The stereodynamics of 1,2-dipropyldiaziridines

Article abstract of DOI:10.1002/chir.20742

N-alkylated trans-diaziridines are an intriguing class of compounds with two stereogenic nitrogen atoms which easily interconvert. In the course of our investigations of the nature of the interconversion process via nitrogen inversion or electrocyclic ring opening ring closure, we synthesized and characterized the three constitutionally isomeric diaziridines 1,2-di-n-propyldiaziridine 1, 1-isopropyl-2-n-propyldiaziridine 2, and 1,2-diisopropyldiaziridine 3 to study the influence of the substituents on the interconversion barriers. Enantiomer separation was achieved by enantioselective gas chromatography on the chiral stationary phase Chirasil-β-Dex with high separation factors α (1-isopropyl-2-n-propyldiaziridine: 1.18; 1, 2-diisopropyldiaziridine: 1.24; 100°C 50 kPa He) for the isopropyl substituted diaziridines. These compounds showed pronounced plateau formation between 100 and 150°C, and peak coalescence at elevated temperatures. The enantiomerization barriers ΔG? and activation parameters ΔH? and ΔS? were determined by enantioselective dynamic gas chromatography (DGC) and direct evaluation of the elution profiles using the unified equation implemented in the software DCXplorer. Interestingly, 1-isopropyl-2-n-propyldiaziridine and 1,2-diisopropyldiaziridine exhibit similar high interconversion barriers ?G? (100°C) of 128.3 ± 0.4 kJ mol^-1 and 129.8 ± 0.4 kJ mol^-1, respectively, which indicates that two sterically demanding substituents do not substantially increase the barrier as expected for a distinct nitrogen inversion process.

Full text of DOI:10.1002/chir.20742

CHIRALITY 22:284–291 (2010)
The Stereodynamics of 1,2-Dipropyldiaziridines
2
2
2
OLIVER TRAPP,1,2 LAILA SAHRAOUI, WERNER HOFSTADT, AND WERNER KONEN
¨
*
1Organisch-Chemisches Institut, Ruprecht-Karls-Universita¨t Heidelberg, Heidelberg, Germany
2Max-Planck-Institut fu¨r Kohlenforschung, Mu¨lheim an der Ruhr, Germany
ABSTRACT
N-alkylated trans-diaziridines are an intriguing class of compounds with
two stereogenic nitrogen atoms which easily interconvert. In the course of our investiga-
tions of the nature of the interconversion process via nitrogen inversion or electrocyclic
ring opening ring closure, we synthesized and characterized the three constitutionally
isomeric diaziridines 1,2-di-n-propyldiaziridine 1, 1-isopropyl-2-n-propyldiaziridine 2, and
1,2-diisopropyldiaziridine 3 to study the influence of the substituents on the interconver-
sion barriers. Enantiomer separation was achieved by enantioselective gas chromatogra-
phy on the chiral stationary phase Chirasil-b-Dex with high separation factors a (1-iso-
propyl-2-n-propyldiaziridine: 1.18; 1, 2-diisopropyldiaziridine: 1.24; 1008C 50 kPa He) for
the isopropyl substituted diaziridines. These compounds showed pronounced plateau
formation between 100 and 1508C, and peak coalescence at elevated temperatures. The
enantiomerization barriers DG{ and activation parameters DH{ and DS{ were deter-
mined by enantioselective dynamic gas chromatography (DGC) and direct evaluation of
the elution profiles using the unified equation implemented in the software DCXplorer.
Interestingly, 1-isopropyl-2-n-propyldiaziridine and 1,2-diisopropyldiaziridine exhibit sim-
ilar high interconversion barriers DG{ (1008C) of 128.3 6 0.4 kJ mol21 and 129.8 6 0.4
kJ mol21, respectively, which indicates that two sterically demanding substituents do
not substantially increase the barrier as expected for a distinct nitrogen inversion pro-
C
VV
cess. Chirality 22:284–291, 2010.
