Steric effect in alkylation reactions by N-alkyl-N-nitrosoureas: A kinetic approach

Article abstract of DOI:10.1002/poc.1402

The alkylation reactions of 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilic characteristics similar to DNA base by five N-alkyl-N-nitrosoureas (methyl-, ethyl-, propyl-, butyl-, and allylnitrosourea) were investigated in 7.3 (v/v) water/dioxane medium in the 5.0-6.5 pH range. Decomposition of alkylnitrosoureas (ANU) gives rise to alkyldiazonium ions that yield NBP-R adducts directly or through carbocations in certain instances. The NBP alkylation rate constants by these species were determined. The following sequence of alkylating potential was found: methyl- > ethyl- > allyl- > propyl- > butyl group. Application of Ingold-Taft correlation analysis to the kinetic results revealed that the NBP alkylation reactions occur mainly through steric control. The values of the molar absorption coefficients of the NBP-R adducts also reveal the determinant influence of a steric effect in the formation of alkylation adducts. The kinetic results are consistent with the biological activity of ANU. Copyright

Full text of DOI:10.1002/poc.1402

Research Article
Received: 13 March 2008,
Revised: 30 April 2008,
Accepted: 6 May 2008,
Published online in Wiley InterScience: 10 June 2008
(www.interscience.wiley.com) DOI 10.1002/poc.1402
Steric effect in alkylation reactions by
N-alkyl-N-nitrosoureas: a kinetic approach
a
a
a
a
´
J. A. Manso , M. T. Perez-Prior , M. P. Garcı´a-Santos , E. Calle
a
*
and J. Casado
The alkylation reactions of 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilic charac-
teristics similar to DNA bases, by five N-alkyl-N-nitrosoureas (methyl-, ethyl-, propyl-, butyl-, and allylnitrosourea)
were investigated in 7:3 (v/v) water/dioxane medium in the 5.0–6.5 pH range. Decomposition of alkylnitrosoureas
(ANU) gives rise to alkyldiazonium ions that yield NBP-R adducts directly or through carbocations in certain instances.
The NBP alkylation rate constants by these species were determined. The following sequence of alkylating potential
was found: methyl- > ethyl- > allyl- > propyl- > butyl group. Application of Ingold–Taft correlation analysis to the
kinetic results revealed that the NBP alkylation reactions occur mainly through steric control. The values of the molar
absorption coefficients of the NBP-R adducts also reveal the determinant influence of a steric effect in the formation of
alkylation adducts. The kinetic results are consistent with the biological activity of ANU. Copyright ß 2008 John Wiley
& Sons, Ltd.
Keywords: reactivity of N-alkyl-N-nitrosoureas; steric effects
Reactions were carried out in the 5.0–6.5 pH range. Acetic/
INTRODUCTION
acetate buffer was used to maintain pH constant. To monitor the
alkylation reactions, 2.4-ml aliquots of the alkylation mixture were
removed at different times and added to a cuvette containing
0.6 ml of 99% triethylamine reagent (Et3N), which stopped the
alkylation process and generated a blue color, whose absorbance
was measured at the wavelength of maximum absorption (shown
below).
Alkylating agents are considered to be archetypical carcino-
gens.[1,2] Since the decomposition of alkylnitrosoureas (ANU)
gives rise to alkyldiazonium ions (RNþ2 ) without any need for
metabolic activation, they offer an ideal series of compounds in
which to examine the effect of variations in chemical structure on
alkylating potential.
Previous studies (Chapter 3 of Reference [3]) have shown that
some ANUs induce tumors in different organs of rats, but do not
have a favorable partition coefficient into organic solvents from
water. If physical properties such as solubility and partition
coefficient play any role, it must be minor and perhaps limited to
effects on potency. Some results[4] have pointed to the structure
of the alkyl group adjacent to the nitroso group as the most
important determinant of the carcinogenic effect.
Since in spite of its chemical relevance, to our knowledge the
chemical reactivity of alkyldiazonium ions as alkylating agents
has not been investigated in a comparative quantitative way, here
we were prompted to address this issue.
The blue NBP adducts showed maximum absorption at
lMNU ¼ 573 nm, lENU ¼ 570 nm, lPNU ¼ 570 nm, lBNU ¼ 570 nm,
and lAlNU ¼ 557 nm. As an example, Fig. 1 shows the increase in
absorption caused by the formation of the NBP-adduct with MNU
over time until no change in absorbance, A, was observed.
