Convenient synthesis of pure fluorous alkyl azides at multigram scale

Article abstract of DOI:10.1016/j.jfluchem.2016.08.005

The reaction of F-alkylation reagents including (perfluoroalkyl)alkyl halides and sulfonates [R_fn(CH₂)_mX (X?=?Br, I, OTs, OTf)], and a slight excess of NaN₃ in DMSO at 100?°C for 5?h, followed by steam distillat

Full text of DOI:10.1016/j.jfluchem.2016.08.005

Accepted Manuscript
Title: Convenient Synthesis of Pure Fluorous Alkyl Azides at
Multigram Scale
´ ´
´
´
´
´
Author: Mate Berta Andras Dancso Aniko Nemes Zoltan
´
´
´ ´
´
Patho Denes Szabo Jozsef Rabai
PII:
S0022-1139(16)30240-8
DOI:
http://dx.doi.org/doi:10.1016/j.jfluchem.2016.08.005
Reference:
FLUOR 8836
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
20-6-2016
9-8-2016
10-8-2016
´ ´
´
´
´
Please cite this article as: Mate Berta, Andras Dancso, Aniko Nemes,
´
´
´
´
´
´
Zoltan Patho, Denes Szabo, Jozsef Rabai, Convenient Synthesis of Pure
Fluorous Alkyl Azides at Multigram Scale, Journal of Fluorine Chemistry
http://dx.doi.org/10.1016/j.jfluchem.2016.08.005
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.

*Manuscript
Convenient Synthesis of Pure Fluorous Alkyl Azides at Multigram Scale
Máté Berta,a András Dancsó,b Anikó Nemes,a Zoltán Pathó,a Dénes Szabóa and József Rábai*a
a Laboratory of Organic Fluorine Compounds, Institute of Chemistry, Eötvös Loránd University,
Budapest, Pázmány Péter sétány 1-A, H-1117
b EGIS Pharmacy PLC, H-1475 Budapest 10, P.O. Box 100
Fax: +36-1-372-2592
E-mail: rabai@elte.hu
1

*Graphical Astract – Pictogram
*Graphical Abstract – Synopsis
Convenient Synthesis of Pure Fluorous Alkyl Azides at Multigram Scale
Máté Berta,a András Dancsó,b Anikó Nemes,a Zoltán Pathó,a Dénes Szabóa and József Rábai*a
The reaction of (perfluoroalkyl)alkyl halides and sulfonates and a slight excess of NaN3 in DMSO
at 100 °C for 5 h, followed by steam distillation, gave the corresponding azides CnF2n+1(CH2)xN3
in good to excellent yields with high purity (GC≥98%). 4-CF3C6F4N3 and CH3(CH2)7N3 were
similarly prepared starting from CF3C6F5 or 1-iodooctane.
2

*Highlights (for review)
Highlights:
 Efficient synthetic route for fluorous-, polyfluoroaryl- and alkyl azides are disclosed here
 Steam-distillation enabled cost-effective separation of highly volatile fluorous azides
 Synthesis and isolation of stable fluorous azides can easily be upscaled to safe processes
3

This article is dedicated to Professor Steven H. Strauss on the occasion of his 2016 ACS Award
for Creative Work in Fluorine Chemistry.
The reaction of F-alkylation reagents including (perfluoroalkyl)alkyl halides and sulfonates
[Rfn(CH2)mX (X = Br, I, OTs, OTf)], and a slight excess of NaN3 in DMSO at 100 °C for 5 h,
followed by steam distillation, allowed the isolation of azides Rfn(CH2)mN3 in good to excellent
yields with high purity (GC assay ≥98%). Due to the stability of these fluorous azides they can be
distilled at atmospheric or lower pressures for further purification. 4-Azidoperfluorotoluene (p-
CF3C6F4N3) and 1-azidooctane were also prepared under similar conditions starting from
perfluorotoluene (CF3C6F5) or 1-iodooctane, respectively. Steam distillation allowed easy and safe
product isolations up to 50 g scale.
4

1. Introduction
The chemistry of organic azides started with the synthesis of phenyl azide one and one-half
century ago [1], flourished in the 1950’s [2], and has today emerged as a broad area of chemistry
of a unique class of compounds with exploding diversity in their synthesis and applications [3].
Since organic azides are the derivatives of the explosive HN3, many of them belong to the class of
high-energy-density molecules [3a, 4]. Similarly to the parent hydrogen azide and the heavy metal
azides, many organic azides may have explosive properties, triggered by friction, impact or excess
of heating [5].
However, certain structural patterns (e.g. longer fluorinated chains [6]) of the molecules result in
the formation of shock-insensitive and nonexplosive azides that can be manipulated safely [7]. In
addition, the recent technology of a continuous-flow microreactor enables the safe syntheses, in
the laboratory and on a larger scale, of potentially hazardous substances like organic azides [8].
Organic azides can be applied to such diverse fields as rocket fuels, explosives, photoaffinity
labeling (PAL) agents [9], surface functionalization [10] and nanomaterial synthesis [11]. The
synthesis of amines [ 12 ] and nitrogen heterocycles including aziridines, azirines, azepines,
carbazoles, furoxanes, tetrazoles and triazoles [3, 13] are based on organic azide; as is the
generation of nitrenes [3, 14].
Several synthetic routes have been developed for the synthesis of azides, which include
nucleophilic substitution, diazotization and diazotransfer reactions.
Contemporary azide syntheses mostly are based on nucleophilic substitutions (SN) reaction, which
are the method of choice for making alkyl-, benzyl-, allyl-, acyl- and heteroaryl-azides [15].
Sodium or potassium azide is used as source of the nucleophile and reactions performed in DMF
[16] or DMSO [17] solution.
Azide chemistry has been associated with the hazards of working with high-energy-density substances since its
beginning. Explosions and detonations occurred during the preparation of certain azides. Therefore guides
and rules were developed for the safe handling and estimation of the explosive nature of such substances [18].
In the early days of azide chemistry steam distillation was used to isolate aromatic azides from
reaction mixtures [19]. In the case of alkyl azides, the crude product usually was obtained by
liquid-liquid extraction. The laboratory scale purification of crude azides is possible by distillation
or flash chromatography [20]; however large scale chromatography should normally be avoided.
2. Results and discussion
Fluorous chemistry, introduced more than two decades ago, offers an exceedingly valuable
technique for isolation processes [21]. Dispersion interactions between fluorous molecules such
as perfluoroalkanes, perfluoroalkyl ethers, and perfluoro(trialkylamines) are weak thus such
compounds are volatile. Moreover, intermolecular attraction forces between fluorous and organic
5