2009 Wiley-Liss, Inc.
KEY WORDS: activation barrier; chiral separation; stereogenic nitrogen;
enantioselective dynamic gas chromatography; interconversion;
kinetics; unified equation
INTRODUCTION
Wagner,13 and Kostyanovsky et al.14 in 1968: (i) Introduc-
tion of lone-pair containing substituents (-OR, Cl, F) at the
stereogenic nitrogen atom,15,16 and (ii) incorporation of
stereogenic nitrogen into a constrained (three-membered)
ring.17 This was demonstrated by the enantiomer separa-
tion of 1-chloroaziridines,11–13,18 1-alkoxyoxazolidines19
and by the enantiomeric or diastereomeric enrichment of
dialkoxyamines, containing the asymmetric nitrogen
solely in the open chain. Despite these efforts, the nature
of the interconversion process in aziridines and diaziri-
dines via nitrogen inversion20–23 as in ammonia, or electro-
cyclic ring opening ring closure as in oxiranes24–26 is still
unknown (cf. Scheme 1). Highly negative activation entro-
pies DS{ were experimentally measured for aziridines and
diaziridines, which were interpreted as an indicator of an
The investigation of conformational and configurational
changes,1,2 e.g., isomerizations, epimerizations, diastereo-
merizations, and enantiomerizations,3 is of great impor-
tance to understand processes ranging from protein fold-
ing to the stereostability of drugs. Compounds with stereo-
genic nitrogen atoms are an intriguing class of compounds
that have inspired many scientists for more than a century.
In 1890, Werner4 transferred the concept of tetrahedral tet-
ravalent carbon of van’t Hoff and Le Bel to trivalent nitro-
gen. Attempts made by Meisenheimer et al. to isolate chi-
ral tertiary amines of the type NRR0R@ suggested that rapid
pyramidal inversion leads to optical inactivity.5 In 1944,
Prelog and Wieland6 recognized the inherent chirality of
Tro¨ger’s base7 due to the two stereogenic nitrogen atoms
related by C2 symmetry. They achieved enantiomer sepa-
ration by liquid chromatography on a 0.9 m column using
lactose hydrate as CSP (op 5 0.99), followed by fractional
crystallization. In 1967, Mannschreck et al.8 reported that
nitrogen inversion in diaziridines (cf. Scheme 1) is hin-
dered on the NMR time scale and determined later inter-
conversion barriers by dynamic NMR (DNMR).9,10
To achieve the isolation of stereoisomers with stereo-
genic nitrogen, two strategies have been successfully
applied by Brois,11 Felix and Eschenmoser,12 Lehn and
C
Contract grant sponsor: Deutsche Forschungsgemeinschaft for an Emmy
Noether grant; Contract grant number: TR 542/3.
Contract grant sponsors: Max-Planck-Institut fu¨r Kohlenforschung, Fond
der Chemischen Industrie (FCI), Merck Research Laboratories (Rahway,
NJ), Nordrhein-Westfa¨lische Akademie der Wissenschaften.
*Correspondence to: Oliver Trapp, Organisch-Chemisches Institut,
Ruprecht-Karls-Universita¨t Heidelberg, Im Neuenheimer Feld 270, 69120
Heidelberg, Germany. E-mail: trapp@oci.uni-heidelberg.de
Received for publication 10 June 2008; Accepted 25 March 2009
DOI: 10.1002/chir.20742
Published online 3 June 2009 in Wiley InterScience
(www.interscience.wiley.com).
VV
2009 Wiley-Liss, Inc.

STEREODYNAMICS OF DIAZIRIDINES
285
tion, and eventually peak coalescence.39 The pronounced
plateau formation and separation of the stereoisomers are
the prerequisite for the determination of interconversion
barriers in dynamic chromatography.
