Synthesis and nmr spectra of tetrahydrofuran-2-13C

Article abstract of DOI:10.1007/s10593-012-1008-0

An original method was developed for the synthesis of THF labeled selectively with the ¹³C isotope at the α-carbon atom. The effective reduction of symmetry brought about by the insertion of the isotopic label removes the excess degeneracy of the spin systems describing the multiplet structure of the ¹H and ¹³C NMR spectra, making it possible to undertake a detailed analysis. Exact values for the ¹H^-1H spin-spin coupling constants through four bonds and also the ¹³C^-1H and ¹³C^-13C spin-spin coupling constants involving the ?-carbon atom were determined for the first time. The isotopic chemical shifts of the protons and ¹³C nuclei caused by replacement of the ¹²C nucleus by ¹³C were determined. These data can be used to construct a quantitative model of the conformational behavior of THF as a molecular system in which pseudorotation in terms of vibrations with large amplitude is realized.

Full text of DOI:10.1007/s10593-012-1008-0

Chemistry of Heterocyclic Compounds, Vol. 48, No. 3, June, 2012 (Russian Original Vol. 48, No. 3, March, 2012)
SYNTHESIS AND NMR SPECTRA OF TETRAHYDROFURAN-2-13C
A. V. Chertkov1*, A. K. Shestakova2, and V. A. Chertkov1
13
An original method was developed for the synthesis of THF labeled selectively with the C isotope at
the α-carbon atom. The effective reduction of symmetry brought about by the insertion of the isotopic
label removes the excess degeneracy of the spin systems describing the multiplet structure of the 1H and
13C NMR spectra, making it possible to undertake a detailed analysis. Exact values for the 1H–1H spin-
spin coupling constants through four bonds and also the 13C–1H and 13C–13C spin-spin coupling
constants involving the α-carbon atom were determined for the first time. The isotopic chemical shifts of
the protons and 13C nuclei caused by replacement of the 12C nucleus by 13C were determined. These
data can be used to construct a quantitative model of the conformational behavior of THF as a
molecular system in which pseudorotation in terms of vibrations with large amplitude is realized.
Keywords: tetrahydrofuran, analysis of multiplet structure of NMR spectra, conformational analysis, high-
resolution NMR spectroscopy, isotopic effects, molecular dynamics.
Five-membered saturated heterocycles, including tetrahydrofuran (THF, 1), are important fragments of
natural compounds – sugars, nucleic acids, etc. The presence of these flexible structure fragments makes the
skeleton of nucleic acids, for example, sufficiently mobile to ensure rapid and reliable recognition of the
substrates. To understand these processes at the molecular level it is necessary to construct a quantitative model
of the conformational behavior of five-membered rings [1]. The first attempt to explain the specific character of
the conformation of five-membered rings and, in particular, the anomalously high entropy of cyclopentane
formation was made by Kilpatrick et al. [2] in terms of pseudorotation – a synchronous cyclic process,
accompanied by the successive going out from the basal plane of the ring from one to four structural elements
forming this ring, with ten pairs of canonical conformations of the "envelope" and "twist" types. In papers by
Pople and co-workers [3], a convenient and sufficiently illustrative scheme was proposed for the
parametrization of this process using the pseudorotation phase angle (φ) and the folding amplitude (Q).
Among five-membered heterocycles, a special place is occupied by THF. Many attempts have been
made to characterize its structure with the use of practically all the principal physical methods: X-ray structural
analysis at -125°C [4]; electron diffraction [5]; microwave spectroscopy [6-9]; NMR spectroscopy both in an
isotropic liquid phase [10-13] and in nematic liquid-crystalline solutions [14, 15]; photoelectron spectroscopy
[16]. There have been numerous attempts to calculate the pseudorotation parameters in tetrahydrofuran by
_______
*To whom correspondence should be addressed, e-mail: alex@mnf-online.ru, chertkov@org.chem.msu.ru.
