2007

VOLUME 7
NUMBER 2

Peptide Synthesis

COUPLING REAGENTS

NEW UNNATURAL
AMINO ACIDS

NEW TOOLS FOR

PEPTIDE PEGYLATION

FLUOROUS PEPTIDE
SYNTHESIS

Key intermediate stage during the -OAt-mediated

coupling of two D-alanines

sigma-aldrich.com
 2

Introduction Vol. 7 No. 2

Peptides play a crucial role in fundamental physiological and biochemical functions
of life. For decades now, peptide research is a continuously growing field of science. Aldrich Chemical Co., Inc.
Sigma-Aldrich is proud of being able to meet all your needs in chemical peptide synthesis Sigma-Aldrich Corporation
offering more than 2,600 products related to this field. You can obtain all the necessary 6000 N. Teutonia Ave.
Introduction

tools for solution- and solid-phase peptide synthesis conveniently from a single source. You Milwaukee, WI 53209, USA
can choose between 2,100 natural and unnatural amino acid building blocks to design
your peptide, and select the coupling method for the most efficient synthesis. Finally,
you will find all required reagents for functionalization, manipulation and analysis of your To Place Orders
products. This ChemFiles highlights a comprehensive listing of coupling reagents available
Contact your local Sigma-Aldrich office
through Sigma-Aldrich and introduces new, unnatural amino acid building blocks, tools for
(see back cover), or visit www.sigma-aldrich.com
PEGylation, and products for fluorous-phase peptide synthesis and separation. For more
information, and access to our complete range of chemistry products, visit our Web site at
sigma-aldrich.com/gochem. Customer & Technical Services
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2007-2008 Aldrich Handbook
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About Our Cover

The cover graphic shows the key intermediate stage during the -OAt-mediated coupling
of two D-alanines (for improved clarity Hydrogen atoms have been omitted and both
s i g m a - a l d r i c h . c o m

amino acids are represented as their unprotected derivatives). The generated D-Ala-D-Ala
dipeptide is the main recognition sequence for the powerful antibiotic vancomycin.
During the coupling reaction the nucleophilic amino group of one D-alanine attacks the
-OAt-activated carbonyl group of another D-alanine. In the process, the pyridine nitrogen
of the -OAt-moiety accelerates the aminolysis of the active ester through intramolecular
base catalysis. This neighbouring group effect explains the high efficiency of HOAt derived
peptide coupling reagents like HATU.
 3

Coupling Reagents Diphenyl phosphoryl azide, technical, >90%

DPPA O
O
In principle, the seemingly simple formation of a peptide bond (C6H5O)2P(O)N3 P N3
O
can be accomplished using all the procedures available in organic FW: 275.2
chemistry for the synthesis of carboxylic acid amides. However, [26386-88-9]
due to the presence of various functional groups in natural and 79627-10ML 10 mL
unnatural amino acids and particularly the requirement for full 79627-50ML 50 mL
retention of chiral integrity, the coupling of amino acids and
peptides under mild conditions can be challenging. A plethora of
coupling reagents has been developed superseding each other in Acid Halogenation Reagents