Because NBP was in large excess, it may be assumed that all the
nitrosourea was consumed.
Figure 2 represents typical kinetic runs for the alkylation of NBP
by nitrosoureas.
The experimental rate equation was
d½ADꢀ
dt
kalkkdec½OHꢁꢀ½NBPꢀ
rate ¼
¼
½ANUꢀ ¼ k1½ANUꢀ (1)
kalk½NBPꢀ þ kH O½H2Oꢀ
2
where [AD] is the concentration of NBP-R adducts, and k1 the
pseudo-first-order rate constant:
RESULTS AND DISCUSSION
The nucleophile 4-(p-nitrobenzyl)pyridine, NBP, a trap for
alkylating agents[5] with nucleophilic characteristics similar to
DNA bases,[6] was used as the alkylation substrate. This method
was previously used by us to investigate the alkylating potential
of strong alkylating reagents, such as lactones,[7–10] as well as to
determine the reactivity of much weaker alkylating molecules
such as sorbates.[11,12]
NBP alkylation reactions by methyl-, ethyl-, propyl-, butyl-, and
allylnitrosourea (MNU, ENU, PNU, BNU, and AlNU, respectively)
were investigated.
kalkkdec½OHꢁꢀ½NBPꢀ
k1
¼
(2)
kalk½NBPꢀ þ kH O ½H Oꢀ
2
2
*
Correspondence to: J. Casado, Departamento de Qu´ımica f´ısica, Universidad
de Salamanca, E-37008 Salamanca, Spain.
E-mail: jucali@usal.es
´
a
J. A. Manso, M. T. Perez-Prior, M. P. Garc´ıa-Santos, E. Calle, J. Casado
In order to render the NBP soluble, the ANUþNBP alkylation
Departamento de Qu´ımica f´ısica, Universidad de Salamanca, E-37008
Salamanca, Spain
mixtures were prepared in 7:3 (v/v) water/dioxane medium.
J. Phys. Org. Chem. 2008, 21 932–938
Copyright ß 2008 John Wiley & Sons, Ltd.

STERIC EFFECT IN ALKYLATION REACTIONS
Figure 1. Spectrograms showing the formation of the NBP-adduct with
MNU over time in 7:3 water/dioxane medium. Variation in absorbance in
the 15–1440 min interval. [MNU]o ¼ 1.6 ꢂ 10ꢁ3 M; [NBP]o ¼ 0.02 M;
T ¼ 32.5 8C; pH ¼ 6.5
Figure 2. Formation of the NBP-R adducts in 7:3 water/dioxane medium:
methyl- (^), ethyl- (~), propyl- (&), butyl- (*), and allyldiazonium ion (x);
[ANU]o ¼ 8 ꢂ 10ꢁ4 M; [NBP]o ¼ 0.02 M; pH ¼ 6.5; T ¼ 35 8C. Ao and At,
designate the absorbance values of the adducts at times, respectively,
of zero and t
The significance of the different rate constants appearing
in Eqn (1) can be seen in Scheme 1. In the case of MNU and
ENU the effective alkylating agents should be methyl- and
ethyldiazonium ions to give rise NBP-R adducts (R ¼ CH3
and C2H5, respectively).[13,14] For the other nitrosoureas, looking
at PNU as an example, the propyldiazonium ion resulting from
its decomposition undergoes, in competition, elimination to
alkenes, concurrent SN2 substitution and hydride shift yielding a
sec-carbocation that can undergo partitioning between the
associated NBP nuclophile and solvent.[15,16] The method here
used to monitoring the alkylation reactions allows one to
determine kalk rate constant that represents globally any
alkylation mechanisms.
responsible for their consumption when the concentration of the
alkylation substrate [NBP] tends to zero:
dk1
kalkkdec½OHꢁꢀ
lim
¼
(3)
½NBPꢀ!0 d½NBPꢀ
kH O½H2Oꢀ
2
By designating the absorbance values of the NBP-R adducts as
A , A , andA at times, respectively, of zero, t, and infinity (i.e.,
1
o
t
The influence of [OHꢁ] and [NBP] fits Eqn (2) (as shown in Figs 3
and 4). Eqn (3) (derived from Eqn (2)) shows that the hydrolysis of
when the plateau is reached; as shown in Fig. 2), "ANU, "NBP, and
"
being the molar absorption coefficients of the ANU, NBP,
and adducts, respectively, and x the adduct concentration,
AD
alkylating ions (rate constant kH O in Eqn (1)) is the main reaction
2
Scheme 1.