1M. V. Lomonosov Moscow State University, 1 Bld. 3, Leninskie Gory, Moscow 119991, Russia.
2The State Scientific Center of the Russian Federation "State Research Institute for Chemistry and Technology
of Organoelement Compounds", 38 Entuziastov Shosse, Moscow 111123, Russia; e-mail: alla@nmrcenter.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 438-449, March, 2012. Original
article submitted February 16, 2011.
412
0009-3122/12/4803-0412©2012 Springer Science+Business Media, Inc.

nonempirical methods [17-19]. However, the results of these investigations are contradictory. Until now there
has been no common view about the most stable conformation of THF in literature. The results depend to a
considerable degree on what model was used to describe the process and even on what methods were used to
process the data. In our opinion [13], the conformational process in THF must be regarded as an exceptionally
fast dynamic process taking place mainly in a scheme of pseudorotation as a vibration with large amplitude. In the
early papers [4, 5], the structure determination was conducted within the model with one fixed form, which was
assigned the "twist" conformation 3T4 with C2 symmetry (φ = 90° with the oxygen atom on the basal plane, see
the designation in [13]). Meyer et al. [8] came to the conclusion that the global minimum of the pseudorotation
potential is at the non-canonical conformation (C1 symmetry, φ ≈ 50°), whereas Mamleev [7] and Mel'nik [9]
concluded on the basis of data from the vibrational-rotational spectra that the most stable conformation is the
3
"twist" conformation T4. Analysis of the photoelectron spectra [16] made it possible to obtain a broad band,
which the authors assigned to the 1E "envelope" configuration (CS symmetry, φ = 0) in addition to the main 3T4
form. The accuracy of modern quantum-chemical calculations is probably insufficient for reliable prediction of
the relative stability of conformers so close in energy. The calculations results depend to a great degree on the
level of the approximation employed [17-19], and in the series of the most complicated and, as could be
expected, more accurate calculations by the MP2 method with aug-cc-pVXZ wave functions (X = D and T) the
global minimum is at the 1E "envelope" [19].
Fig. 1. The downfield part of the 1H NMR spectrum of tetrahydrofuran (1a) (a) and tetrahydrofuran-2-13C (1b) (b).
413

Fig. 2. The upfield part of the 1H NMR spectrum of THF (1a) (a) and THF-2-13C (1b) (b).
An important method for determination of the conformation and dynamic behavior of molecules is high-
resolution NMR spectroscopy. The development of methods for nonempirical calculation of the spin-spin
coupling constants [10, 12] made it possible to raise the problem of characterizing the THF conformational
state according to the NMR spectroscopy data. In a recent paper, we proposed a more complete scheme for the
assessment of the parameters of the potential energy surfaces based on experimental data for the spin-spin
coupling constants, on calculated conformational dependencies of the spin-spin coupling constants, and on
solution of the reverse spectroscopic structural problem [13]. Having at our disposal a limited set of
experimental spin-spin coupling constants (four vicinal constants from [20]) we came to the conclusion that the
main conformation for THF is the 3T4 conformation.
In the present work, we set out to obtain more accurate experimental data on the spin-spin coupling
constants in THF. For correct and reliable estimation of the conformation it is necessary to have numerical
values of the spin-spin coupling constants between protons through four bonds (4JH,H), accurate values of the
spin-spin coupling constants through three bonds (3JH,H), and long-range spin-spin coupling constants of protons
with 13C nuclei (nJC–H). It should be noted that it is not by accident that the 4JH,H values had not been previously
1
determined with sufficient accuracy. In principle, they could be determined from analysis of the H NMR
spectrum of THF, but this spectrum has such complicated multiplet structure (Figures 1a and 2a) that its
interpretation is exceedingly difficult.