Coupling Reagents
efficiency and suitability for specific applications (e.g., solid-phase The generation of an acid chloride is an obvious way to activate
peptide synthesis or fragment condensation). the carboxy group for amide bond formation. However, practical
application of acid chlorides in peptide synthesis is restricted,
Amino Acid I Amino Acid II Dipeptide
O because they are prone to side reactions and racemization. In spite
H2 N
O
PGO peptide bond of this disadvantage, acid chlorides are frequently recommended
2
PG 2 2
PG R1 1
2
PG
R2 O
to link extremely hindered or achiral amino acids. 1-Chloro-N,N,2-
R R2 PG H
PGN OH PGN N PGO trimethyl-1-propenylamine, developed by Ghosez, enables the
N PGN X N O
H
O
N
H -HX H
O R1 conversion of carboxylic acids into the corresponding chlorides
O PG1
Activation Coupling under strictly neutral conditions.1 This method was successfully
applied by Fürstner in the total synthesis of Caloporoside and
Scheme: Simplified general mechanism of peptide bond formation.
Roseophilin.2
All coupling methods have the same reaction principle in common:
The most notable advance in acid halogenation has been the
after activation of the carboxy group of the first amino acid, the
introduction of fluoroamidinium salts by Carpino.3 Compared to
second amino acid can form the peptide bond by a nucleophilic
the chlorides, the acid fluorides show greater stability towards
attack of its amino group. In order to prevent uncontrolled
water and a relative lack of conversion to the corresponding
peptide bond formation the amino group of the first amino acid
oxazolones upon treatment with organic bases. TFFH (Fluoro-
and all functional side chain groups need to be reversibly blocked.
N,N,N’,N’-tetramethylformamidinium hexafluorophosphate)
Repeated de-blocking, activation, and coupling build the peptide
and BTFFH (Fluoro-N,N,N’,N’-bis(tetramethylene)formamidinium
to its desired final sequence.
hexafluorophosphate) are stable, non-hygroscopic salts. They act
A broad variety of coupling reagents available through in situ as fluorinating reagents and are suitable both for solution
Sigma-Aldrich will be presented and discussed. For further syntheses and for SPPS (Solid-Phase Peptide Synthesis).
reading, detailed reviews are available.1,2
References: (1) Haveaux, B.; Dekoker, A.; Rens, M.; Sidani, A. R.; Toye, J.; Ghosez, K.
References: (1) Goodman, M. Methods of Org. Chem. (Houben-Weyl) add. and suppl. Org. Synth. 1980, 59, 26. (2) Fürstner, A.; Konetzki, I. J. Org. Chem. 1998, 63, 3072.
vol. to the 4th ed., Vol. E 22 a, 2002, pp. 425–888. (2) Han, S.-Y.; Kim, Y.-A. Tetrahedron (3) Carpino, L. A.; El-Faham, A. J. J. Am. Chem. Soc. 1995, 117, 5401.
2002, 60, 2447.

1-Chloro-N,N,2-trimethyl-1-propenylamine, 96%
Azide Formation (CH3)2C=C(Cl)N(CH3)2
Azide coupling procedures were introduced by Curtius as one FW: 133.62 N

of the first successful strategies for the synthesis of peptides. [26189-59-3] Cl

For a long time they were thought to be the only racemisation 498270-5ML 5 mL
free method. A very convenient way to form N-acylamino acid
azides is to apply DPPA (diphenyl phosphoryl azide). This method Chloro-N,N,N’,N’-bis(tetramethylene)formamidinium
is particularly useful in cyclization reactions of peptides.1,2 DPPA tetrafluoroborate, purum, >97.0% (AT)
can also be used in the preparation of urethanes by reaction with C9H16BClF4N2 Cl
alcohols. FW: 274.49 BF4-
N N+
[115007-14-2]
References: (1) Hoffmann, E.; Beck-Sickinger, A. G.; Jung, G. Liebigs Ann. Chem 1991,
585. (2) Yamada, T.; Omote, Y.; Nakamura, Y.; Miyazawa, T.; Kuwata, S. Chem. Lett. 23957-1G-F 1g
1993, 1583.
23957-5G-F 5g
23957-25G-F 25 g
Diphenyl phosphoryl azide, purum, >98.0%
DPPA O
O
PyClU, purum, >98.0% (CHN)
(C6H5O)2P(O)N3 P N3
O C9H16N2Cl · PF6 Cl
FW: 275.2 FW: 332.65 N N+ PF6-
[26386-88-9] [135540-11-3]
72935-10ML-F 10 mL
23955-1G-F 1g
72935-50ML-F 50 mL
23955-5G-F 5g
Diphenyl phosphoryl azide, 97% 23955-25G-F 25 g
DPPA O
O
(C6H5O)2P(O)N3 P N3 Chloro-N,N,N’,N’-tetramethylformamidinium
FW: 275.2
O hexafluorophosphate, purum, >98.0% (T)
[26386-88-9] C5H12ClF6N2P Cl
FW: 280.58 PF6-
178756-5G 5g N N+
[207915-99-9]
178756-25G 25 g
178756-100G 100 g 09658-5G 5g
09658-25G 25 g

To discuss how our expertise can benefit your next scale-up project or to obtain a quote,
contact your local Sigma-Aldrich office or visit www.safcglobal.com
 4

Fluoro-N,N,N’,N’-tetramethylformamidinium Fluoro-N,N,N’,N’-bis(tetramethylene)formamidinium
hexafluorophosphate, puriss., >99.0% hexafluorophosphate, >99.0%
TFFH BTFFH
F F
[FC[=N(CH3)2]N(CH3)2]PF6 C9H16F7N2P
+ PF6- N N+ PF6-
FW: 264.12 N N FW: 316.2
[164298-23-1] [164298-25-3]
47440-1G-F 1g 17380-5G 5g
47440-5G-F 5g 17380-25G 25 g

