Reactions of Grignard reagents with 1,3-dicyanoadamantane

Article abstract of DOI:10.1023/B:RUCB.0000009650.93387.41

Reactions of Grignard reagents RMgX (R = Me, Et, Pr, Bu; X = Br, I) with 1,3-dicyanoadamantane (1) were studied. Optimum conditions for the synthesis of monoaddition products of Grignard reagents to compound 1 were established. The first stage of the reaction of cyanoadamantane 1 with MeMgBr was studied by the MNDO-PM3 method. According to calculations, the more preferable reaction mechanism involves formation of a six-membered cyclic intermediate containing two Mg atoms, two C atoms, and one Br and one N atom.

Full text of DOI:10.1023/B:RUCB.0000009650.93387.41

2048
Russian Chemical Bulletin, International Edition, Vol. 52, No. 9, pp. 2048—2051, September, 2003
Reactions of Grignard reagents with 1,3ꢀdicyanoadamantane
a
b
b
I. A. Novakov,a B. S. Orlinson,a E. N. Savel´ev, V. N. Urazbaev, and Yu. B. Monakov
ꢀ
aVolgograd State Technical University,
28 prosp. Lenina, 400131 Volgograd, Russian Federation.
Fax: +7 (844 2) 34 9941. Eꢀmail: phanchem@vstu.ru
bInstitute of Organic Chemistry, Ufa Research Center of the Russian Academy of Sciences,
71 prosp. Oktyabrya, 450054 Ufa, Russian Federation.
Fax: +7 (347 2) 35 6166. Eꢀmail: monakov@anrb.ru
Reactions of Grignard reagents RMgX (R = Me, Et, Pr, Bu; X = Br, I) with 1,3ꢀdiꢀ
cyanoadamantane (1) were studied. Optimum conditions for the synthesis of monoaddition
products of Grignard reagents to compound 1 were established. The first stage of the reaction of
cyanoadamantane 1 with MeMgBr was studied by the MNDOꢀPM3 method. According to
calculations, the more preferable reaction mechanism involves formation of a sixꢀmembered
cyclic intermediate containing two Mg atoms, two C atoms, and one Br and one N atom.
Key words: adamantane, cyanoadamantanes, Grignard reagents, 1ꢀcyanoꢀ3ꢀoxoꢀadamantaꢀ
nes, quantumꢀchemical calculations, reaction mechanism.
Dicyanoadamantanes are intermediate compounds,
which are used in the synthesis of some derivatives (in
particular, diamines possessing various types of therapeuꢀ
tic activity1) and polymeric materials with improved opꢀ
erating characteristics.2 In this work we studied the reacꢀ
tions of 1,3ꢀdicyanoadamantane (1) with Grignard reꢀ
agents RMgX (R = Me, Et, Pr, Bu; X = Br, I) in Et2O and
Et2O—THF mixture (Scheme 1).
Nꢀhalomagnesiumketimine 2, which made the yield of
the target product 3 very low. The solubility of ketimine 2
can be enhanced by using THF as coꢀsolvent; in this case
the duration of the reaction somewhat increases. Thereꢀ
fore, subsequent experiments were performed with
THF—Et2O mixtures (the solvents were taken in a 1 : 1 to
1 : 2 (v/v) ratio).
The kinetics of the reactions under study are strongly
affected by the structure of the substrate, as well as by the
solvent nature and temperature. To ensure control of the
course of the reactions and to establish the mechanism of
the reactions of compound 1 with Grignard reagents, the
first stage of the process was studied by the MNDOꢀPM3
method.
Scheme 1
First, to be certain that nonvalent (bridging) bonds
formed by the Mg atom are correctly described by this
quantumꢀchemical method, we carried out a theoretical
study of MeMgBr dimerization. The Grignard reagent
molecules form associates in solution; the coordination
sphere of the Mg atom can also contain some solvent
molecules while the coordination number of Mg can vary
from 4 to 6.3 The calculated geometric parameters of
three possible MeMgBr dimers (Table 1) are in reasonꢀ
able agreement with the experimental values for organoꢀ
magnesium compounds.3 Based on the dimerization enꢀ
ergies ∆E (see Table 1), the dimer with two bridging Br
atoms is the most energetically favorable; this is consisꢀ
tent with the experimental data.3 The rather high ∆E valꢀ
ues are due to the fact that the models chosen ignored the
presence of solvent molecules within the coordination
sphere of the metal atom (cf. ∆E = –17.6 kJ mol–1 obꢀ
R = Me (a), Et (b), Pr (c), Bu (d); X = I (a, b), Br (c, d)
The starting point was to study the reactions of
Grignard reagents with compound 1 in Et2O. However,
the reactions were complicated by the precipitation of
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1938—1941, September, 2003.
1066ꢀ5285/03/5209ꢀ2048 $25.00 © 2003 Plenum Publishing Corporation