molecules or water are even weaker [22] which results in their low solubility in each other (cf.
Hildebrand solubility parameters of fluorocarbons, common organic solvents and water [23]).
Azidotrifluoromethane (b. p. -28.5oC) [24], which is formally a combination of the shortest
fluorous ponytail (Rf1 = CF3) and the azido group, is considered to be the parent compound for
all fluorous azides (Figure 1.). We thought that the substitution of CF3-group with longer
perfluoroalkyl groups (CnF2n+1 = Rfn) and the introduction of different length of insulating groups
between the trifluoromethyl and the azido groups could allow the construction of F-organic
azides with tunable reactivity and acceptable stability (e.g. nonexplosive, long shelf life).
F-CF2-N3
Rf-CF2-CH2-N3
Rf-CF2-CH2-CH2-N3
(CF3)3C-O-CH2-CH2-N3
Rf-CF2-CH2-CH2-CH2-N3
Rf-CF2-CH2-CH2-CH2-CH2-N3
p-CF3-C6F4-N3
Figure 1. Evolution of fluorous azides
We also considered whether steam distillation would be a suitable method for the isolation of
fluorous azides, since they are immiscible with water and volatile. Indeed, we observed that this was the
case. As a limiting factor, however, azides should be stable at the steam distillation temperature
(~100 oC).
Fluorous azides (2a-l) were synthesized by the reaction of (perfluoroalkyl)alkyl sulfonates (1a-d)
or (perfluoroalkyl)alkyl halides (1e-k) and CF3C6F5 (1l) and a slight excess of ~0.5 M sodium azide
in DMSO at 100 °C for 5 h. The crude fluorous azides (2a-l) were isolated from the reaction
mixture by steam distillation in good to excellent yields and in high purity (GC assay ≥98%)
(Scheme 1, Table 1.). The precursor (perfluoroalkyl)alkyl sulfonates (1a-d) and halides (1e-k)
were synthesized and purified as published (GC assay ≥98%, cf. Experimental Section).
6

Scheme 1. Synthesis of F-azides by nucleophilic substitution reactions
7

Table 1. Selected Physical Properties and Yields of Fluorous Azides a
Azide a
MW [g/mol] N [%]b
Boiling Point c
[°C/mmHg]
61-62/1
86-87/15
67-68/15
140/760
53-55/15
84-85/15
Yield d
[%]
Scale
[mmol]
2a (p.n.c.) [25]
2b (n.c.)
2c [13, 26]
2d [27]
425.10
457.11
389.12
305.10
303.13
403.14
503.16
553.17
603.17
9.88
9.19
85
78
85
81
85
95
84
77
88
50
20
120
60
8
100
10
6
10.80
13.77
13.86
10.42
8.35
2e (n.c.)
2f (p.n.c.) [28]
2g (p.n.c.) [29]
2h (n.c.)
104-105/15
114-116/15
mp 52-53
7.60
6.97
2i (n.c.)
7
2j (p.n.c.) [30]
2k (n.c.)
517.18
501.14
259.08
155.24
8.12
8.38
16.22
27.07
118-120/15
103-104/15
54-55/5
73-75/3
79
43
81
89
7
6
2l [16, 31]e
9 e
14
1-C8H17N3 [32]
a n. c. = new compound; p.n.c = prepared or purchased, but not characterized.
b
Using the rule of the carbon to nitrogen ratio only 1-octyl azide should be considered as an unsafe azide [5b].
c Boiling point values for 2a-k were determined by distillation of pure azides and disclosed first time here.
d The steam-distilled azides are of high purity (GC assay: ≥98%, cf.: Experimental Section).
e At larger scale the exothermic reaction of 1l and NaN3 should be controlled by the addition of the NaN3 solution.
Dipolar-aprotic solvents DMSO, DMF and CH3CN are the most suitable for azidation of R-X
type compounds and for their work-up water – ether partition is the method of choice for azide
o
isolation. However, when we used this technique for the isolation of 2d (b. p. = 140 C)
significant product loss was observed during the atmospheric evaporation of the ether solvent
due to its volatility, which is an unusual property compared with classical organic compounds
having similar boiling points. Consequently we adapted the so-called ‘concentrate’ work-up
procedure, without using solvents for collecting the lower fluorous phase [33].
All but one azide 2k were obtained in good to excellent yields (Table 1.). Although the precursor
F-allylic bromide 1k was consumed quantitatively, only 43% yield of azide 2k was obtained as a
colorless liquid using steam distillation. However, on longer standing at room temperature this
oily product became amorphous white solid insoluble in common organic solvents. The other
fluorous azides appeared unchanged if they were kept at ambient temperature for several weeks.
For the synthesis of azides with one methylene spacer, we used triflates 1a and 1b due to the well
documented reluctance of RfCH2OSO2R type sulfonates to react with nucleophiles [34]. Some
RfCH2N3 type azides with one methylene spacer have been prepared using mesylates
o
RfCH2OSO2CH3 under forcing conditions (NaN3-DMSO/110 C, 24 h, 18-crown-6) allowed by
their higher stability [6].
Tosylates 1c and 1d with a two-carbon spacer showed adequate reactivity with sodium azide to
afford 2c and 2d, respectively, in excellent yields. Perfluoroalkyl-ethyl azide 2c has been prepared
8