In recent years, considerable progress has been made to
determine reaction rate constants k and activation parame-
ters from elution profiles of dynamic chromatographic
experiments. Broadly used are computer simulations
based on the iterative comparison of experimental and
simulated chromatograms,40–42 which are computationally
expensive for highly efficient separation techniques with
theoretical plate numbers N greater than 20,000. In 2001,
the approximation function43,44 was introduced for fast,
direct, and precise access to rate constants to study enan-
tiomerization of racemic mixtures. A major breakthrough
was the derivation of the unified equation45–47 to access
directly all kinds of first-order reactions taking place during
a chromatographic or electrophoretic separation. This
Scheme 1. Enantiomerization of trans-1,2-disubstituted diaziridines
and possible mechanism of interconversion via nitrogen inversion (top) or
electrocyclic ring opening ring closure mechanism.
electrocyclic ring opening-ring closure mechanism
because of the charge separation in the transition state. In
an effort to elucidate the mechanism of interconversion, equation is an analytical solution of the theoretical plate
model and is superior in precision to any computer simula-
tion where errors arise from the imprecision of billions of
we synthesized the set of the three constitutionally iso-
meric of N-propyl substituted diaziridines 1,2-di-n-propyl-
diaziridine 1, 1-isopropyl-2-n-propyldiaziridine 2, and 1,2- floating point operations. The unified equation also opened
the field to study catalytic reactions by on-column reaction
diisopropyldiaziridine 3 (cf. Scheme 2). 3,3-Unsubstituted
diaziridines are of great interest because the barrier is
increased due to the lack of 1,2-nonbonded interactions
which destabilize the ground state.27
chromatography48–52 in a high-throughput fashion.53
MATERIALS AND METHODS
General
These diaziridines were chosen, because increasing the
steric demand by introduction of a methyl group at the a-
C atom of the substituent is more effective for shorter than
for longer alkyl groups without introducing further stereo-
genic centers, e.g., for sec-butyl substituents. Furthermore,
it is expected that if the interconversion barrier depends
on the steric hindrance of the substitutents in a distinct
inversion process, the barrier of the heterosubstituted dia-
ziridine 2 should be the average of the barriers of the
homosubstituted diaziridines 1 and 2.
To study conformational and configurational changes in
molecules, sophisticated techniques were developed
which require only racemic mixtures to quantify intercon-
version kinetics, e.g., dynamic NMR,28,29 stopped-flow
chromatographic techniques,30–33 and enantioselective
dynamic chromatography.34–38 Enantioselective dynamic
chromatography has been used for the determination of
the kinetics of stereolabile compounds, e.g., atropisomers,
drugs and drug-related compounds, compounds with stereo-
genic nitrogen and sulfur, and pheromones covering the
range of interconversion barriers DG{ between 75 and
170 kJ mol21. Depending on the physical properties of the
analyte molecule and the expected interconversion barrier,
different dynamic chromatographic or electrophoretic
techniques (e.g., DGC, DSFC, DHPLC, DCE, DCEC,
DMEKC) can be applied to determine interconversion bar-
riers. The major advantage over classical racemization
experiments, which require enantiomer separation of ster-
eolabile compounds, are the use of standard experimental
setups, the minute analyte consumption of arbitrary mix-
tures of interconverting stereoisomers and the precise
determination of kinetic and thermodynamic parameters.
In enantioselective dynamic chromatography, peak pro-
files are characterized by peak broadening, plateau forma-
n-Propylamine, isopropylamine, formaldehyde, sodium
hydroxide, and sodium hypochlorite were purchased from
Fluka (Buchs, Switzerland). Nuclear magnetic resonance
(1H-NMR and 13C-NMR) spectra were recorded at 400 and
100 MHz, respectively, on a Bruker AV 400 spectrometer
(Rheinstetten, Germany) in deuterochloroform. Electron
impact mass spectra (EIMS, ion source temperature
2008C, electron energy 70 eV) were recorded on a Thermo
GC quadrupole-ion trap mass spectrometer Trace GC
PolarisQ (San Jose, CA).
General Procedure for the Synthesis of 1,2-Substituted
Diaziridines 1, 2, and 3
The diaziridines were prepared according to a modifica-
tion of the method Ohme et al.47,54 250 mmol Alkylamine
and 50 ml 5N NaOH are combined in a 250 ml flask
Scheme 2. Enantiomeric pairs of (a) 1,2-di-n-propyldiazirine 1, (b) 1-
isopropyl-2-n-propyldiaziridine 2, and (c) 1,2-diisopropyldiaziridine 3.