Fluoro-N,N,N’,N’-tetramethylformamidinium
Coupling Reagents

hexafluorophosphate, 97%
TFFH
F
[FC[=N(CH3)2]N(CH3)2]PF6
N+ PF6-
FW: 264.12 N

[164298-23-1]
520330-1G 1g
520330-5G 5g

Phosgene Cartridge for Phosgene Generation, 0.02 mole 8

Phosgene is an extremely versatile reagent allowing easy access COCl2
to isocyanates, ureas, carbamates, carbonates, acyl and alkyl FW: 98.92
[75-44-5]
chlorides.1 Many of these can be used as reactive intermediates
in peptide coupling reactions. As a dehydrating agent, phosgene 519758-1PAK 1 Pak
can also lead to isocyanides, cyanides, and carbodiimides. Though 519758-5PAK 5 Pak
highly toxic itself byproducts resulting from reactions with
phosgene are harmless. When treated with alkaline solution, only Cartridge for Phosgene Generation, 0.05 mole 8
biocompatible salts are formed like sodium chloride or carbonate. COCl2
In cooperation with Buss ChemTech, Sigma-Aldrich offers a safe FW: 98.92
[75-44-5]
and reliable phosgene generation kit giving simple access to
small quantities of high purity, gaseous phosgene exactly when 519766-1PAK 1 Pak
needed, while no transport and storage of liquid phosgene is 519766-5PAK 5 Pak
necessary. The generator converts safe triphosgene into phosgene
on demand using a patented catalyst (licensed from “BUSS Triphosgene, reagent grade, 98%
ChemTech AG” U.S. Patent 6,399,822 B1 and foreign equivalents Cl3COCOOCCl3
O
apply).2 Phosgene generation can be stopped at any time. A total FW: 296.75 Cl3C C CCl3
containment approach eliminates the risk that phosgene can reach [32315-10-9] O O

the environment.
330752-5G 5g
References: (1) Babad, H.; Zeiler, A. G. Chem. Rev. 1973, 73, 75. (2) Eckert, H.; Forster, 330752-25G 25 g
B. Angew. Chem. Int. Ed. 1987, 26, 894. 330752-100G 100 g

Cartridge for Phosgene Generation, Starter Kit 8 Phosgene solution, purum, ~20% in toluene
Contains one 0.02 mole cartridge (519758), hose connector with COCl2
O
sealing lips, Viton tubing, dosimeter badge, and instructions for use. FW: 98.92 C
[75-44-5] Cl Cl
519782-1KT 1 Kit
79380-100ML 100 mL
79380-500ML 500 mL

Thiophosgene, 97%
CSCl2
S
FW: 114.98 C
[463-71-8] Cl Cl

115150-5G 5g
115150-25G 25 g
115150-100G 100 g

Thiophosgene, technical, ~90%

CSCl2
Application example for the Phosgene Generation Starter Kit 519782-1KT. S
FW: 114.98
s i g m a - a l d r i c h . c o m

C
[463-71-8] Cl Cl

89030-25ML 25 mL
89030-100ML 100 mL

To order: Contact your local Sigma-Aldrich office (see back cover),

or visit www.sigma-aldrich.com/order.
 5

Carbodiimides WSC, N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide,

Carbodiimide-mediated peptide coupling remains to the most purum, >97.0%
EDC, WSC
frequently used technique. As a major advantage, carbodiimides CH3
C8H17N3
do not require prior activation of the carboxylic acid. N N
FW: 155.24 H3C N
C CH3
Dicyclohexylcarbodiimide (DCC) has been predominantly used [1892-57-5]
and is now well established. Since the generated urea derivatives
39391-10ML 10 mL
as byproducts often have similar solubilities as the desired
39391-50ML 50 mL
peptides, water-soluble carbodiimides have been developed whose
corresponding ureas are readily separated by extraction with
N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide, polymer-