In our opinion the early attempt at analysis of this spectrum [10] led to insufficiently accurate results. In
order to get round this problem Lambert et al. [20] realized the synthesis of a series of selectively deuterated
1
tetrahydrofuran derivatives and studied their H NMR spectra with spin decoupling from the deuterium. The
deuterated compounds were specially selected by the authors [20] in such a way that long-range 4JH,H constants
were not observed in them. This method allows to greatly simplify the multiplet structure of the NMR spectra.
414

If all possible fast dynamic processes on the NMR time scale (pseudorotation and ring inversion) are
1
taken into account tetrahydrofuran has C2V symmetry and its H NMR spectrum is described by an eight-spin
system of the AA'A"A"'MM'M"M"' type.
The series of control model calculations that we conducted made it possible to conclude that the
1
multiplet structure of the H NMR spectra of THF is degenerately simple. This means that in spite of the
abundance of transitions their position does not depend on all the possible values of the eight spin-spin coupling
3
4
constants (four JH,H and four JH,H). The high symmetry of the molecule creates substantial difficulties for
interpretation. In order to overcome this problem we used the isotopic perturbation method that was used earlier
for measurement of the spin-spin coupling constants in such highly symmetrical systems as benzene [21],
cyclohexane [22-24], nortricyclene [25], benzaldehyde [26], and toluene [27]. The isotopic perturbation method
is based on the fact that the symmetry of a molecule can decrease if an isotopic tag is inserted into the molecule.
1
In the case of THF-2-13C the symmetry of the molecule corresponds to the CS point group, and the H NMR
13
spectra and proton-coupled C NMR spectrum are described by an AA'BB'MM'NN'X spin system (Fig. 3). In
this case, the proton sub-spectrum is no longer described by two chemical shifts, as in the case of
Fig. 3. Types of spin systems and symmetry of THF (1a) and THF-2-13C (1b)
averaged among the fast dynamic processes.
tetrahydrofuran itself, but by four since the protons of the methylene groups at the C-2 and C-5 atoms and at the
C-3 and C-4 atoms become non-equivalent in pairs. It could be expected that isotopic substitution of 12C by 13C
would cause the same nonequivalence for the spin-spin coupling constants, for example, 3JA–M and 3JB–N or 4JA–N
4
and JB–M. However, the results of our early calculations showed that the effects of replacement of the heavy
isotopes for the spin-spin coupling constants are extremely small (e.g., see [21, 28]). Effects of this type have
been recorded reliably by experiment in only one case – during analysis of the set of acetylene isotopomers
[29]. Thus, analysis of the NMR spectra of isotope-labeled molecules has made it possible in a number of cases
to evaluate the spin-spin coupling constants for highly symmetrical molecular systems with high accuracy.
13
In the present work, we have used selective enrichment with the heavy isotope of carbon C. In THF
one isotopomer 1a not containing a 13C label, two isotopomers 1b,c containing one labeled atom, and four
isotopomers 1d-g containing two labeled carbon atoms are possible (Fig. 4).
13C
13C
13C
13C
13C 13C
13C
13C
13C
13C
O
O
O
O
O
O
O
1g
1a
1c
1d
1f
1b
1e
Fig. 4. The 12C/13C-isotopomeric forms of THF 1a-g.
415

The main form of THF with the natural content of the carbon isotope is isotopomer 1a (mass fraction
95.469%) alongside which there are relatively insignificant amounts of isotopomers 1b,c (2.216% of each) and
negligibly small amounts of the isotopomers 1d-g with two labeled carbon atoms (total 0.099%). In the NMR
spectra of normal THF the isotopomeric forms 1b,c can be observed as relatively weak satellite signals. Their
recording involves considerable difficulties on account of overlap with the stronger signals of the main
isotopomer 1a (Fig. 4).