for the first time by the reaction of C6F13CH2CH2I with NaN3 in wet t-butyl alcohol, but as a
difficult to separate mixture of the product and unreacted C6F13CH2CH2I [26b].
The reaction of fluorous iodides 1e-1j with sodium azide occurs as easily as with 1-iodooctane,
since the propylene- and butylene spacers almost completely insulate the electron withdrawing
effect of the perfluoroalkyl-chain from the reaction center [21].
The fluorine to azide exchange reaction in DMSO on the activated aromatic system of
octafluorotoluene 1l occurred in para-position, as reported for the cases of using CH3CN [30] or
DMF [16] solvents and NaN3, and azide 2l was isolated in excellent yield.
All crude azide products isolated by steam distillation showed high GC purity (GC assay ≥98%).
Their purity can further be improved by distillation at atmospheric or reduced pressure (Table 1.)
Table 2. Selected spectral data of fluorous azides.
as(cm-1)
ps(cm-1)
15N, ppm 15N, ppm
2a
2b
2c
2e
2f
2116
2116
2109
2103
2103
2103
2104
2106
2102
1306
1308
1238
1225
1239
1241
1255
1258
1242
-340.6
-340.7
-330.5
-329.8
-329.7
-329.7
-329.9
-329.9
-329.9
-154.1
-154.1
-152.9
-152.4
-152.3
-152.3
-152.5
-152.6
-151.8
2g
2h
2i
2j
IR spectra of azides 2a-l show that asymmetric stretching vibrations of azide groups appear near
2100 cm-1, and their frequency depends on the number of methylene groups between the azide
group and the fluorous chain (2a, 2c, 2f) but varied only slightly with the length of the
perfluorinated moiety (2e-i). The frequency of the symmetric stretching vibration of the azide
group (between 1306 and 1225 cm-1) depends both on the length of the spacer and the fluorous
15
chain. N NMR data show the same tendency. The difference in the chemical shifts is more
pronounced in the case of the  nitrogen atom (Table 2.).
3. Conclusion
In conclusion a series of fluorous azides were synthesized by nucleophilic substitution reactions.
Steam distillation proved to be a mild and effective method for isolation of pure azides from the
reaction mixture up to 50 g scale. They can be distilled under reduced pressure without
decomposition to further improve their purity.
9

4. Experimental Section
4.1. General description of methods and materials
The precursor fluorous alkylation reagents were prepared as reported: 1a [35], 1c [36], 1d [30], 1e-
j [37]. NMR spectra (1H, 19F, 1H-15N HMBC, 1H-19F HMBC) were recorded on a Bruker Avance
III 400 MHz instrument using a 5 mm1H- and BB-channel probe head at room temperature (295
± 2 K) in CDCl3. Chemical shifts (δ) are given in ppm units relatively to the internal standards:
TMS (δ = 0.00 for 1H) and CFCl3 (δ = 0.00 for 19F). The 15N spectra were projected from 1H-15N
HMBC experiment: reference was CH3NO2 (δ = 0.00 for15N). GC-MS spectra were recorded on
a Perkin Elmer Precisely (Clarus 500 Gas Chromatograph, Clarus 560 D Mass Spectrometer,
70eV). IR spectra were recorded on Bruker Alpha Spectrophotometer. Melting points were
determined on a Boetius micro melting point apparatus and are uncorrected. Purity of F-azides
was determined by GC (Hewlett-Packard 5890 Series II; PONA [crosslinked methylsilicon gum]
50 m × 0.2 mm × 0.5 mm column, H2 carrier gas, FID detection); the liquid ones with neat
injection.
Warning: Organic azides are considered as explosives whenever the azido content is remarkably high. Of course,
there is no sharp threshold at which the explosive hazard starts. However, as a rule of thumb violent decomposition
reactions are expected for azido compounds having a (C + O)/N ratio of < 3 [4c, 5b]. Appropriate safety
measures (e.g small scale reactions, safety shields, manipulators, etc) should be used when working with explosive
azides (e.g. copper(I) azide, mono-, di- and polyazido alkanes or arenes of lower molecular weight) and their
incidental formation should be avoided; for more details, see [3, 4, 18]. In addition the toxic nature of hydrazoic
acid and sodium azide should also be considered [3, 4, 18].
2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9-Hexadecafluorononyl-1-trifluoromethanesulfonate (1b)
To a stirred solution of H(CF2)8CH2OH (13.0 g, 30 mmol) and 2.85 g (36 mmol) of pyridine in
60 ml of CH2Cl2 at 0-5oC was added 10.2 g (36 mmol) trifluoromethanesulfonic anhydride during
1 h. The mixture was stirred for 36 h at 20oC and ice-water added to dissolve the precipitated salt,
while some CH2Cl2 to dissolve the phase separating oil. Then the separated organic layer was
washed with brine, dried (Na2SO4), filtered and the solvent evaporated. The residual oil was
purified by short-path distillation to afford 1b as a colorless liquid. Yield: 15.0 g (93%) bp = 135-
140 oC/30 mmHg (Lit. [38] bp = 117-119 oC/20 mmHg). GC-FID assay: 98.0 %.
3
2
3
1H NMR (CDCl3): δ 4.82 (t, 2H, JHF = 12.3 Hz, CH2O); 6.05 (tt, 1H, JHF= 51.8 Hz, JHF =
5.1Hz, HCF2,). 19F NMR (CDCl3): δ -74.94 (s, 3F), -120.51 (m, 2F), -122.46 (m, 6F), -123.53 (m,
2F), -123.93 (m, 2F), -130.09 (m, 2F), -137.96 (m, 2F). IR (KBr) , cm-1: 1432, 1212, 1144, 1027,
820, 764, 703, 661, 612, 540, 504, 477. MS (EI) m/z 564 [M+], 495, 345, 231, 213, 181, 163, 151,
131, 113, 100, 99, 83, 69, 51 Da.
(E)-1-Bromo-4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoroundec-1-ene (1k) (n. c.)
10