J. Phys. Org. Chem. 2008, 21 932–938
Copyright ß 2008 John Wiley & Sons, Ltd.
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J. A. MANSO ET AL.
Figure 3. Influence of [OHꢁ] in the alkylation reaction of NBP by MNU at
25.0 8C (*), 27.5 8C (&), 30.0 8C (~), 32.5 8C (ꢂ), and 35.0 8C (*);
[NBP]o ¼ 0.02 M; [MNU]o ¼ 8 ꢂ 10ꢁ4 M
Figure 5. Fitting of the results to Eqn (8). [MNU]o ¼ 8 ꢂ 10ꢁ4 M;
pH ¼ 5.72
Eqn (2) can be written in the form:
k1
k
alk=kH O½NBPꢀ
2
¼
(8)
½OHꢁꢀkdec
k
alk=kH O½NBPꢀ þ ½H Oꢀ
2
2
Figure 5 plots the k1/([OHꢁ] kdec) values against those of
[NBP]. The kalk=kH O ratios for the different alkyldiazonium
2
ions were calculated by a nonlinear optimization method.
Since the kdec values were needed to be known, ANU
decomposition reactions were investigated directly. These
reactions were monitored spectrophotometrically at the
wavelengths of maximum absorption for each of the ANUs
studied here (lMNU ¼ 251 nm, lENU ¼ 248 nm, lPNU ¼ 244 nm,
lBNU ¼ 244 nm, and lAlNU ¼ 243 nm).
In the 5.0–7.0 pH range, the following rate equation was
observed for ANU decomposition:
d½ANUꢀ
ꢁ
¼ kdec½OHꢁꢀ½ANUꢀ ¼ k0 ½ANUꢀ
(9)
dt
where k0 is the pseudo-first-order rate constant (in this pH range,
the decomposition reaction of ANU is not catalyzed by the
buffer[17]).
Figure 6 shows a typical kinetic run for the decomposition of
MNU. Experiments at different pHs were carried out (Fig. 7), the
slope a ¼ 1 revealing first order with respect to the concentration
of OHꢁ.
Figure 4. Influence of [NBP] in the alkylation reaction of NBP by MNU at
25 8C in 7:3 water/dioxane medium. [MNU]o ¼ 8 ꢂ 10ꢁ4 M; pH ¼ 5.72
Eqns (4)–(6) can be written as
Table 1 gives the values of kdec measured for the decompo-
sition of the five nitrosoureas investigated here. These results are
consistent with those measured earlier in water medium.[17,18]
Table 2 shows the values of the activation parameters DH# and
DS# for the decomposition reactions.
As is known,[19,20] the existence of an isokinetic relationship
can serve as an argument – but not proof – that the reactions
studied share a common feature. The meaning of the isokinetic
relationship is the existence of a compensation effect between
the values of enthalpy, DH#, and the entropy of activation, DS#,
such that the Gibbs’ energy of activation, DG#, is approximately
constant.
Ao ¼ "ANU½ANUꢀo þ "NBP½NBPꢀ
(4)
(5)
(6)
At ¼ "ANUð½ANUꢀo ꢁ xÞ þ "NBP½NBPꢀ þ x"AD
A
¼ "AD½ANUꢀo þ "NBP½NBPꢀ
1
Integration of Eqn (1) gives
At ꢁ Ao ¼ ðA ꢁ AoÞð1 ꢁ eꢁk t
Þ
(7)
1
1
The results shown in Fig. 8 support the idea of a common
mechanism.
Figure 2 shows the fitting of the experimental data to Eqn (7).
