Probing Molecular Shape
was still observed. The signals for the axial and the equatorial
proton were moving toward each other until the inner signals
overlapped at 363 K. The increased intensity of the inner peaks
and the highly diminished intensity of the outer peaks may be
explained by this movement of the doublets toward each other.
Experimental Section
Synthesis: 5-Hydroxyhexahydropyrimidine (1). Formalin (39%,
0.88 mL, 11.1 mmol) was added dropwise to a stirred solution of
1,3-diamino-2-propanol (1.0 g, 11.1 mmol) in water (2 mL). The
reaction mixture was stirred for 24 h at room temperature and then
lyophilized. The crude residue was purified by vacuum sublimation,
which yielded a highly hygroscopic white solid at 70 °C/55 Torr
Conclusions
(0.6 g, 53%); mp 101-103 °C (lit.5 mp 99-102 °C). H NMR
1
We have demonstrated by 1H NMR and IR spectroscopy that
the hydroxyl group in 5-hydroxyhexahydropyrimidine (1) is
stabilized in an axial orientation by hydrogen bonding and that
the N-H bonds are also stabilized in an axial orientation,
presumably by anomeric interactions. For 1,3-dioxan-5-ol (4)
the stabilization of the axial OH group by hydrogen bonding is
even more pronounced. We also attempted to determine the
extent to which intramolecular hydrogen bonding stabilizes the
dominant conformer and inhibits ring inversion; however, that
was not possible in these systems due to solubility problems in
suitable solvents.
To gain further insights into the steric and electronic effects
governing the stability of conformers of 5-hydroxyhexahydro-
pyrimidine (1), we have undertaken molecular modeling cal-
culations on 1 and on simpler model systems (4, 2, cyclohexanol,
and piperidine). The results from these calculations which were
performed in vacuo at two different levels of theory (ab initio
and DFT methods) agreed very well with the experimental
findings in solution (CDCl3 for NMR spectroscopy and CHCl3
for IR spectroscopy).
No gauche effect can be observed in either 1 or 4 in CDCl3
or in our modeling in vacuo; rather the opposite effect is seen.
Due to steric crowding of the heterocycles, an equatorial position
of the hydroxyl group is preferred even more strongly than in
cyclohexanol (1.9 kcal mol-1 for 4, 1.9 kcal mol-1 for 1, and
0.8 kcal mol-1 for cyclohexanol). This tendency is more than
counterbalanced by intramolecular hydrogen bonding, which is
only possible when the OH group is axial. This situation is
dependent upon the solvent. It has recently been demonstrated,
for example, that intramolecular hydrogen bonding in ethylene
glycol27 is unlikely to be important in determining conforma-
tional preferences, except possibly in fairly nonpolar solvents,
and that the gauche effect is very important for ethylene glycol,
particularly in polar solvents such as water.
(CDCl3, 300 MHz) δ 1.78 (br s, 3H, OH and NH), 2.87 (dd,
J4e,5 ) 3.1 Hz, J4e,2e < 1 Hz, 2H, H4e and H6e), 3.07 (dd, J4a,4e
)
12.8 Hz, J4a,5 ) 2.9 Hz, 2H, H4a and H6a), 3.57 (m, 1H, H5), 3.70
(d, J2a,2e ) 12.5 Hz, 1H, H 2a), 3.75 (d, 1H, H2e). 1H NMR (D2O,
300 MHz) δ 1.94 (dd, J4a,5 ) 7.8 Hz, 2H, H4a and H6a), 2.41 (dd,
J4a,4e ) 12.9 Hz, J4e,5 ) 3.8 Hz, 2H, H4e and H6e), 2.76 (d,
J2a,2e ) 12.5 Hz, 1H, H2a), 2.90 (m, 1H, H5), 3.00 (d, 1H, H2e).
1H NMR (DMSO-d6, 500 MHz) δ 3.31 (dd, J4a,4e ) 12.9 Hz,
J4a,5 ) 7.9 Hz, 2H, H4a and H6a), 2.93 (dd, J4e,5 ) 3.1 Hz, 2H,
H4e and H6e), 3.19 (m, 1H, H5), 3.25 (d, J2a,2e ) 12.6 Hz, 1H,
H2a), 3.50 (d, 1H, H2e), 5.07 (very broad flat singlet, 3H, NH and
OH). 13C NMR (CDCl3, 75 MHz) δ 48.9 (C4, C6), 58.8 (C2), 63.2
(C5). Low-resolution EI MS 102 ([M]+), 101 ([M - H]+). The
1
quoted H and 13C NMR shifts are in agreement with published
values.5
Hexahydropyrimidine (2).6 Formalin (39%, 45.8 mL, 0.3 mol)
was added dropwise to an ice-cooled, stirred solution of 1,3-
diaminopropane (40 g, 0.27 mol) in water (40 mL) and the mixture
was then stirred for 2 h at room temperature. The mixture was
cooled in an ice bath and NaOH pellets were added. The layers
that formed were separated and the upper layer of crude hexahy-
dropyrimidine was dried over NaOH pellets and vacuum distilled.