To a solution of E-C8F17CH=CHCH2OH [39] (30.0 g, 63 mmol) in 100 ml of ether PBr3 (7.21 g,
2.50 ml, 26.6 mmol) was added drop-by-drop at 0oC with stirring, then refluxed and stirred for 9
h. Cooled to 10 oC and the excess of PBr3 decomposed by addition of water. The water and ether
layer were separated, the water phase was extracted with ether, and then the combined organics
were washed with brine and dried (Na2SO4). It was filtered and the solvent evaporated then the
title F-allyl bromide was isolated by fractional distillation. Yield: 30.2 g (89%) colorless liquid; bp
= 150-155 oC/15 mmHg. GC-FID assay: 98.1% (96.1% E – 3.9 % Z ratio).
3
3
1H NMR (CDCl3): δ 3.99 (2H, m, CH2Br), 5.90 (dt, 1H, JHH(E) = 15.39 Hz, JHH= 11.95 Hz,
3
3
4
19
CH2CH), 6.55 (dtt, 1H, JHH(E) = 15.39 Hz, JHF = 7.1 Hz, JHF = 2.2 Hz, CF2CH). F NMR
(CDCl3): δ -81.60 (t, 3F, JFF = 10.1 Hz), -112.68 (m, 2F), -121.87 (m, 2F), -122.38 (m, 4F), -
3
123.23 (m, 2F), -123.78 (m, 2F), -126.74 (m, 2F). IR (KBr) , cm-1: 1721, 1675, 1440, 1369, 1314,
1206, 1150, 1014, 1068, 970, 876, 792, 722, 705, 656, 559, 531. MS (EI) m/z 538 [M+], 459, 389,
345, 219, 181, 169, 119, 90, 69 Da.
4. 2. General procedure for the synthesis of azides
A stirred solution of NaN3 (0.715 g, 11 mmol) and perfluoroalkyl-alkyl halide or perfluoroalkyl-
alkyl sulfonate (10 mmol) in DMSO (22 ml) was heated to 100 °C for 5 h. Then the reaction
mixture was allowed to cool to room temperature and water (60 ml) was added. The resulting
mixture was steam distilled applying an external steam generator. The phases of the distillate were
separated; the fluorous layer was dried over Na2SO4. The obtained “crude product” (GC-FID assay
≥98%) can further be purified by distillation or crystallization (GC-FID assay ≥99.5%).
4.2.1. 8-Azido-1,1,1,2,2,3,3,4,4,5,5,6,6,7,7-pentadecafluorooctane (2a)
A solution of NaN3 (3.90 g, 60 mmol) and 1a (28.8 g, 54.1 mmol) in DMSO (120 ml) was
reacted. Yield: 21.4 g (93%) crude by steam distillation, which on distillation gave 19.6 g (85%)
colorless viscous oil, bp 61-62 °C/12 mmHg, GC-FID assay: 99.0 %. 1H NMR (CDCl3): δ 3.77 (t,
3
19
3
2H, JHF = 14.5 Hz). F NMR (CDCl3): δ -81.33 (t, 3F, JFF = 9.9 Hz), -117.94 (m, 2F), -122.50
(m, 4F), -123.22 (m, 4F), -126.63 (m, 2F). 15N NMR (CDCl3): δ -154.1, -340.6. IR (KBr) , cm-1:
2116, 1306, 1205, 1147, 436. MS (EI) m/z 425 [M+], 397 [M-N2]+, 378, 328, 231, 219, 181, 169,
131, 119, 100, 78, 69, 56 Da.
4.2.2. 9-Azido-1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-hexadecafluorononane (2b)
A solution of NaN3 (1.43 g, 22 mmol) and 1b (11.3 g, 20.0 mmol) in DMSO (18 ml) was reacted.
Yield: 7.13 g (78 %) colorless viscous oil, bp 86-87 °C/15 mmHg, GC-FID assay: 99.0. 1H NMR
3
2
3
(CDCl3): δ 3.76 (t, 2H, JHF = 14.51 Hz, CH2N3), 6.03 (tt, 1H, JHF = 51.80 Hz, JHF = 5.13 Hz,
HCF2). 19F NMR (CDCl3): δ -117.72 (m, 2F), -122,10 (m, 6F), -123.36 (m, 2F), -123.55 (m, 2F), -
129.61 (m, 2F), -137.32 (m, 2F). N NMR (CDCl3): δ -154.1, -340.7. IR (KBr) , cm-1: 2116,
15
1308, 1208, 1146, 434. MS (EI) m/z 457 [M+], 430, 410, 360, 181, 131, 119 Da.
4.2.3. 8-Azido-1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluorooctane (2c)
11