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J. Phys. Org. Chem. 2008, 21 932–938

STERIC EFFECT IN ALKYLATION REACTIONS
Table 2. Activation parameters for decomposition reactions
of N-alkyl-N-nitrosoureas in 7:3 water/dioxane medium
N-Alkyl-N-nitrosourea DH# (kJ molꢁ1 a
)
DS# (J molꢁ1 Kꢁ1 a
)
MNU
ENU
PNU
BNU
AlNU
104 ꢃ 2
116 ꢃ 2
116 ꢃ 2
113 ꢃ 1
105 ꢃ 2
159 ꢃ 8
193 ꢃ 6
192 ꢃ 7
191 ꢃ 5
186 ꢃ 10
a Values are given with their standard deviations.
Figure 6. Decomposition of MNU at 32.5 8C in 7:3 water/dioxane med-
ium. [MNU]o ¼ 4 ꢂ 10ꢁ4 M; pH ¼ 6.49
Figure 7. Variation in the MNU decomposition rate constant with the
acidity of the medium. [MNU] ¼ 4 ꢂ 10ꢁ4 M; T ¼ 32.5 8C
Figure 8. Isokinetic relationship in decomposition reactions of
N-alkyl-N-nitrosoureas
Table 3 gives the kalk=kH O values for the alkylation/hydrolysis
reactions studied here.
The results show: (i) the following sequence of reactivity
electronic structure of that ion. Since unlike the propyldiazonium
ion (with the same number of carbon atoms) the allyldiazonium
ion has two possible electrophilic sites[21] (C1 and C3 positions),
the reactivity of AlNþ2 should be appreciably greater than that of
PNþ2 (approx. twofold greater), as was indeed observed (this
assumption requires that the NBP alkylation reaction by AlN2þ
be more sensitive to the particular structure of this ion than its
competitive solvent reaction); (iii) the hydrolysis of the
2
(expressed as kalk=kH O, as shown in Scheme 1) for diazonium
2
ions (directly or through alkyl cations): MNþ2 > EN2þ > AlN2þ >
PNþ2 > BNþ2 ; (ii) a higher value of kalk=kH O for the allyldiazonium
2
ion as compared with those obtained for propyl- and
butyldiazonium ions. This can be rationalized in terms of the
Table 1. Decomposition rate constants (kdec in Scheme 1) as a function of temperature for N-alkyl-N-nitrosoureas in 7:3 water/
dioxane medium
T (8C)
10ꢁ4 kMNU
10ꢁ4 kENU
10ꢁ4 kPNU (Mꢁ1 minꢁ1 a
)
10ꢁ4 kBNU
10ꢁ4 kAlNU
25.0
27.5
30.0
32.5
35.0
4.2 ꢃ 0.1
5.5 ꢃ 0.1
7.9 ꢃ 0.1
11.7 ꢃ 0.2
16.0 ꢃ 0.3
2.4 ꢃ 0.2
3.6 ꢃ 0.2
4.5 ꢃ 0.5
7.4 ꢃ 0.6
12.6 ꢃ 0.4
2.14 ꢃ 0.03
3.1 ꢃ 0.1
4.5 ꢃ 0.3
7.0 ꢃ 0.1
10.2 ꢃ 0.3
2.56 ꢃ 0.03
4.00 ꢃ 0.02
5.68 ꢃ 0.04
8.38 ꢃ 0.07
12.4 ꢃ 0.1
4.81 ꢃ 0.01
7.6 ꢃ 0.1
10.9 ꢃ 0.2
15.0 ꢃ 0.2
23.4 ꢃ 0.3
a Values are given within the 95% confidence interval.
J. Phys. Org. Chem. 2008, 21 932–938
Copyright ß 2008 John Wiley & Sons, Ltd.
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J. A. MANSO ET AL.
In order to analyze the influence of steric and polar effects
on the relative alkylating potential of alkyldiazonium ions
Table 3. Alkylating potential of alkyldiazonium ions,
expressed as the alkylation rate/hydrolysis rate ratio
(expressed as kalk=kH O), the Ingold–Taft correlation equation[23]
was applied:
2
Alkyldiazonium ion
k
alk=kH O (35 8C)a
2
ðkalk=kH O
Þ
RNþ2
2
¼ sꢄrꢄ þ Es
(10)
Methyl
Ethyl
Propyl
Butyl
Allyl
12 878 ꢃ 102
10 809 ꢃ 179
4691 ꢃ 61
log
ðkalk=kH O
Þ
CH3Nþ2
2
*
The values for s (polar constant) and Es (steric constant) were
3204 ꢃ 117
8169 ꢃ 167
taken from the literature.[24,25]
Correlations with Es, on the one hand, and with s , on the other,
*
a Values given with their standard deviations.