Chirality DOI 10.1002/chir

286
TRAPP ET AL.
Scheme 3. Statistical synthesis of 1,2-homosubstituted and 1,2-heterosubstituted diaziridines by formation of the aminal from amines using formalde-
hyde, followed by an oxidative ring closure with sodium hypochlorite solution.
equipped with a magnetic stirrer and cooled to 08C. Form-
aldehyde solution (36% w/w, 12.5 ml) is slowly added. Af-
ter 1 h, 75 ml sodium hypochlorite solution (13% w/w) is
added dropwise at 08C and after complete addition the
mixture is allowed to warm up to r.t. The mixture is stirred
at r.t. for 12 h, then after 1 h waiting for phase separation
the organic layer is separated and washed with diluted so-
dium thiosulfate solution and water. After drying over
KOH and filtration the crude diaziridine is distilled under
reduced pressure.
1,2-Di-n-propyldiaziridine. 1,2-Di-n-propyldiaziridine
1 is obtained as a colorless liquid in 22.5% (3.6 g) yield. bp
1
3
378C (37 mbar); H-NMR (CDCl3) d 0.95 (t, J(H,H) 5 7.4
Hz, 6H, CH3), 1.61 (m, J(H,H) 5 7.4 Hz, 4H, CH2), 2.21
3
(m, J(H,H) 5 7 Hz, 2Ha, CH2ꢀꢀN), 2.42 (m, J(H,H) 5
7 Hz, 2Hb, CH2ꢀꢀN), 2.44 (s, 2H, NꢀꢀCH2ꢀꢀN); 13C-NMR
(CDCl3) d 11.5 (CH3), 21.6 (CH2), 56.4 (NꢀꢀCH2ꢀꢀN),
62.8 (CH2ꢀꢀN); MS m/z (relative intensity) 128.07 (M1,
0.63), 100.14 (2.85), 99.1 (47), 86.13 (1.6), 85.12 (8.42),
72.11 (7.12), 71.07 (28.12), 70.08 (8.08), 68.13 (1.3), 58.09
(7.32), 57.04 (100), 56.09 (6.3), 55.14 (0.72), 54.1 (1.75),
51.98 (1.36).
3
3
1-Isopropyl-2-n-propyldiaziridine. 1-Isopropyl-2-n-
propyldiaziridine 2 is obtained as a colorless liquid in
1
16.4% (2.66 g) yield. bp 448C (67 mbar); H-NMR (CDCl3)
3
d 0.95 (t, J(H,H) 5 7.4 Hz, 3H, CH3, n-propyl), 1.04 (d,
3
3J(H,H) 5 6.4 Hz, 3Ha, CH3, isopropyl), 1.2 (d, J(H,H) 5
3
6.4 Hz, 3Hb, CH3, isopropyl), 1.62 (m, J(H,H) 5 7.4 Hz,
2H, CH2, n-propyl), 1.72 (m, 3J(H,H) 5 6.4 Hz, 1H,
Fig. 2. Selected experimental enantiomerization profiles of the enantio-
selective DGC experiments. (a) 1,2-Di-n-propyldiazirine 1, (b) 1-isopropyl-
2-n-propyldiaziridine 2, and (c) 1,2-diisopropyldiaziridine
between 100 and 1508C. Chromatographic conditions: 25 m Chirasil-b-Dex
(0.25 mm i.d., film thickness 0.5 lm). Carrier gas: He.
3 separated
Fig. 1. 1H-13C correlation NMR spectrum of 1-isopropyl-2-n-propyldia-
ziridine 2.