A solution of NaN3 (8.33 g, 128 mmol) and 1c (60.4 g, 117 mmol) in DMSO (260 ml) was
reacted. Yield: 42.8 g (94%) crude by steam distillation, which on distillation gave 38.6 g (85%)
1
colorless viscous oil, bp 67-68 °C/15 mmHg, GC-FID assay: 98.80%. H NMR (CDCl3): δ 3.61
(t, 2H, 3JHH = 7.2 Hz, CH2N3), 2.39 (tt, 2H, 3JHH = 7.2 Hz, 3JFH = 18.5 Hz, CH2CH2N3). 19F NMR
(CDCl3): δ -88.36 (t, 3F, 3JFF = 9.9 Hz), -114.44 (m, 2F), -122.36 (m, 2F), -123.35 (m, 2F), -124.01
(m, 2F), -126.63 (m, 2F). 15N NMR (CDCl3): δ -152.9, -330.5. IR (KBr) , cm-1: 2109, 1238, 1202,
1145, 441. MS (EI) m/z 389 [M+], 361 [M-N2]+, 340, 169, 131, 119, 100, 95, 69, 42 Da.
4.2.4. 5-Azido-1,1,1-trifluoro-2,2-bis(trifluoromethyl)-3-oxapentane (2d)
A solution of NaN3 (4.161 g, 64 mmol) and 1d (25.00 g, 58 mmol) in DMSO (75 ml) was reacted.
Yield: 14.2 g (81 %) colorless easily moving liquid, bp 140 °C/760 mmHg, GC-FID assay:
98.80%. The spectroscopic data were in agreement with a sample prepared and reported
previously in this laboratory [27].
4.2.5. 7-Azido-1,1,1,2,2,3,3,4,4-nonafluoroheptane (2e)
A solution of NaN3 (0.572 g, 8.8 mmol) and 1e (3.10 g, 8.0 mmol) in DMSO (17 ml) was reacted.
1
Yield: 2.05 g (85 %) colorless viscous oil, 53-55 °C/15 mmHg, GC-FID assay: 98.0%. H NMR
3
(CDCl3): δ 3.42 (t, 2H, JHH = 6.5 Hz, CH2N3), 2.18 (m, 2H, CH2CH2N3), 1.90 (m, 2H,
19
3
CH2CH2CH2N3). F NMR (CDCl3): δ -81.21 (t, 3F, JFF = 9.4 Hz), -114.62 (m, 2F), -124.54 (m,
2F), -126.16 (m, 2F). N NMR (CDCl3): δ -152.5, -329.7. IR (KBr) , cm-1: 2103, 1225, 1133,
15
442. MS (EI) m/z 303 [M+], 275 [M-N2]+, 169, 119, 69, 42 Da.
4.2.6. 9-Azido-1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluorononane (2f)
A solution of NaN3 (7.37g, 0.113 mol) and 1f (50.4 g, 0.103 mol) in DMSO (205 ml) was reacted.
Yield: 39.75 g (95 %) colorless viscous oil, bp 104-105 °C/15 mmHg, GC-FID assay: 98.30%. 1H
3
NMR (CDCl3): δ 3.43 (t, 2H, JFH = 6.5 Hz, CH2N3), 2.18 (m, 2H, CH2CH2N3), 1.91 (m, 2H,
19
3
CH2CH2CH2N3). F NMR (CDCl3): δ -81.31 (t, 3F, JFF = 9.9 Hz), -114.71 (m, 2F), -122.40 (m,
15
2F), -122.36 (m, 2F), -122.95 (m, 2F), -126.65 (m, 2F). N NMR (CDCl3): δ -152.5, -329.7. IR
(KBr) , cm-1: 3444, 2955, 2879, 2103, 1456, 1357, 1239, 1204, 1145. MS (EI) m/z 403 [M+], 375
[M-N2]+, 169, 119, 69, 42 Da.
4.2.7. 11-Azido-1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluoroundecane (2g)
A solution of NaN3 (0.501 g, 7.7 mmol) and 1g (4.13 g, 7.0 mmol) in DMSO (15 ml) was reacted.
1
Yield: 2.37 g (84 %) colorless viscous oil, bp 104-105 °C/15 mmHg, GC-FID assay: 98.8%. H
3
NMR (CDCl3): δ 3.43 (t, 2H, JHH = 9.9 Hz, CH2N3), 2.18 (m, 2H, CH2CH2N3), 1.90 (m, 2H,
CH2CH2CH2N3). 19F NMR (CDCl3): δ -81.47 (t, 3F, 3JFF = 10.1 Hz), -114.77 (m, 2F), -122,18 (m,
15
2F), -122.40 (m, 4F), -123.23 (m, 2F), -123.93 (m, 2F), -126.69 (m, 2F). N NMR (CDCl3): δ -
152.4, -329.7. IR (KBr) , cm-1: 3358, 2955, 2879, 2103, 1642, 1456, 1357, 1320, 1205, 1150,
12