The fraction with bp 37-53 °C/55 Torr (lit.6 bp 58-60 °C/20
mmHg) contained approximately 90% hexahydropyrimidine and
10% 1,3-diaminopropane (14 g in total). An ice-cooled aliquot of
this fraction (6 g total, containing 5.6 mmol of 1,3-diaminopropane)
was stirred over K2CO3 and then o-hydroxybenzaldehyde (1.51 g,
12.4 mmol) was added dropwise to the suspension. The resulting
bright yellow mixture was stirred on ice for 30 min with the addition
of extra K2CO3 desiccant as the reaction progressed. The crude
reaction mixture was decanted from the K2CO3 and placed under
vacuum (55 Torr) and a liquid nitrogen cooled trap was attached
to collect the product, which was a colorless fuming liquid (2.4 g,
51% based on the mass of hexahydropyrimidine in 6 g of mixture).
1H NMR (CDCl3, 300 MHz) δ 1.52 (m, 2H, H5), 1.72 (br s, 2H,
NH), 2.98 (t, J5,4 ) 5.5 Hz, 4H, H4 and H6), 3.80 (s, 2H, H2). 13
NMR (CDCl3, 75 MHz) δ 28.9 (C5), 45.8 (C4, C6), 63.0 (C2).
1,3-Dioxane (3). This compound was obtained commercially and
dried over NaOH pellets before use. H NMR (CDCl3, 300 MHz)
δ 1.77 (m, 2H, H5), 3.91 (t, J5,4 ) 5.4 Hz, 4H, H4 and H6), 4.86
(s, 2H, H2). 13C NMR (CDCl3, 75 MHz) δ 26.6 (C5), 66.9 (C4,
C6), 94.2 (C2).
1,3-Dioxan-5-ol (4). 1,3-Dioxan-5-ol benzoate (6) was isolated
as colorless, needlelike crystals (26.7 g, 10%), mp 75.5-76.5 °C
(lit.9 mp 72 °C), using the method of Hibbert.9 1H NMR (CDCl3,
300 MHz) δ 4.06 (dd, J4e,5 ) 3.9 Hz, 2H, H4e and H6e), 4.12 (dd,
J4a,4e ) 12.0 Hz, J4a,5 ) 3.0 Hz, 2H, H4a and H6a), 4.87 (d,
J2a,2e ) 6.3 Hz, 1H, H2a), 4.98 (d, 1H, H2e), 4.97 (m, 1H, H5),
7.46-7.50 (m, 2H, H4′ and H6′), 7.54-7.62 (m, 1H, H5′), 8.08-
8.14 (m, 2H, H3′ and H7′). 13C NMR (CDCl3, 126 MHz) δ 66.1
(C5), 68.6 (C4, C6), 93.7 (C2), 128.4(C4′ and C6′), 129.6 (C2′),
129.8 (C3′ and C7′), 133.3 (C5′), 166.2 (C1′). Low-resolution EI
MS 207 ([M - H]+).
C
1
In 4, a bifurcated hydrogen bond has been calculated to
contribute 3.6 kcal mol-1 to the stability of the lowest energy
conformer. For 1 three different hydrogen bonds are possible,
depending on the orientation of the N-H bonds. A single OH
to N hydrogen bond leads to a stabilization of 3.7 kcal mol-1
,
a bifurcated reverse hydrogen bond involving the oxygen and
two axial N-H atoms contributes 1.5 kcal mol-1, and a
bifurcated hydrogen bond involving the OH hydrogen adds 3.2
kcal mol-1
.
The orientation of the N-H bonds appears to be governed
by anomeric interactions which are maximal for axial N-H
bonds. Two axial N-H bonds are, however, destabilized by
dipole repulsions. We have been able to estimate that stabiliza-
tion by one anomeric effect amounts to 3.2 kcal mol-1 and that
the further stabilizing effect by a second anomeric interaction
is slightly more (about 0.2 kcal mol-1) than the dipole repulsion
between two axial N-H atoms.
1,3-Dioxan-5-ol was isolated as a colorless liquid (0.48 g, 48%),
bp 50 °C/55 Torr (lit.10 bp 80-85 °C/11 mmHg), using the method
of Barker.10 1H NMR (CDCl3, 300 MHz) δ 2.96 (d, JOH,H5 ) 9.9
Hz, 1H, OH), 3.62 (m, 1H, H5), 3.87 (ddd, J4e,5 ) 3.2 Hz, J2e,4e
)
0.5 Hz, 2H, H4e and H6e), 3.92 (dd, J4a,4e ) 11.1 Hz, J4a,5 ) 2.2
Hz, 2H, H4a and H6a), 4.76 (d, J2a,2e ) 6.2 Hz, 1H, H2a), 4.93
(dd, 1H, H2e). 1H NMR (DMSO-d6, 300 MHz) δ 3.31 (dd,
(27) Petterson, K. A.; Stein, R. S.; Drake, M. D.; Roberts, J. D. Magn.
Reson. Chem. 2005, 43, 225.
J. Org. Chem, Vol. 72, No. 11, 2007 4161