were used to check whether these reactions were controlled
mainly by steric or mainly by polar effects. Figure 9 shows the
respective plots, together with the plot representing the
influence of steric and polar effects jointly (Eqn (10)).
alkyldiazonium ions is not sufficiently effective to prevent
alkylation; (iv) the kinetic results are consistent with the known
fact that the biological activity of ANU decreases when their
molecular size increases, hindered ANU being biologically
inactive.[3,22]
The results show that: (i) owing to the positive signþof the
*
reaction constant r the NBP alkylation reactions by RN2 must
occur through nucleophilic attack; (ii) these reactions are mainly
controlled by the size of the alkyl R groups; (iii) the deviation
Figure 9. Influence of (a) steric; (b) polar, and (c) steric þ polar effects on the reactivity of alkyldiazonium ions as alkylating agents
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STERIC EFFECT IN ALKYLATION REACTIONS
Table 4. Molar absorption coefficients of the NBP-R adducts
NBP-R adduct
l (nm)
" (Mꢁ1 cmꢁ1
)
NBP-Me
NBP-Al
NBP-Et
NBP-Bu
NBP-Pr
573
557
570
570
570
521 ꢃ 30
282 ꢃ 20
204 ꢃ 8
93 ꢃ 11
65 ꢃ 8
shown by the allyldiazonium ion is quite understandable due to
its above-cited particular electronic structure.
Figure 11. Correlation between the structure of NBP-R adducts and their
molar absorption coefficients, "
Molar absorption coefficients of the NBP-R adducts
We were also interested in knowing the molar absorption
coefficients (") of the NBP-R adducts. Knowledge of these values
should permit easy determination of the concentration of
adducts by simply measuring the absorbance.
ions, the stronger the linkage between DNA nucleophile sites and
the electrophilic alkyldiazonium ions.
Experiments were performed with [NBP] ¼ 0.02 M and ANU
concentrations in the 4 ꢂ 10ꢁ4–1.5 ꢂ 10ꢁ3 M range.
The correlations between A ꢁAo values and those of [ANU]o
1
give the values of the molar absorption coefficients shown in
Table 4.
CONCLUSIONS
ꢅ The alkylation reactions of the nucleophile NBP by
The structures of the NBP-R adducts obtained by geometry
optimization (as shown in Experimental Section) revealed (Fig. 10)
that the values of " increase when the size of RNþ2 decreases (the
second highest value for NBP-Al must be due to the particular
electronic structure of the allyl group; refer to comments given
above). The greater the non-planarity in the NBP-R adducts,
disrupting the p-electron cloud to interlink the two phenyl rings,
the smaller the values of " (Fig. 11).
N-alkyl-N-nitrosoureas occur through
a mechanism that
includes the decomposition of ANU to alkyldiazonium ions
(RNþ2 ) that yield NBP-R adducts directly or through carbo-
cations in certain instances.
ꢅ The sequence of reactivity of RNþ2 ions as direct/indirect
NBP alkylating agents is: methyl- > ethyl- > allyl- > propyl- >
butyldiazonium ion. Application of Ingold–Taft treatment to
the kinetic results revealed that the NBP alkylation reactions
by diazonium ions occur under steric control. This may
explain why the biological activity of ANU decreases when
their molecular size increases (hindered ANUs are biologically
inactive).
A similar argument can be invoked to rationalize the fact that
the biological activity of ANUs decreases when their molecular
size increases:[3,22] the smaller the alkyl group of the diazonium
ꢅ The values of the molar absorption coefficients for the NBP-R
adducts also reveal the determinant influence of steric effect in
the formation of alkylation adducts.
EXPERIMENTAL
General remarks
A Shimadzu UV-2401-PC spectrophotometer with a thermoelec-
tric six-cell holder temperature control system (ꢃ0.1 8C) was used.
The reaction temperature was kept constant (ꢃ0.05 8C) with a
Lauda Ecoline RE120 thermostat.
A Crison Micro pH 2000 pH-meter was used to perform pH
measurements (ꢃ0.01).
Water was deionized with a MilliQ-Gradient (Millipore).
All kinetic runs were performed in triplicate.