1116, 1076, 1031, 1000, 876, 825, 780, 737, 722, 705, 656, 622, 585, 560, 529, 431, 411, 408). MS
(EI) m/z 503 [M+], 475 [M-N2]+, 456, 169, 131, 119, 69, 42 Da.
4.2.8. 11-Azido-1,1,1,2,3,3,4,4,5,5,6,6,7,7,8,8-hexadecafluoro-2-(trifluoromethyl)undecane (2h)
A solution of NaN3 (0.415 g, 6.4 mmol) and 1h (3.72 g, 5.8 mmol) in DMSO (12 ml) was reacted.
1
Yield: 2.36 g (73 %) colorless viscous oil, bp 114-116 °C/15 mmHg, GC-FID assay: 98.0 %. H
3
NMR (CDCl3): δ 3.42 (t, 2H, JHH = 6.5 Hz, CH2N3), 2.18 (m, 2H,CH2CH2N3), 1.90 (m,
19
2H,CH2CH2CH2N3). F NMR (CDCl3): δ -72.13 (m, 6F), -114.49 (m, 2F), -115.17 (m, 2F), -
15
120.92 (m, 2F), -121.67 (m, 2F), -121.84 (m, 2F), -123.63 (m, 2F), -186.30 (m, 1F). N NMR
(CDCl3): δ -152.4, -330.0. IR (KBr) , cm-1: 2104, 1255, 1207, 1115, 985, 440. MS (EI) m/z 553
[M+], 506, 131, 69, 56, 42 Da.
4.2.9. 13-Azido-1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10-henicosafluorotridecane (2i)
A solution of NaN3 (0.465 g, 7.2 mmol) and 1i (4.49 g, 6.5 mmol) in DMSO (16 ml) was reacted.
After steam distillation the solid product was extracted with DCM (30 ml). The organic phase
was dried over Na2SO4, and the solvent was removed under reduced pressure. Yield: 3.47 g (88
%) white wax-cloth, mp 52-53 °C, GC-FID assay: 99.3 %. 1H NMR (CDCl3): δ 3.43 (t, 2H, 3JHH
=
6.1 Hz, CH2N3), 2.18 (m, 2H, CH2CH2N3), 1.90 (m, 2H, CH2CH2 CH2N3). 19F NMR (CDCl3): δ -
81.38 (t, 3F, 3JFF = 9.9 Hz), -114.77 (m, 2F), -122.23 (m, 10F), -123.24 (m, 2F), -123.96 (m, 2F), -
126.68 (m, 2F). 15N NMR (CDCl3): δ -152.3, -329.9. IR (KBr) , cm-1: 2106, 1212, 1152, 588. MS
(EI) m/z 575 [M-N2]+, 556, 504, 169, 131, 119, 104, 69, 56, 42 Da.
4.2.10. 12-Azido-1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluorododecane (2j)
A solution of NaN3 (0.508 g, 7.8 mmol) and 1j (4.25 g, 7.1 mmol) in DMSO (15 ml) was reacted.
After steam distillation the product was extracted with DCM (30 ml). The organic phase was
dried over Na2SO4, and the solvent was removed under reduced pressure. Yield: 2.88 g (79 %), bp
1
3
118-120 °C/15 mmHg, GC-FID assay: 97.7 %. H NMR (CDCl3): δ 3.34 (t, 2H, JFH = 6.1 Hz),
19
3
2.11 (m, 2H), 1.70 (m, 4H). F NMR (CDCl3): δ -81.36 (t, 3F, JFF = 9.8 Hz), -114.93 (m, 2F), -
122.22 (m, 2F), -122.42 (m, 4F), -123.22 (m, 2F), -123.99 (m, 2F), -126.64 (m, 2F). N NMR
15
(CDCl3): δ -151.9, -329.0. IR (KBr) , cm-1: 3351, 2957, 2882, 2102, 1659, 1462, 1442, 1352, 1326,
1242, 1206, 1150, 1117, 1038, 974, 919, 873, 826, 791, 736, 722, 705, 656, 585, 560, 529, 447, 441,
422, 408. MS (EI) m/z 487, 467, 440, 389, 181, 169, 148, 131, 121, 90, 69, 56 Da.
4.2.11. 11-Azido-1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluoroundec-9-ene (2k)
A solution of NaN3 (0.436 g, 6.7mmol) and 1k (3.28 g, 6.1 mmol) in DMSO (13 ml) was reacted.
After steam distillation the solid product was extracted with DCM (20 ml). The organic phase
was dried over Na2SO4, and the solvent was removed under reduced pressure. Yield: 1.32 g (43
%) colorless oil, bp 103-104 °C/15 mmHg, GC-FID assay: 97.6%. 1H NMR (CDCl3): δ 6.42 (m,
19
1H), 5.95 (1H, ~q, J=13.1 Hz), 4.04 (m, 2H). F NMR (CDCl3): δ -81.40 (t, 3F, 3JFF = 9.8 Hz), -
112.47 (m, 2F), -121.87 (m, 2F), -122.42 (m, 4F), -123.22 (m, 2F), -123.87 (m, 2F), -126.65 (m,
13