In the present work, we have synthesized THF-2-13C (1b) and interpreted the multiplet structure of its
1H and 13C NMR spectra. The insertion of the isotopic tag was the key stage of our synthesis. For this,
thoroughly dried 13CO2 was brought into reaction with an equimolar amount of "solid" Grignard reagent, which
was obtained after vacuum distillation of the solvent from a solution of the Grignard reagent (obtained from
4-bromo-1-butene and magnesium) in ether. The starting 4-bromo-1-butene was obtained with a high yield by
dehydrobromination by the modified method [30] of thermolysis of 1,4-dibromobutene in HMPA solution.
1) Mg–Et2O
HMPA
220°C
Br
Br
2) 13CO2
3) H3O+
H2C
Br
195
2
3
EtOH
NaIO4–K2OsO4
THF–dioxane
H2C
13COOEt
13СОOH
H2C
O
Me3SiCl
5
4
6
13C
1) LiAlH4–Et2O
2) H2O, NaOH
H2SO4
OH
HO
1b
13COOEt
7
The double bond was used as latent protection of the second functional group required for cyclization.
In fact, the double bond at the γ-position does not interfere with Grignard synthesis from the corresponding
alkyl bromide. We then planned to oxidize this double bond (in penten-4-oic-1-13C acid) to an aldehyde group
by the action of periodate in the presence of catalytic amounts of osmate [31]. However, control tests revealed
complications during the isolation of the 4-oxobutanoic-1-13C acid formed here at the level of semimicro
quantities (with loads in the order of 5-10 mmol). This problem was solved by conversion of the carboxyl group
into an ester group. Then, both the aldehyde and the ester group were reduced to alcohol groups with lithium
aluminum hydride. At the final stage the butane-1,4-diol-1-13C was cyclized with conc. H2SO4. Control of the
13
isotopic purity of the C-enriched compounds showed that at all stages of the synthesis it corresponded to the
degree of enrichment of the employed source of the isotopic tag (from 98.5 to 99.2% according to the high-
precision 13C NMR spectra).
The 1H NMR spectrum of the THF-2-13C (1b) obtained in this way (Figs. 1b and 2b) differ significantly
13
from the spectrum of the THF with natural content of the C isotope (Figs. 1a and 2a). The most significant
differences are observed in the downfield part of the spectrum, i.e., in the region where the signals for the H-2
protons of the isotopomer 1b are observed.
An important feature of this multiplet is splitting on the large constant 1JC,H (see the splitting scheme in
1
Fig. 1). This signal can also be observed with high amplification in the H NMR spectrum of THF with the
natural 13C content (the "outer satellite"). However, full interpretation of the complex multiplet structure
1
requires all the remaining signals of the isotopomer 1b: the "inner satellites" in the regions of the H NMR
spectrum from 1.76 to 1.84 ppm (the H-3,4 protons, see Fig. 2b) and from 3.61 to 3.67 ppm (the H-5 protons,
Fig. 1b), and also the corresponding multiplet of the proton-coupled 13C NMR spectrum. Interpretation of all the
1
components of the multiplet structure of the NMR spectrum of the isotopomer 1b (824 lines in the H NMR
spectrum and 273 lines in the proton-coupled 13C NMR spectrum) was achieved by means of the LACX
iteration software [31, 32] within a spin system of the AA'BB'MM'NN'X type, taking into account the chemical
416

equivalence of the protons of the methylene groups and the weak coupling of the three types of nuclei (the α-
and β-methylene protons and the 13C nucleus). The scheme employed for factorization of the Hamiltonian
proved adequate for effective convergence of the iteration process. The vicinal 3JH,H constants from [20] and the
4
long-range JH,H constants for related derivatives of cyclopentane (see [33-35]) were used as the initial
n
n
approximation. The final values of the spin-spin coupling constants JH,H and JC,H and the isotopic chemical
shifts of the protons due to replacement of the 12C nuclei by 13C are presented in the Table 1.