Coupling Reagents
water. The most popular carbodiimide of this kind is EDC (N-(3-
Dimethylaminopropyl)-N’-ethylcarbodiimide). Furthermore EDC bound, 200–400 mesh, extent of labeling: 0.5–1.5 mmol/g
or EDAC allow peptide coupling in alcohol or aqueous solutions loading, 2% cross-linked with divinylbenzene
EDC, WSC
involving proteins or peptide cyclizations.1 CH3
N N
C CH3
In solid-phase peptide synthesis, diisopropylcarbodiimide (DIC) H3C N

is especially helpful due to the enhanced solubility of its urea

424331-5G 5g
derivatives.
Reference: (1) Nozaki, S. J. Peptide Res. 1999, 54, 162. 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide
EDC methiodide
H3C
N,N’-Dicyclohexylcarbodiimide, puriss., >99.0% C2H5N=C=N(CH2)3N(CH3)3I N N+
CH3
I-
FW: 297.18 C
DCC H3C N CH3

C6H11N=C=NC6H11 N
[22572-40-3]
C
FW: 206.33 N 165344-1G 1g
[538-75-0] 165344-10G 10 g
36650-100G 100 g
36650-500G 500 g N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide
36650-2.5KG 2.5 kg hydrochloride, BioChemika, >99.0%
EDC hydrochloride, EDAC
CH3
N,N’-Dicyclohexylcarbodiimide, 99.0% C8H17N3 · HCl N N HCl

DCC FW: 191.7 H3C N

C CH3

C6H11N=C=NC6H11 [25952-53-8]
N
C
FW: 206.33 N 03449-1G 1g
[538-75-0] 03449-5G 5g
D80002-25G 25 g 03449-25G 25 g
D80002-100G 100 g
D80002-1KG 1 kg N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide
hydrochloride, SigmaUltra
N,N’-Dicyclohexylcarbodiimide solution, purum, ~1 M in EDC hydrochloride, EDAC
CH3
methylene chloride C8H17N3 · HCl N N HCl

DCC FW: 191.7 H 3C N

C CH3

C6H11N=C=NC6H11 [25952-53-8]
N
C
FW: 206.33 N E1769-1G 1g
[538-75-0] E1769-5G 5g
36652-100ML 100 mL E1769-10G 10 g
E1769-25G 25 g
N,N’-Dicyclohexylcarbodiimide solution, 1.0 M in methylene
chloride N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide
DCC hydrochloride, purum, >98.0%
C6H11N=C=NC6H11 N EDC hydrochloride, EDAC
C CH3
FW: 206.33 N C8H17N3 · HCl HCl
N N
[538-75-0] FW: 191.7 H3C N
C CH3

379115-100ML 100 mL [25952-53-8]

379115-800ML 800 mL 03450-1G 1g
03450-5G 5g
N,N’-Dicyclohexylcarbodiimide solution, purum, ~1 M in NMP 03450-25G 25 g
DCC
C6H11N=C=NC6H11 N
C
FW: 206.33 N

[538-75-0]
36651-100ML-F 100 mL
36651-250ML-F 250 mL

To discuss how our expertise can benefit your next scale-up project or to obtain a quote,
contact your local Sigma-Aldrich office or visit www.safcglobal.com
 6

N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide N-Cyclohexyl-N’-(2-morpholinoethyl)carbodiimide metho-p-

hydrochloride, commercial grade, powder toluenesulfonate, puriss., >97.0%
EDC hydrochloride, EDAC CMC
CH3 CH3
C8H17N3 · HCl N N HCl C14H26N3O · C7H7O3S C
N
N+ -O3S CH3
N
FW: 191.7 H3C N
C CH3 FW: 423.57
[25952-53-8] [2491-17-0] O

E7750-5G 5g 29470-5G 5g
E7750-10G 10 g 29470-25G 25 g
E7750-25G 25 g
E7750-100G 100 g N-Cyclohexyl-N’-(2-morpholinoethyl)carbodiimide metho-p-
Coupling Reagents

E7750-1KG 1 kg toluenesulfonate, 95%

E7750-5KG 5 kg CMC
CH3
C14H26N3O · C7H7O3S C
N
N+ -O3S CH3
N
FW: 423.57
N,N’-Diisopropylcarbodiimide, purum, >98.0% O
[2491-17-0]
DIC
(CH3)2CHN=C=NCH(CH3)2 N
C106402-5G 5g
C
FW: 126.2 N C106402-25G 25 g
[693-13-0]
38370-25ML 25 mL N,N’-Di-tert-butylcarbodiimide, 99%
38370-100ML 100 mL (CH3)3CN=C=NC(CH3)3
N
FW: 154.25 C
38370-500ML 500 mL N
[691-24-7]
N,N’-Diisopropylcarbodiimide, 99% 235563-1G 1g
DIC 235563-5G 5g
(CH3)2CHN=C=NCH(CH3)2 N
C
FW: 126.2 N
N,N’-Di-tert-butylcarbodiimide, purum, >99.0% (GC)
[693-13-0] (CH3)3CN=C=NC(CH3)3
D125407-5G 5g N
FW: 154.25 C
N
D125407-25G 25 g [691-24-7]
D125407-100G 100 g 34640-5ML 5 mL
D125407-1KG 1 kg 34640-25ML 25 mL