Chirality DOI 10.1002/chir

STEREODYNAMICS OF DIAZIRIDINES
287
TABLE 1. Experimental data of the enantiomerization of 1,2-diisopropyldiaziridine 3 between 100 and 1408C
T (8C)
p (kPa)
tAR (min)
tBR (min)
N
a
hp (%)
hB (%)
k1 (1024 s21
)
100.0
100.0
100.0
110.0
110.0
110.0
120.0
120.0
120.0
130.0
130.0
130.0
140.0
140.0
140.0
50.0
50.0
50.0
50.0
50.0
50.0
40.0
40.0
40.0
40.0
40.0
40.0
40.0
40.0
40.0
9.4
9.4
9.4
7.9
7.9
7.9
8.4
8.4
8.4
7.6
7.6
7.7
7.1
7.1
7.1
10.5
10.5
10.5
8.6
8.6
8.6
8.9
8.9
8.9
7.9
7.9
7.9
7.3
7.3
7.3
40,100
41,900
42,800
35,200
33,400
41,700
31,800
32,400
34,000
30,200
28,100
30,100
29,500
27,200
27,200
1.24
1.24
1.24
1.22
1.21
1.22
1.18
1.18
1.18
1.15
1.15
1.15
1.12
1.12
1.12
0.1
0.1
0.1
0.2
0.2
0.2
0.7
0.8
0.7
3.5
3.6
3.5
23.8
23.5
23.3
88.6
87.0
89.1
92.4
92.9
93.0
95.5
94.9
94.3
96.3
97.0
95.4
98.3
98.8
95.7
0.05
0.06
0.05
0.13
0.14
0.15
0.32
0.37
0.32
0.94
0.95
0.94
1.98
1.23
1.30
Chromatographic conditions: 25 m Chirasil-b-Dex (0.25 mm i.d.; film thickness 0.5 lm). Carrier gas: He.
3
CHꢀꢀN), 2.13 (m, J(H,H) 5 7.4 Hz, 1H, CH2ꢀꢀN), 2.44 time t0, the plateau height hp, the peak widths at half
2
3
(d, J(H,H) 5 2.7 Hz, 2H, NꢀꢀCH2ꢀꢀN), 2.49 (m, J(H,H) height wh, the number of theoretical plates N, and the ini-
5 7.4 Hz, 1H, CH2ꢀꢀN); 13C-NMR (CDCl3) d 11.4 (CH3, n- tial ratio [A0/B0] are used.
propyl), 19.3 (CaH3, isopropyl), 21.4 (CbH3, isopropyl),
If the signal intensity at the retention time tAR is higher
21.7 (CH2), 55.7 (NꢀꢀCH2ꢀꢀN), 60.4 (CHꢀꢀN), 63.0 (CH2- or equal compared to the signal intensity at the retention
N); MS m/z (relative intensity) 128.1 (M1, 0.79), 113.13 time tRB eq. 1a has to be used.
(27.84), 99.12 (24.02), 86.13 (3.2), 85.09 (30.5), 72.12
0
À
À
ÁÁ
1
ꢀ
ꢁ
pffiffiffi
(8.34), 71.09 (43.95), 70.12 (6.64), 59.1 (2.21), 58.08 (18.7),
57.06 (100), 56.08 (30.64), 55.12 (2.2), 54.11 (3.25), 51.98
(2.15).