15
2F). N NMR (CDCl3): δ -152.9, -331.3. IR (KBr) , cm-1: 2113, 1682, 1438, 1354, 1209, 1150,
989, 437, 415. MS (EI) m/z 501[M+], 473 [M-N2]+, 381, 169, 135, 131, 119, 104, 77, 69, 54 Da.
4.2.12. 1-Azido-4-trifluoromethyl-2,3,5,6-tetrafluorobenzene (2l)
Warning: multiple fluorine substitution with formation of explosive side products should be avoided (Table 1.).
A solution of NaN3 (0.608 g, 9.4 mmol) and CF3C6F5 (2.00 g, 8.5 mmol) in DMSO (17 ml) was
stirred at room temperature for 4 h. Yield: 1.78 g (81 %) yellow oil, 54-55 °C/5 mmHg, GC-FID
assay: 99.8%. 19F NMR (CDCl3): δ -55.92 (m, 3F), -140.39 (m, 2F), -150.09 (m, 2F). MS (EI) m/z
259 [M-N2]+, 231, 212, 181, 162, 131, 117, 93, 69 Da.
4.2.13. 1-Azido-n-octane
A solution of NaN3 (1.02 g, 15.6 mmol) and 1-iodooctane (3.42g, 14.2 mmol) in DMSO (30 ml)
was reacted. Yield: 1.97 g (89 %) colorless oil, bp 73-75 °C/3 mmHg, GC-FID assay: 99.9%. 1H
NMR (CDCl3): δ 0.88 (t, 3H), 1.28 (m, 10H), 1.59 (m, 2H), 3.25 (t, 2H, 3JHH = 6.84 Hz).
.
Acknowledgement
This work was financed by the National Research, Development and Innovation Office (NKFIH) as part
of the M.ERA-NET transnational COR_ID program (NN 117633). We thank dr. Éva Szabó for
her assistance in the interpretation of GC-MS spectra.
14

1 P. Grieß, Justus Liebigs Ann. Chem., 135 (1865) 121-121.
2 (a) C. Grundmann, In Houben-Weyl, 4th ed., Vol.10/3; Müller, E., Ed.; Thieme: Stuttgart, 1965, p. 777-
836;
(b) S. Lang, J.A. Murphy, Chem. Soc. Rev. 35 (2006) 146-156;
(c) E.F.V. Scriven, K. Turnbull, Chem. Rev. 88 (1988) 297-368;
(d) G. L’abbe, Chem. Rev. 69 (1969) 345-363;
(e) J.H. Boyer, F.C. Canter, Chem. Rev. 54 (1954) 1-57;
(f) P.A.S. Smith, Org. React. 3 (1946) 337-449.
3 (a) S. Bräze, C. Gil, K. Kepper, V. Zimmermann, Angew. Chem. Int. Ed.44 (2005) 5188-5240;
(b) OrganicAzides: Syntheses and Applications, Edited by S. Bräse and K. Banert, Wiley: New York,2010.
4 (a) O.V. Dorofeeva, O.N. Ryzhova, M.A. Suntsova, J. Phys. Chem. A., 117 (2013) 6835-6845;
(b) T.M. Klapötke, B. Krumm, Azide-Containing High Energy Materials; In Organic Azides: Synthesis
and Applications; S. Bräse and K. Banert, Eds. Wiley: New York, 2010, Chapter 13, pp. 391-411;
(c) T. Keicher, S. Löbbecke, Lab-scale Synthesis of Azido Compounds: Safety Measures and Analysis; In
OrganicAzides: Synthesis and Applications; S. Bräse and K. Banert, Eds. Wiley: New York, 2010, Chapter
1, pp. 3-27.
5 (a) R. Kulsky, M. Lim, Z. Hachmeister, Process Safety News 17 (2010) 1-5;
https://www.fauske.com/sites/default/files/ShockExplosionandFrictionHazards-
IdentificationandMitigation.pdf, (accessed 24.07.2016);
(b) P.A.S. Smith, The Chemistry of Open-Chain Organic Nitrogen Compounds, Vol. 2, 1966, W.A.
Benjamin Inc., New York, pp. 211-256;
(c) Recommendations on Transport of Dangerous Goods. In Manual of Tests and Criteria, 5th revision,
Part I: Classification Procedures, Test Methods and Criteria Relating to Explosives of Class I; United
Nations: New York and Geneva, 2009.
6 Y.-M. Wu, J. Deng, X.Fang, Q.-Y. Chen, J. Fluorine Chem. 125 (2004) 1415–1423.
7 (a) Z. Kaleta, O. Egyed, T. Soós, Org. Biomol. Chem. 3 (2005) 2228-2230;
(b) H.C. Kolb, M.G. Finn, K.B. Sharpless, Angew. Chem. Int. Ed., 40 (2001) 2004-2021.
8 (a) P. Zanirato, Chimica e Industria, 94 (2012) 98-101.
(b) M.M.E. Delville, P.J. Nieuwland, P. Janssen, K. Koch, J.C.M. van Hest, F.P.J.T. Rutjes, Chemical
Engineering Journal, 167 (2011) 556-559.
9 N.H. Soundararajan, S.H. Liu, S. Soundararajan, M.S. Platz, Bioconjug Chem. 4 (1993) 256-261
10 G. Godeau, T. Darmanin, F. Guittard, J. Fluorine Chem. 184 (2016) 8-15.
11 L.-H. Liu, M. Yan, Acc. Chem. Res. 43 (2010) 1434-1443.
12 F. Rolla, J. Org. Chem. 47 (1982) 4327-4329.
13 R.W. Read, X.B. Wang,. Chiang Mai J. Sci. 6 (2009) 247-257.
14 S. Chiba, Synlett 23 (2012) 21–44.
15 M.E.C. Biffin, J. Miller, D.R. Paul, Chap. 2. Introduction of the Azido Group; In: Patai, S. The
Chemistry of the Azido Group. Wiley Interscience, New York, 1971; pp. 57-190.
15