Reactions of RMgX with 1,3ꢀdicyanoadamantane
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 9, September, 2003
2049
Table 1. Molecular and electronic structure of MeMgBr and its
Scheme 3
dimers
Compound
∆Е
/kJ mol–1
QMg
rMg—Br rMg—C
Å
—
+0.72
+0.69
2.37
—
1.87
2.15
–162.4
–228.8
–256.0
+0.61
+0.67
2.42
2.38
2.15
—
Note. ∆E = Edimer – 2Emonomer is the dimerization energy, QMg is
the atomic charge of Mg, rMg—Br and rMg—C are the correspondꢀ
ing average bridging bond lengths (interatomic distances for
MeMgBr).
tained in our calculations for MeMgBr with inclusion of
these effects) (Scheme 2).
Note. Figures preceded by the "+" or "–" sign are the atomic
charges; other figures are the bond orders.
Scheme 2
To choose the preferred mechanism of the reaction of
compound 1 with MeMgBr, we analyzed the results of
calculations of intermediate products 4—6, carried out
with full geometry optimization. The attainment of a gloꢀ
bal energy minimum was checked by performing calculaꢀ
tions with modified initial molecular geometries. Accordꢀ
ing to calculations, the formation of intermediates 4 and 5
is energetically favorable (Table 2). Structure 6 does not
correspond to a minimum on the potential energy surface
(geometry optimization leads to the starting compounds);
therefore, the corresponding reaction route is hardly probꢀ
able. We also calculated some other possible structures
containing fourꢀ and sixꢀmembered rings with different
types of arrangement of the constituent atoms; however,
Thus, the geometric parameters and energy characterꢀ
istics of the bridging bonds in the Grignard reagent molꢀ
ecules can be qualitatively reproduced by the PM3
method, but obtaining quantitatively correct results reꢀ
quires the inclusion of solvent molecules within the coorꢀ
dination sphere of the metal. However, in order to make
the calculations less difficult, because the exact number
of solvent molecules involved in the reaction is unknown,
and taking into account that the chemical properties of a
Grignard reagent and its behavior in chemical reactions
can always be qualitatively explained by the formula
RMgX,4 subsequent computations were carried out withꢀ
out inclusion of solvent molecules.
A study5 on the kinetics of the first stage of the reacꢀ
tion between BuMgBr and benzonitrile revealed a rapid
formation of an intermediate complex of the reactants
and showed that intramolecular rearrangement in the
complex is the rateꢀdetermining step for the overall reacꢀ
tion. Three possible mechanisms of the reactions between
nitriles and Grignard reagents were proposed.5—9 All of
them involve the formation of an intermediate product
containing a fourꢀ or a sixꢀmembered ring (Scheme 3).
Table 2. Energy characteristics of different reaction mechanisms
Intermediate
complex
∆Е1
∆Е2
∆Е3
kJ mol–1
4
5
6
–153.9
–163.9
—
+19.4
+29.4
—
–134.5
–134.5
–134.5
Note. ∆E1 is the energy of formation of intermediate comꢀ
plexes (4—6) from 1, ∆E2 is the formation energy of the end
product (rearrangement of 4—6 into 2), and ∆E3 is the energy of
formation of Nꢀhalomagnesiumketimine 2 from 1.