2
pN
100B0þA0 100ꢀhp 1þ
tRBꢀtRA
ln
B
B
B
B
B
B
B
B
B
B
B
B
B
@
C
C
C
C
C
C
C
C
C
C
C
C
C
A
0
1
0
1
A
B
2
A
B
R
2
ðt ꢀt
Þ
ðt ꢀt
Þ
R
R
2
R
ꢀ
ꢀ
2
B
2r
8r
B
B
@
C
A
B
B
B
B
B
B
B
B
@
hpe
ꢀ100e
C
C
C
C
C
C
C
C
A
100
pffiffiffiffi
1,2-Diisopropyldiaziridine. 1,2-Diisopropyldiaziridine
3 is obtained as a colorless liquid in 38.5% (6.2 g) yield. bp
268C (61 mbar); 1H-NMR (CDCl3) d 1.71 (d, 3J(H,H) 5
B0
þ
1
tRA
tRBꢀtRA
rB 2p
k1 ¼ ꢀ
ꢀ ln
0
1
B
A
R
2
2
ðt ꢀt
Þ
R
8r
À
Á
3
6.4 Hz, 6Ha, CH3), 1.21 (d, J(H,H) 5 6.4 Hz, 6Hb, CH3),
ꢀ
pffiffiffi
2
hp 1þ
ꢀ100
A
B
C
100e
ꢀhp
pN
1.71 (m, 3J(H,H) 5 6.4 Hz, 2H, CH), 2.42 (s, 2H,
NꢀꢀCH2ꢀꢀN); 13C-NMR (CDCl3) d 19.3 (CaH3), 21.5
(CbH3), 54.8 (NꢀꢀCH2ꢀꢀN), 60.4 (CH); MS m/z (relative
intensity) 128.07 (M1, 1.39), 114.14 (4.69), 113.1 (61.44),
86.08 (1.06), 85.14 (1.75), 82.14 (2.14), 72.12 (5.64), 71.07
(100), 70.14 (2.75), 69.14 (1.36), 58.11 (11.54), 57.12
(2.07), 56.08 (32.15), 55.11 (1.21), 54.1 (2.55).
pffiffiffiffi
ꢀA0
þ
@
A
tRBꢀtRA
rA 2p
ð1aÞ
wi
pffiffiffiffiffiffiffi
with ri ¼ 8 ln 2 and i 5 {A, B}
If the peak at tBR is higher than at tAR eq. 1b has to be
applied.
Enantioselective Dynamic Gas Chromatography
0
À
À
ÁÁ
1
ꢀ
ꢁ
pffiffiffi
2
pN
100A0þB0 100ꢀhp 1ꢀ
tRBꢀtRA
Dynamic gas chromatography was performed on a
Thermo Trace PolarisQ GC-MS equipped with a split injec-
tor (2508C) and a flame-ionisation detector (2508C). For
the separation of the enantiomers of 1,2-di-n-propyldiazirine
1, 1-isopropyl-2-n-propyldiaziridine 2, and 1,2-diisopropyl-
diaziridine 3 a fused silica column coated with Chirasil-b-
Dex55–57 (25 m 3 0.25 mm i.d., 0.5 lm film thickness)
was used. The dynamic measurements were repeated
three times at each temperature in steps of 10 K between
100 and 1608C.
ln
B
B
B
B
B
B
B
B
B
B
B
B
B
@
C
C
C
C
C
C
C
C
C
C
C
C
C
A
0
1
0
1
B
A
2
B
A
R
2
ðt ꢀt
Þ
ðt ꢀt
Þ
R
R
2
R
ꢀ
ꢀ
2
A
2r
8r
A
B
@
C
A
B
B
B
B
B
B
B
B
@
hpe
ꢀ100e
C
C
C
C
C
C
C
C
A
100
pffiffiffiffi
A0
þ
1
tRA
tRBꢀtRA
rA 2p
k1 ¼ ꢀ
ꢀ ln
0
1
A
B
R
2
2
ðt ꢀt
Þ
R
8r
À
Á
ꢀ
pffiffiffi
2
hp 1ꢀ
ꢀ100
B
B
C
100e
ꢀhp
pN
pffiffiffiffi
ꢀB0
þ
@
A
tRBꢀtRA
rB 2p
ð1bÞ
Evaluation by the Unified Equation
For the evaluation of the forward reaction rate constants
k1 with the unified equation45–47 (1a and 1b), the total
The principle of microscopic reversibility58 has been
retention times of the enantiomers tAR and tRB, the hold-up fully considered in eqs. 1a and 1b. Moreover, these
Chirality DOI 10.1002/chir

288
TRAPP ET AL.
equations are no longer restricted to the evaluation of
elution profiles of racemic mixtures. Calculations were per-
formed with the software program DCXplorer (The soft-
ware DCXplorer is available from the corresponding author
as executable program running under Windows 2000, XP,
and Vista).59 Therefore, single elution profiles are directly
integrated and evaluated in a graphical interface by zoom-
ing into the area of the interconversion profile.