13
Important information about the structure of the minor isotopomeric forms is carried by the C NMR
1
spectra, which have a significantly simpler multiplet structure than the H NMR spectra. Figure 5 shows the
upfield part of the 13C NMR spectrum of 2-13C-enriched THF, corresponding to the β-carbon atoms. The
reference point here is the C-3 signal of the minor form 1c, which is present in an insignificant amount in the
investigated mixture of isotopomers. The splittings of the β-carbon atoms of the C-3 form 1d and the C-4 form
1e at the labeled atom C-2 are clearly seen in the spectrum presented in Fig. 5. In this spectrum there are also
12
13
relatively large isotopic chemical shifts of C-3 of form 1d, due to replacement of C by C at the C-2 carbon
atom (1∆δC-3), and of C-4 of form 1e due to replacement of 12C by 13C at the C-2 carbon atom (2∆δC-4).
13
Analogous signals are observed in the downfield part of the C NMR spectrum in the region of the α-carbon
atoms. These parameters of the NMR spectra are also presented in the Table 1.
13
Fig. 5. The C NMR spectrum of 2-13C-enriched THF (1b). The labeling scheme of
the signals for the C-3 and C-4 carbons of isotopomers 1c-e is presented.
n
It can be seen that the JC,C spin-spin coupling constants that we recorded first are close in value to the
n
corresponding JC,C constants in cyclopentane (see [23]). In all cases the isotopic chemical shifts that we
obtained in THF are negative, which agrees with the current theoretical model for NMR parameters of this type
(for more detail, see [23, 24, 29]).
417

Analysis of the NMR spectra of the synthesized THF-2-13C made it possible to refine the existing
3
experimental data on the vicinal JH,H constants and to determine for the first time a whole series of previously
unknown parameters of the NMR spectra required for the construction of a quantitative model of the
conformational dynamics of THF.
TABLE 1. The Parameters of the 1H and 13C NMR Spectra in the Series of
Isotopomers of THF 1a-f*
Isotopomer
Parameter
Experimental value *2
1a
3.641
Н-2
Н-3
1.800
1b*3
1ΔН-2
2ΔН-3
3ΔН-4
3ΔН-5
C-2
–1.541 (0.002)
–0.399 (0.002)
–0.171 (0.002)
–0.084 (0.002)
68.282
2J2,2'
-8.130 (0.120)
-12.010 (0.120)
2J3,3'
cis
3J
7.607 (0.002)
6.163 (0.003)
8.773 (0.002)
6.149 (0.002)
0.022 (0.003)
-0.494 (0.003)
-0.161 (0.002)
-0.161 (0.002)
2,3
trans
2,3
3J
cis
3,4
3J
trans
3,4
3J
cis
2,4
4J
trans
2,4
4J
cis
2,5
4J
trans
2,5
4J
1JC-2,H-2
2JC-2,H-3
3JC-2,H-4
3JC-2,H-5
C-3
145.094 (0.001)
-2.471 (0.001)
3.288 (0.001)
3.864 (0.001)
26.266
1c
1d
1ΔC-2
1ΔC-3
1JC-2,C-3
2ΔC-2
2ΔC-4
2JC-2,C-4
2ΔC-5
-9.470 (0.030)
-5.650 (0.020)
33.150 (0.010)
-3.330 (0.030)
-7.530 (0.03)
0.510 (0.010)
-4.640 (0.020)
1e
1f
_______
*The values of the chemical shifts δH and δC are given in parts per million, the
n
n
isotopic chemical shifts ∆δH and ∆δC are given in parts per billion, the spin-
spin coupling constants are given in Hz (0.16 M solution in CD3CN, 303 K,
Bruker AV-600).
*2The standard deviations for the isotopic chemical shifts and spin-spin
coupling constants are given in parentheses.
*3The mean-square deviation of 1097 frequencies of the transitions of the
calculated spectra and lines of the experimental spectra amounts to 0.016 Hz.