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Russ.Chem.Bull., Int.Ed., Vol. 52, No. 9, September, 2003
Novakov et al.
Table 3. Effect of substituents in the Grignard reagent molecules
on the yields of ketonitriles 3a—d
compounds 4 and 5 were found to be the most energetiꢀ
cally favorable.
According to calculations, the fourꢀ and sixꢀmemꢀ
bered rings in molecules 4 and 5, respectively, are nearly
planar. The atomic charge distribution patterns (alternaꢀ
tion of negative and positive charges) for these rings are
typical of rather stable cyclic structures (see Scheme 3).
The bond orders for the newly formed C—Me and N—Mg
bonds (0.90—0.96 and 0.81—1.05, respectively) are charꢀ
acteristic of single bonds. The multiplicities of the carꢀ
bon—nitrogen bonds in molecules 4 and 5 are reduced
to 2 (the corresponding bond orders lie between 1.90
and 1.99). This means that the intermediates 4 and 5
correspond to the situation where the addition of the
Grignard reagent to dinitrile 1 is nearly completed.
Namely, one should only cleave a weak Mg—Me bond
Grignard Molar excess of
reagent Grignard reagent
Duration of
first stage/h
Yield
3a—d (%)
MeMgI
EtMgI
PrMgBr
BuMgBr
2.8
3.2
3.2
3.2
3
3
8
78
75
70
72
12
Note. The concentration of substrate 1 was 0.3 mol L–1
.
route via the fourꢀmembered ring 4. The choice of a parꢀ
ticular reaction pathway is determined by the steric hinꢀ
drances produced by reactants, by the reactant concenꢀ
trations, and by the solvent nature. The conditions for the
synthesis of alkyl(cyanoadamantyl)ketones in 70—78%
yields are substantiated.
(bond order is 0.06 and bond energy is +19.4 kJ mol–1
)
for 4 and eliminate a rather loosely bound MeMgBr (inꢀ
teraction energy is +29.4 kJ mol–1) for 5 (see Table 2) to
obtain ketimine 2.
Experimental
Thus, the reaction of dinitrile 1 with MeMgBr can
involve the formation of two cyclic intermediates, 4 and 5,
the latter being somewhat more energetically favorable.
The choice of particular reaction route seems to be deꢀ
pendent on many factors. In particular, if either molꢀ
ecule 1 or the Grignard reagent molecule produce some
steric hindrances, only one RMgBr molecule is involved
in the formation of the cyclic intermediate and the reacꢀ
tion proceeds via the fourꢀmembered ring 4. For instance,
our calculations of structures of the types 4 and 5 for
the reaction of compound 1 with sterically hindered
PhCH2MgBr showed that the structure with the fourꢀ
membered ring is by 38.3 kJ mol–1 more preferable than
the structure containing the sixꢀmembered ring. The
course of the reaction can also be strongly affected by the
reagent concentrations. For instance, an increase in the
RMgBr concentration should favor the reaction via the
sixꢀmembered ring 5.
IR spectra were obtained on a SpecordꢀM82 spectrometer
(KBr pellets) and 1H NMR spectra were recorded on a Bruker
AMꢀ300 spectrometer (300.13 MHz) in DMSOꢀd6 with Me4Si
as internal standard. GLC analyses were performed on a
Perkin—Elmer—Sigma 2S chromatograph equipped with
a flameꢀionization detector and a stainless steel column
(0.3×100 cm, 10% PPMSꢀ4, Chromatone NꢀAWꢀDMCS,
nitrogen as the carrier gas) with linear temperature programꢀ
ming in the range from 80 to 230 °C. Quantumꢀchemical calcuꢀ
lations were carried out by the MNDOꢀPM3 method10 with
full geometry optimization for all compounds involved in reꢀ
actions.
3ꢀAcetylꢀ1ꢀcyanoadamantane (3a). A reactor equipped with
a stirrer, a reflux condenser with a calcium chloride tube, and a
dropping funnel was charged with Mg (8.16 g, 0.28 mol) and
Et2O (100 mL). Then, MeI (17.4 mL, 0.28 mol) dissolved in
Et2O (50 mL) and compound 1 (18.6 g, 0.10 mol) dissolved in
THF (100 mL) were added successively from a dropping funnel
over a period of 0.5 h. The reaction mass was stirred for 3 h,
cooled, and then water (25 mL), 12% NaOH solution (40 mL),
an additional 30 mL of water and NH4Cl (5 g) was added. The
precipitate that formed was filtered and extracted with THF
(3×150 mL). The extract was evaporated and the stillage resiꢀ
due was distilled in vacuo. The yield was 15.8 g (78%), b.p.
165—168 °C (2 Torr). Recrystallization from PriOH gave the
target product of 98% (GLC monitoring), b.p. 98—102 °C.
Found (%): C, 76.62; H, 8.38; N, 6.81. C13H17NO. Calcuꢀ
Based on the results of our calculations, this can be
done with certainty using a twofold excess of the Grignard
reagent. In practice, the use of a THF—Et2O (1 : 2)
mixture and a 2.8 to 3.2 excess of the Grignard reagent
allows one to obtain the monoaddition products in
70—78% yields (Table 3). It should be noted that a reaꢀ
sonably high (up to 80%) yield of the diaddition product
in the reaction of dinitrile 1 with MeMgI can be obtained
if the molar excess of the Grignard reagent is greater
than 4.4 and the substrate concentration is at least
lated (%): C, 76.81; H, 8.43; N, 6.89. IR spectrum, ν/cm–1
:
2910, 2853 (≡C—H); 2230 (C≡N); 1704 (C=O). 1H NMR,
δ: 1.51—1.75 (m, 12 H, CH2 adamantane); 1.97 (s, 2 H,
CH adamantane); 2.10 (s, 3 H, Me).
0.1—0.2 mol L–1
.
Thus, we proposed the most probable mechanism of
the reaction of 1,3ꢀdicyanoadamantane with Grignard reꢀ
agents, involving the formation of cyclic intermediates 4
and 5. The route via the sixꢀmembered ring 5 is somewhat
more energetically preferable (by 10 kJ mol–1) than the
1ꢀCyanoꢀ3ꢀpropionyladamantane (3b) was synthesized analoꢀ
gously to compound 3a using EtI (25.6 mL, 0.32 mol) instead of
MeI. The yield was 16.2 g (75%), b.p. 179—181 °C (2 Torr).
Recrystallization from PriOH—hexane mixture (1 : 3, v/v) gave