Evaluation of Activation Parameters DH{ and DS{
For the evaluation experiments between 100 and 1408C
were considered. At higher temperatures peak coales-
cence occurred and therefore rate constants could not be
determined with sufficient precision. The Gibbs free acti-
vation energy DG{(T) was calculated according to the Eyr-
ing eq. 2 where kB is the Boltzmann constant (kB
5
1.380662 3 10223 J K21), T is the enantiomerization tem-
perature [K], h is Planck’s constant (h 5 6.62617 3 10234
J s), and R is the gas constant (R 5 8.31441 J K21 mol21).
The statistical factor j was set to 0.5 for a reversible
degenerated interconversion process.
ꢀ
ꢁ
k1h
DGþðTÞ ¼ ꢀRT ln
ð2Þ
jkBT
As the studies were performed at temperatures between
100 and 1408C, the activation enthalpy DH{ of the enantio-
merization was obtained from the slope and the activation
entropy DS{ from the intercept of the Eyring plot (ln(k1/T)
vs. T21). Deviations of the activation parameters DH{ and
DS{ have been calculated by error band analysis of the lin-
ear regression with a level of confidence of 95%.
RESULTS AND DISCUSSION
1,2-Di-n-propyldiaziridine 1 and 1,2-diisopropyldiaziri-
dine 3 were synthesized from the corresponding amines
by formation of the aminal with formaldehyde and oxida-
tive ring closure with sodium hypochlorite (cf. Scheme 3)
and isolated by vacuum distillation. 1-Isopropyl-2-n-propyl-
diaziridine 2 was obtained by statistical synthesis using n-
propylamine and isopropylamine and was isolated from
the other constitutional isomers by vacuum spinning band
column distillation. The obtained diaziridines were com-
Fig. 3. Eyring plots for the determination of the activation parameters
DH{ and DS{ of the enantiomerization of (a) 1,2-di-n-propyldiazirine, (b) 1-
pletely characterized by 1H and 13C NMR spectroscopy isopropyl-2-n-propyldiaziridine, and (c) 1,2-diisopropyldiaziridine from the
(DEPT-135 and 1H-13C correlation NMR; cf. Fig. 1), as
well as EI MS employing a quadrupole ion trap mass
analyzer.
enantioselective DGC experiments. The upper and lower curves represent
the error bands of the linear regression with a level of confidence of 95%.
For the linear regression, three measurements for each temperature were
considered.
The enantiomer separation of 1,2-di-n-propyldiaziridine
1, 1-isopropyl-2-n-propyldiaziridine 2, and 1,2-diisopropyl-
diaziridine
3
was achieved by enantioselective gas
To determine the activation barrier DG{ and the activa-
chromatography using the chiral stationary phase (CSP) tion parameters DH{ and DS{ of the enantiomerization of
Chirasil-b-Dex.55–57 The separation factors a are strongly these propyl-substituted diaziridines (cf. Scheme 1), tem-
influenced by the presence of the more bulky and rigid perature-dependent enantioselective dynamic gas chroma-
isopropyl group. While the separation factor a is only 1.04 tography (DGC) was performed between 100 and 1608C.
for 1,2-di-n-propyldiaziridine 1, a increases to 1.18 for At 1408C coalescence occurred for 1,2-di-n-propyldiaziri-
1-isopropyl-2-n-propyldiaziridine 2, and 1.20 for 1,2-diiso- dine 1, at 1508C for 1-isopropyl-2-n-propyldiaziridine 2,
propyldiaziridine 3 at 1008C.
and at 1608C for 1,2-diisopropyldiaziridine 3. Elution
Chirality DOI 10.1002/chir

STEREODYNAMICS OF DIAZIRIDINES
289
TABLE 2. Separation factors a (at 1008C/50 kPa He) and the activation parameters
of the investigated 1,2-propyldiaziridines
DGz100ꢁC
DGz298K
DH{
DS{
Diaziridine
a1008C
(kJ mol21
)
(kJ mol21
)
(kJ mol21
)
(J K21 mol21
)
r
sy
1.04
125.3 6 0.6
118.7
100.7 6 2.1
260 6 3
0.9978
0.0663
1.18
1.24
128.3 6 0.4
123.3
113.7 6 2.5
233 6 1
0.9933
0.9951
0.1297
0.1210
129.8 6 0.4
123.3
106.5 6 2.0
256 6 2
r denotes the correlation coefficient and sy is the residual deviation of the linear regression of the Eyring plots.