Numerical treatment of the data was performed using the
7.1.44 Data Fit software. Geometry optimization of the NBP-R
adducts was carried out with the Chem3D Ultra Molecular
Modeling and Analysis software, version 9.0, and with Gaussian
03W Client Pro 9.0. The PM3 semiempirical method was used.
Figure 10. Lack of coplanarity in the NBP-R adducts
J. Phys. Org. Chem. 2008, 21 932–938
Copyright ß 2008 John Wiley & Sons, Ltd.
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J. A. MANSO ET AL.
Procedures: synthesis of N-alkyl-N-nitrosoureas
[3] W. Lijinsky, Chemistry and Biology of N-Nitroso Compounds, Chapter 3,
Cambridge University Press, Cambridge, GB, 1992.
[4] W. Lijinsky, R. K. Elespuru, A. W. Andrews, Mutat. Res. 1987, 178,
157–165.
N-Methyl-N-nitrosourea and N-ethyl-N-nitrosourea were obtained
from Sigma.
[5] J. H. Kim, J. J. Thomas, Bull. Environ. Contam. Toxicol. 1992, 49,
879–885.
[6] S. E. Shephard, W. K. Lutz, Cancer Surv. 1989, 8, 401–421.
N-Propyl-N-nitrosourea, N-butyl-N-nitrosourea, and N-allyl-N-
nitrosourea were prepared from the respective N-alkylureas.
N-butylurea was obtained from Fluka while N-propylurea and
N-allylurea were Alfa and Merck products, respectively.
PNU, BNU, and AlNU were prepared as by Werner.[26] The
respective N-alkylureas (approx. 1 g) were dissolved in water and
10 g of sodium nitrite was added. The mixture was cooled to
below 0 8C and ice-cold sulfuric acid (10%) was added dropwise
during continuous stirring. The nitrosoureas precipitated as
yellow crystals. After vacuum filtration, the crystals collected were
repeatedly washed with cool water and then desiccated.
´
´
[7] M. P. Garc´ıa Santos, S. Gonzalez Mancebo, J. Hernandez Benito, E.
Calle, J. Casado, J. Am. Chem. Soc. 2002, 124, 2177–2182.
´
[8] J. A. Manso, M. T. Perez Prior, M. P. Garc´ıa Santos, E. Calle, J. Casado,
Chem. Res. Toxicol. 2005, 18, 1161–1166.
[9] M. P. Garc´ıa Santos, E. Calle, J. Casado, J. Am. Chem. Soc. 2001, 123,
7506–7510.
´
[10] J. A. Manso, M. T. Perez Prior, M. P. Garc´ıa Santos, E. Calle, J. Casado,
J. Solution Chem. 2008, 37, 451–457.
´
[11] M. T. Perez Prior, J. A. Manso, M. P. Garc´ıa Santos, E. Calle, J. Casado,
J. Agric. Food Chem. 2005, 53, 10244–10247.
´
[12] M. T. Perez Prior, J. A. Manso, M. P. Garc´ıa Santos, E. Calle, J. Casado,
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[13] B. T. Golding, C. Bleasdale, J. McGinnis, S. Mu¨ller, H. T. Rees, N. H. Rees,
P. B. Farmer, W. P. Watson, Tetrahedron 1997, 53, 4063–4082.
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[14] S. Miertus, V. Frecer, J. Belkova, J. Bella, L. Bahna, B. Bohmova,
¨
´
´
The authors thank the Spanish Ministerio de Educacion y Ciencia
(Projects CTQ2004-05048/BQU and CTQ2007-63263), as well as
´
the Spanish Junta de Castilla y Leon (Grant SA011A05) for
supporting the research reported in this paper. J.A.M. and
Neoplasma 1986, 33, 283–296.
[15] D. Brosch, W. Kirmse, J. Org. Chem. 1991, 56, 907–908.
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1988, p. 106.
´
M.T.P.P. also thank the Ministerio de Educacion y Ciencia and
the Junta de Castilla y Leon for Ph.D. grants. The authors also
´
thank the referees for their valuable comments.
[20] J. E. House, Principles of Chemical Kinetics, WCB Publishers, Dubuque,
1997, p. 162.
[21] W. Kirmse, Angew. Chem. Int. Ed. 1976, 15, 251–320.
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