII with the corresponding dihydro-compounds XIX, VIII, II, XVIII and XVI). The presence of this double bond permits the withdrawal of electrons from the adjoining carbon atoms, thus decreasing the electron density in the lone pair orbital of nitrogen, resulting in a base weakening effect. Saturation of the double bond removes this influence and results in the observed increase in the basic strength of the dihydrocompounds.
[Ed.: The research reported above is continuing, and the authors hope to prepare another paper for publication in a later number of the Bulletin.]
Mennicke, Dis. Leipzig (1897)
002Mauz, Dis. Tubingen (1904)
003C. Morton (1926) Pharm. J. 116, 567
004I. M. Kolthoff (1925) Biochem. Z., 162, 289.
005H. Baggesgaard-Rasmussen, and I. Martin (1929) Dansk. Tidsskr. Farm., 3, 197.
006H. Baggesgaard-Rasmussen and F. Reimer (1935) Arch. Pharm. 273, 129.
007N. Schoorl (1939) Pharm. Weekblad., 76, 1479.
008F. W. Oberst (1943) J. Pharmacol. Exptl. Therap., 79, 266.
009H. Rapoport and G. W. Stevenson (1954), J. Amer. Chem. Soc. 76, 1796.
010Y. M. Perel'man (1957), Sb. Nauchn. Tr. Leiningr. Khin, Farmatseut. Instr. 2, 38.
011G. W. Stevenson and D. Williamson (1958), J. Amer. Chem. Soc. 80, 5943.
012R. Rouffiac. A. Lattes and P. Valdiquie (1963) Ann. Pharm. Franc., 21, 413.
013G. Schill and K. Guslavii (1964), Acta. Pharm. Suecica, 1, 24.
014C. W. Davies and G. H. Nancollas, (1950), Nature, 165, 237.
015K. W. Bentley (1954)," The Chemistry of Morphine Alkaloids ", London: Oxford.
016D. Waldi K. Schnakarz and F. Munter (1961), J. Chromatog., 6, 61.
017A. A. Noyes (1893), Z. Physik. Chim., 11, 495.
018A. Albert, and E. P. Serjeant (1962), "Ionization Constants of Acids and Bases ", London: Methuen.
019C. Schopf and F. Borkowsky (1927), Ann. der Chim., 452, 249.
020H. Rapoport and S. Masamune (1955), J. Amer. Chem. Soc., 77, 4330.
021F. W. Oberst and H. L. Andrews (1941), J. Pharmacol. Exptl. Therap., 71, 38.