418

EXPERIMENTAL
1
13
1
The H and C NMR spectra were recorded on Bruker AM-360 (360 MHz for H nuclea and 90 MHz
for 13C nuclei), Bruker AV-600 (600 MHz for H nuclei and 150 MHz for 13C nuclei), and JNM-ECA-600 (600
1
MHz for 1H nuclei) spectrometers. The 13C NMR spectra for determining the isotopic purity of the 13C-enriched
products and the 1H NMR spectra of the target product were recorded in enhanced accuracy mode at the narrow
frequency bands with data sampling times from 24 to 30 sec and digital resolution in the transformed spectrum
from 0.002 to 0.003 Hz. The use of such rigorous parameters makes it possible to secure the sufficient accuracy
required for subsequent interpretation of the complex multiplet structure of these spectra and for the adoption of
sound decisions about the values and signs of the long-range spin-spin coupling constants and isotopic effects
caused by the replacement of 12C by 13C.
Reagents and deuterated solvents from Aldrich and Merck were used. The solvents ethanol, ether, THF,
hexane, and chloroform were submitted to further purification before use in the reaction and/or before
chromatography.
The Ba13CO3 with 98% purity in 13C produced by Matheson was used as source of the isotopic tag.
Precise measurements of the intensities of the signals of the 13C-enriched carboxylic acid 3 showed that the
13
13
actual content of the C isotope in the Ba13CO3 used in this work was 99.2%. The carbon dioxide CO2 was
obtained by the action of phosphoric acid on Ba13CO3 [36] followed by thorough separation of the CO2 from
13
traces of water (for greater detail, see below).
The sample of THF-2-13C (1b) for recording the NMR spectra was prepared by dissolving 7 mg of the
compound in 0.68 ml of acetonitrile-d3 (containing 0.1% of TMS as internal standard), after which the solution
was degassed by threefold repetition of the freezing–evacuating–unfreezing cycle in a 5-mm ampoule, and the
ampoule was then sealed off. The spectra were recorded at 303 K. The isotopic chemical shifts (∆δ) are given in
13
parts per billion (ppb). The data of C-INADEQUATE and 2-D COSY, HSQC, and HMBC experiments were
used for the assignment of the signals of compounds 3, 4, and 1b,d,e [37].
4-Bromo-1-butene (3). HMPTA (15 ml, 83 mmol) was added with vigorous stirring to
1,4-dibromobutane (9.77 ml, 82 mmol) heated to 195°C in an argon atmosphere over 20 min. The
temperature of the reaction mixture was then brought to 220°C, and the mixture was kept at this temperature for
a further 20 min. The volatile reaction products were collected at a pressure of 2 mm Hg in a trap with
phosphorus(V) oxide, cooled to -80 to -90°C. By repeated refreezing under high vacuum it was possible to
1
isolate 4.95 g (yield 45%) of 4-bromo-1-butene. H NMR spectrum (600 MHz, CDCl3), δ, ppm (J, Hz): 2.60
(2H, qt, Jq = 6.9, Jt = 1.3, 3-CH2); 3.39 (2H, t, J = 7.0, 4-CH2); 5.10 (1H, dq, Jd = 10.2, Jq = 1.3, trans-H-1);
5.12 (1H, dq, Jd = 17.1, Jq = 1.5, cis-H-1); 5.78 (1H, ddt, Jd = 10.2, Jd = 17.1, Jt = 6.6, H-2). 13C NMR
spectrum (150.9 MHz, CDCl3), δ, ppm: 32.0 (С-4); 37.0 (С-3); 117.5 (С-1); 135.2 (С-2).
Penten-4-oic-1-13C Acid (4). 1,2-dibromoethane (three drops) was added to magnesium (0.64 g, 26.5
mmol) in ether (5 ml) in an atmosphere of argon. After 10 min, 4-bromo-1-butene (3) (2.7 ml, 26.0 mmol) was
added over 30 min, and the reaction mixture was then stirred for a further 2 h. The reaction mixture was frozen
with liquid nitrogen and degassed by threefold repetition of the evacuating (on vacuum apparatus to a residual
pressure of 10−4 mm Hg)–unfreezing–freezing cycle.