Reactions of RMgX with 1,3ꢀdicyanoadamantane
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 9, September, 2003
2051
the target product of 97% purity (GLC monitoring), b.p.
References
58—62 °C. Found (%): C, 77.18; H, 8.72; N, 6.36. C14H19NO.
Calculated (%): C, 77.38; H, 8.81; N, 6.45. IR spectrum, ν/cm–1
2911, 2850 (≡C—H); 2235 (C≡N); 1710 (C=O). 1H NMR, δ:
0.82 (br.s, 3 H, Me); 1.49—1.71 (m, 12 H, CH2 adamantane);
2.18 (s, 2 H, CH adamantane); 2.45 (q, 2 H, CH2C=O,
J = 7 Hz).
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3ꢀButyrylꢀ1ꢀcyanoadamantane (3c) was synthesized analoꢀ
gously to compound 3a using PrBr (29.1 mL, 0.32 mol) instead
of MeI. The reaction was carried out over a period of 8 h. The
yield was 16.2 g (70%), b.p. 187—190 °C (2 Torr). Found (%):
C, 78.73; H, 9.07; N, 5.97. C15H21NO. Calculated (%): C, 77.88;
H, 9.15; N, 6.06. IR spectrum, ν/cm–1: 2912, 2852 (≡C—H);
2241 (C≡N); 1706 (C=O). 1H NMR, δ: 0.90 (t, 3 H, Me,
J = 6 Hz); 1.28 (m, 2 H, CH2CH2Me); 1.51—1.71 (m, 12 H,
CH2 adamantane); 2.05 (s, 2 H, CH adamantane); 2.38 (t, 2 H,
CH2CH2C=O, J = 7 Hz).
1ꢀCyanoꢀ3ꢀpentanoyladamantane (3d) was synthesized
analogously to compound 3a using BuBr (33.7 mL, 0.32 mol)
instead of MeI. The reaction was carried out over a peꢀ
riod of 12 h. The yield was 17.6 g (72%), b.p. 197—200 °C
(2 Torr). Found (%): C, 78.18; H, 9.36; N, 5.62. C16H23NO.
Calculated (%): C, 78.32; H, 9.45; N, 5.71. IR spectrum,
ν/cm–1: 2908, 2855 (≡C—H); 2247 (C≡N); 1701 (C=O).
1H NMR, δ: 0.90 (t, 3 H, Me, J = 6.5 Hz); 1.23—1.33 (m,
4 H, CH2CH2CH2); 1.63—1.92 (m, 12 H, CH2 adamantane);
2.05 (s, 2 H, CH adamantane); 2.41 (t, 2 H, CH2CH2C=O,
J = 7 Hz).
7. H. G. O. Becker, Einführung in die Elektronentheorie
organischꢀchemischer Reaktionen, VEB Deutscher Verlag der
Wissenchaften, Berlin, 1974, 564 pp.
8. H. Edelstein and E. I. Becker, J. Org. Chem., 1966, 31, 3375.
9. V. F. Raaen and J. F. Eastham, J. Am. Chem. Soc., 1957,
79, 6088.
10. J. J. P. Stewart, J. Comput. Chem., 1989, 10, 209.
Received November 19, 2001;
in revised form January 22, 2003