profiles of the diaziridines between 1008C and 1508C are tion barrier of 1-isopropyl-2-n-propyldiaziridine 2 and 1,2-
depicted in Figure 2.
diisopropyldiaziridine 3 are similar. There is also a signif-
Reaction rate constants k of enantiomerization were cal- icant difference in the activation enthalpy DH{ and en-
culated with the analytical function of the unified equa- tropy DS{ of 1-isopropyl-2-n-propyldiaziridine 2 compared
tion45–47 (eqs. 1a and 1b) considering three experiments at to diaziridines 1 and 3. The increase of the activation en-
each temperature. Elution profiles showing coalescence at tropy DS{ can be attributed to the increased number of
elevated temperature were not considered for the calcula- possible states, because of the unsymmetrical substitu-
tion of the reaction rate constants. Experimental data of tion pattern.
1,2-diisopropyldiaziridine 3 determined from the elution
Taking into consideration that the enantiomerization
profiles and the calculated reaction rate constants are sum- barrier of 1-isopropyl-2-n-propyldiaziridine 2 is different
marized in Table 1.
from the mean enantiomerization barrier of diaziridines 1
The activation enthalpies DH{ and activation entropies and 3 and that the activation entropies DS{ are negative,
DS{ of the three diaziridines were obtained by plotting an interconversion mechanism via electrocyclic ring open-
ln(k1/T) as a function of T21 according to the Eyring equa- ing ring closure mechanism with charge separation in the
tion (cf. Fig. 3).
transition state can be suggested (cf. Scheme 1).
By linear regression analysis, the activation parameters
could be determined and are summarized in Table 2.
In conclusion, this investigation of the diaziridines 1,2-
di-n-propyldiaziridine 1, 1-isopropyl-2-n-propyldiaziridine
These enantiomerization barriers are in very good 2, and 1,2-diisopropyldiaziridine 3 demonstrates that enan-
agreement with previously determined values for 1,2-di- tioselective gas chromatography (DGC) and direct evalua-
tert-butyldiaziridine (DH{ 5 113.0 6 2.0 kJ mol21 and DS{ tion of the obtained elution profiles by the unified equation
5 44 6 5 J K21 mol21), 1,2-di-n-butyldiaziridine (DH{ 5 constitutes a valuable and straightforward tool for the mea-
118.9 6 1.0 kJ mol21 and DS{ 5 17 6 3 J K21 mol21), surement of enantiomerization barriers to look into mecha-
and 1-n-butyl-2-tert-butyldiaziridine (DH{ 5 112.6 6 2.5 kJ nistic aspects of the interconversion process. The study of
mol21 and DS{ 5 27 6 2 J K21 mol21). A comparison of structurally related sets of compounds under the same ex-
the enantiomerization barriers of the diaziridines investi- perimental conditions gives further insights into the ster-
gated here reveals a significant increase for the more eodynamics. We have shown that the enantiomerization
sterically demanding isopropyl group. However, the sec- barrier of diaziridines does not necessarily correlate with
ond isopropyl group in 1,2-diisopropyldiaziridine 3 does increasing steric hindrance by sterically demanding sub-
not significantly contribute as it is expected for two steri- stituents. Furthermore, the results suggest that the inter-
cally demanding groups to increase even more the bar- conversion in diaziridines proceeds via an electrocyclic
rier by steric hindrance. Furthermore, the enantiomeriza- ring opening ring closure mechanism.
Chirality DOI 10.1002/chir

290
TRAPP ET AL.
23. Kostyanovsky RG, Kadorkina GK, Kostyanovsky VR, Schurig V, Trapp
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