16 A.V. Kashkin, Yu. L. Bakhmatov, N.N. Marchenko. Zh. Vses. Khim. Obshchest. 15 (1970) 591-592.
Chem. Abstr. 74 (1971) 12729k.
17 (a) A.A. Malik, D. Tzeng, P. Cheng, K. Baum, J. Org. Chem. 1991, 56, 3043-3044; (b) S.G. Alvarez, M.
T. Alvarez, Synthesis (1997) 413-414.
18 (a) University of California Santa Barbara, Laboratory safety fact sheet #26: Synthesizing, purifying, and
handling organic azides, http://www.ehs.ucsb.edu/files/docs/ls/factsheets/Azides_FS26.pdf, (accessed
12.06.2016);
(b) Stanford University, Environmental health and safety, information on azide compounds, Rep# 08-203,
2008, https://web.stanford.edu/dept/EHS/prod/researchlab/lab/safety_sheets/08-203.pdf, (accessed
12.06.2016).
19 (a) E. Noelting, E. Grandmougin, O. Michel, O., Ber. Dtsch. Chem. Ges., 25 (1892) 3328–3342;
(b) O. Dimroth, K. Pfister, Ber. Dtsch. Chem. Ges., 43 (1910) 2757–2767;
(c) W.R. Carpenter, US Patent 3,138,609, 23 June 1964.
20 S.H. Park, Bull. Korean Chem. Soc. 24 (2003) 253-255.
21 (a) I.T. Horváth, J. Rábai, Science 266 (1994) 72-74;
(b) Handbook of Fluorous Chemistry, ed. J.A. Gladysz, D.P. Curran, and I.T. Horváth, Wiley-WCH,
Weinheim, 2004.
(c) Fluorous Chemistry in Topics of Chemistry, ed. I.T. Horváth, Springer, Heidelberg, 2012.
22 (a) M.C. DosRamos, F.J. Blas, Molecular Physics, 105 (2007) 1319-1334; (b) R. Berger, G. Resnati, P.
Metrangolo, E. Weber, J. Hulliger, Chem. Soc. Rev., 40 (2011) 3496–3508.
23 (a) A.E.C. Collis, I.T. Horváth, Catal. Sci. Technol., 1 (2011) 912–919; (b) S.-W. Lo, E. Law, M.Y. Lui, X.-
G. Wei, K.-C. Lau, C.Y. Ma, M.B. Murphy, I.T. Horváth, Org. Chem. Front., 1 (2014) 1180-1187; (c) A.S.W.
Lo, I.T. Horváth, Green Chem. 17 (2015) 4701-4714.
24 (a) K.O. Christe, C.J. Schack, Inorg. Chem. 20 (1981) 2566-2570;
(b) S.P. Makarov, A.Ya. Yakubivich, V.A. Ginsburg, A.S. Filatov, M.A. Englin, N.F. Privezentseva, T.Ya.
Nikiforova, Dokl. Acad. Nauk. SSSR 141 (1961) 357-360.
(c) S.P. Makarov, A.Ya. Yakubivich, A.S. Filatov, M.A. Englin, T.Ya. Nikiforova, Zh. Obshch. Khim. 38
(1968) 709-715.
25 D.V. Francis, J.B. Harper, R.W. Read, Aust. J. Chem. 68 (2015) 57-68.
26 (a) A.A. Pavia, B. Pucci, J.G. Riess, L. Zarif, C. Guedj, US Patent 5,650,393A, 10 June 1997;
(b) C.S. Rondestvedt, Jr. et G.L. Thayer, Jr., J. Org. Chem. 42 (1977) 2680-2683.
27 D. Szabó, J. Mohl, A.-M. Bálint, A. Bodor, J. Rábai,. J Fluorine Chem., 127 (2006) 1496-1504.
28 R.K. Manova, S.P. Pujari, C.A.G.M. Weijers, H. Zuilhof, T.A. van Beek, Langmuir 28, (2012) 8651−8663.
29 (a) D.M. Beal, V.E. Albrow, G. Burslem, L. Hitchen, C. Fernandes, C. Lapthorn, L.R. Roberts, M.D.
Selby, L.H. Jones, Org. Biomol. Chem., 10, (2012) 548-554;
(b) M.-K. Jeon, M.-K. Kang, K.H. Park, Tetrahedron 68 (2012) 6038-6053.
16

30 M. Park, S.-H. Jung, J. Lim, D.-Y. Kim, H.-J. Kim, S. Lee, H. Jung, S. Lee, C. Lee, J.K. Lee J. Mater.
Chem. C, 3 (2015) 2759-2762.
31 R.E. Banks, A. Prakash, J. Chem. Soc. Perkin 1 1974, 1365-1371.
32 F. Rolla, J.Org. Chem. 47 (1982) 4327-4329.
33 Cs. Szíjjártó, P. Ivanko, F.T. Takács, D. Szabó, J. Rábai. J. Fluorine Chem. 129 (2008) 386-389.
34 (a) T. Bříza, V. Král, P. Martásek, R. Kaplánek,. J. Fluorine Chem. 129 (2008) 235–247.
(b) T. Bříza, J. Kvíčala, P. Mysík, O. Paleta, J. Čermák, Synlett (2001) 685-687.
35 J. Rábai, D. Szabó, E. K. Borbás, I. Kövesi, I. Kövesdi, A. Csámpai, Á. Gömöry, V.E. Pashinnik, Y.G.
Shermolovich,. J. Fluorine Chem. 114 (2002), 199-207.
36 S. Elshani, E. Kobzar, R.A. Bartsch,, Tetrahedron 56 (2000) 3291-3301.
37 B. Menzinger, G. Jakab, D. Szabó, J. Rábai, Fluorine Notes, No 3(94) 2014 (May – June);
38 Minnesota Mining and Manufacturing Company, FR Patent 1,470,669A, 24 February 1967
39 P. Ivanko, Cs. Szíjjártó, D. Szabó, J. Rábai, Fluorine Notes, No 5 (84) 2012 (September – October).
17