Finely ground Ba13CO3 (4.76 g, 24.0 mmol) was evacuated in a 500-ml flask to a pressure of 10−4 mm
Hg for 45 min, after which previously degassed 85% phosphoric acid (35 ml) was added to it drop by drop with
13
stirring. The released CO2 was refrozen in a trap cooled with liquid nitrogen. The compound was degassed
13
again and dried from traces of moisture, for which purpose the CO2 was refrozen three times in a new trap
cooled with liquid nitrogen, while the gas was passed through a spiral trap cooled to ~ -80°C.
The reaction flask with the Grignard reagent was cooled with liquid nitrogen and all the obtained 13CO2
was refrozen in it. Without removing the vacuum the reaction flask was heated on a bath with a mixture of
alcohol and liquid nitrogen at -80°C and was kept under these conditions for 1 h. After this, the temperature of
the bath was gradually raised to 0°C over 30 min. The reaction flask was filled with nitrogen, ether (20 ml)
419

was added, after that water (5 ml) and 5% hydrochloric acid (5 ml) were added drop by drop. The ether layer
was separated, and the target compound was extracted with a 5% aqueous NaOH solution (3×5 ml). The
combined aqueous layer was acidified to pH 0 with hydrochloric acid and extracted with ether (4×7 ml). After
distillation of the solvent, 1.7 g (70%) of penten-4-oic-1-13C acid (4) was obtained.
1H NMR spectrum (600 MHz, CDCl3), δ, ppm (J, Hz): 2.379 (2H, tq, Jt = 1.37, Jq ≈ 6.2, 3-CH2); 2.455
(2H, ddt, Jd = 6.84, Jd = 1.48, Jt = 7.25, 2-CH2); 5.018 (1H, dq, Jd = 10.24, Jq = 1.38, trans-H-5); 5.075 (1H,
dq, Jd = 17.12, Jq = 1.63, cis-H-5); 5.835 (1H, ddt, Jd = 10.24, Jd = 17.12, Jt = 6.36, H-4); 11.32 (1H, br. s,
COOH). 13C NMR spectrum (150.9 MHz, CDCl3), δ, ppm (J, Hz): 28.456 (d, Jd = 1.63, ∆δ < 0.2, С-3); 33.339
(d, Jd = 55.47, ∆δ = 13.3, С-2); 115.696 (s, С-5); 136.254 (d, Jd = 3.58, ∆δ < 0.2, С-4); 179.641 (s, intensity
~100, С-1 (13С-satellite: d, Jd = 55.47, ∆δ = -1.9)]. According to data from the high precision 13C NMR
spectrum the degree of enrichment of the carboxyl carbon was 99.2%.
Ethyl Penten-4-oate-1-13C (5). Trimethylchlorosilane (2.7 ml, 23.3 mmol) was slowly added (over
15 min) to a mixture of penten-4-oic-1-13C acid (4) (0.78 g, 7.7 mmol) and alcohol (6 ml). The reaction mixture
was refluxed for 3 h and was purified by flash chromatography on silica gel with CHCl3 as eluent. After slow
1
distillation of the solvent 0.82 g (82%) of the ester 5 was obtained. H NMR spectrum (360 MHz, DMSO-d6), δ,
ppm (J, Hz): 1.21 (3H, t, J = 7.2, ОCH2СН3); 2.25-2.34 (4H, m, 2,3-CH2); 4.04 (2H, dq, Jd = 3.1, Jq = 7.2,
ОCH2СН3); 4.93 (1H, dd, Jd = 1.3, Jd = 10.2, trans-H-5); 4.97 (1H, dd, Jd = 1.5, Jd = 17.2, cis-H-5); 5.76 (1H,
ddt, Jd = 10.2, Jd = 17.2, Jt = 6.4, H-4).
Ethyl 4-Oxobutanoate-1-13C (6). A solution of NaIO4 (2.46 g, 11.5 mmol) in water (18 ml) was added
to an alcohol solution of ethyl penten-4-oate-1-13C (5) (0.82 g, 6.3 mmol) and then with stirring K2OsO4·2H2O
(30 mg) and THF (2 ml) was added. The mixture was stirred at room temperature for a further 1 h and extracted
four times with ether. The extract was washed six times with small portions of a saturated solution of Na2SO3
1
and dried with MgSO4. After evaporation of the solvent 0.54 g (65%) of the ester 6 was obtained. H NMR
spectrum (360 MHz, DMSO-d6), δ, ppm (J, Hz): 1.33 (3H, t, Jt = 7.1, ОCH2СН3); 2.53 (2H, q, Jq = 6.84, 2-CH2);
2.71 (2H, q, Jq = 6.1, 3-CH2); 4.08 (2H, dq, Jd = 3.1, Jq = 7.1, ОCH2СН3); 9.70 (1H, s, CHO).
Butane-1,4-diol-1-13C (7). LiAlH4 (1.25 g, 33.0 mmol) was slowly added with stirring to a solution of
compound 6 (0.54 g, 4.1 mmol) in ether (17 ml) and THF (3 ml). The reaction mixture was refluxed for 6 h and
treated successively with water (1.25 ml, 0.07 mol) and with a 10% solution of NaOH (4.23 ml). The obtained
clotted mass was extracted with boiling THF in Soxhlet apparatus for 8 h. The compound was chromatographed
on a column of silica gel in chloroform. After slow distillation of the solvent 0.20 g (62%) of butane-1,4-diol-
1-13C (7) was obtained. 1H NMR spectrum (360 MHz, CDCl3), δ, ppm (J, Hz): 1.64-1.74 (4H, m, 2,3-СН2); 3.68
(2H, dt, Jd = 141.2, Jt = 5.8, 1-СН2); 3.68 (2H, t, Jt = 5.8, 4-СН2).
Tetrahydrofuran-2-13C (1b). With cooling to 0°C and vigorous stirring, conc. H2SO4 (0.03 ml) was
added to butane-1,4-diol-1-13C (7) (0.20 g, 2.7 mmol). The flask containing the reaction mixture was then
quikly connected to freezing apparatus, cooled to liquid nitrogen temperature, and degassed under high vacuum
(10−4 mm Hg) with threefold repetition of the evacuating–unfreezing–freezing cycle. The reaction mixture was
heated to 90-100°C, and the volatile compounds were refrozen in a receiver cooled with liquid nitrogen.
Compound 1b was purified by refreezing twice over KOH and with calcium hydride. The tetrahydrofuran-2-13C
(1b) was stored in the gas phase in a 250-ml glass gasholder at room temperature. The reaction product creates a
1
pressure of 38 mm Hg (yield 20%). H NMR spectrum (600 MHz, CD3CN), δ, ppm (J, Hz): 1.762-1.834 (4H,
m, 2,3-СН2); 3.502-3.776 (2H, dm, Jd = 145.089, 1-СН2); 3.622-3.658 (2H, m, 4-СН2). 13C NMR spectrum
(150.9 MHz, CD3CN), δ, ppm (J, Hz): 26.267 (d, Jd = 33.15, ∆δ = -9.47, С-2); 26.269 (d, Jd = 0.51, ∆δ = -7.53,
С-3); 115.696 (s, С-5); 68.309 (s, intensity ~100, C-1 (13C-satellite from C-2: d, Jd = 33.14, ∆δ = -5.6.
13
13C-satellite from C-3: d, Jd = 0.51, ∆δ = -3.3. C-satellite from C-4: s, ∆δ = -4.6)). According to the high-
precision 13C NMR spectrum the degree of enrichment in 13C amounted to 98.5%.
The work was carried out with support from the Russian Foundation for Basic Research (grants 09-03-
00779 and 12-03-00219).
420

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