1-tert-Butyl-3-ethylcarbodiimide, 99% 1,3-Di-p-tolylcarbodiimide, 96%

BEC CH3C6H4N=C=NC6H4CH3 H3C
(CH3)3CN=C=NC2H5 N FW: 222.29 N
C C
FW: 126.2 N
[726-42-1]
N
CH3
[1433-27-8]
426393-1G 1g D219800-1G 1g
426393-5G 5g D219800-5G 5g

N-Cyclohexyl-N’-(2-morpholinoethyl)carbodiimide metho-p-
toluenesulfonate, puriss., >99.0%
CMC
CH3
C14H26N3O · C7H7O3S C
N
N+ -O3S CH3
N
FW: 423.57
[2491-17-0] O

29469-5G 5g
29469-25G 25 g

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or visit www.sigma-aldrich.com/order.
 7

Imidazolium Derived Reagents Oxalic acid diimidazolide, technical grade

N-Acylimidazoles were recognized in the early 1950s as reactive C8H6N4O2 O O
FW: 190.16
intermediates suitable for the acylation of amino compounds. N N
[18637-83-7]
The search for better coupling reagents than DCC led to the N N
development of CDI (1,1’-carbonyldiimidazole) and related 366439-1G 1g
carbonylimidazoles.1 For practical considerations it should be 366439-5G 5g
noted that moisture must be carefully excluded during work with
CDI. Also, CDI excess should be avoided. Apart from peptide 2-Chloro-1,3-dimethylimidazolidinium chloride, purum,
synthesis, carbonyldiimazoles find use as an efficient replacement >97.0%

Coupling Reagents
for highly toxic phosgene in the preparation of carbamates and DMC
Cl
ureas from alcohols and amines.2,3 C5H10Cl2N2
FW: 169.05 N N+ Cl-
Kiso developed modified imidazolium reagents like CIP (2-Chloro-
[37091-73-9]
1,3-dimethylimidazolidinium hexafluorophosphate) as new peptide
coupling reagents and later as new esterification reagents to avoid 24374-10G-F 10 g
the toxic HMPA by-product of the BOP reagent (benzotriazol-1- 24374-50G-F 50 g
yloxytris(dimethylamino)phosphonium hexafluorophosphate).4 CIP
was successfully applied to the coupling of a,a-dialkylated amino 2-Chloro-1,3-dimethylimidazolidinium chloride
acids and proved to be especially efficient in combination with DMC
Cl
HOAt (1-hydroxy-7-azabenzotriazole).5 C5H10Cl2N2
FW: 169.05 N N+ Cl-

References: (1) Staab, H. A. Angew. Chem. Int. Ed. Engl. 1962, 1, 351. (2) Staab, H. [37091-73-9]
A. Justus Liebigs Ann. Chem. 1957, 609, 83. (3) Staab, H. A. Justus Liebigs Ann. Chem.
1957, 609, 75. (4) Akaji, K.; Kuriyama, N.; Kimura, T.; Fujiwara, Y.; Kiso, Y. Tetrahedron
529249-25G 25 g
Lett. 1992, 33, 3177. (5) Albericio, A.; Bailén, F. M.; Chinchilla, R.; Dodsworth, D. J.;
Nájera, C. Tetrahedron 2001, 57, 9607. 2-Chloro-1,3-dimethylimidazolidinium tetrafluoroborate,
purum, >96.0%
1,1’-Carbonyldiimidazole, reagent grade CIB
Cl
CDI C5H10BClF4N2
FW: 220.40 N N+ BF4-
C7H6N4O N N N N
FW: 162.15 [153433-26-2]
O
[530-62-1] 24377-1G-F 1g
115533-5G 5g 24377-5G-F 5g
115533-10G 10 g
115533-25G 25 g 2-Chloro-1,3-dimethylimidazolidinium hexafluorophosphate,
115533-100G 100 g purum, >98.0%
CIP
Cl
C5H10ClF6N2P
1,1’-Carbonyldiimidazole, purum, >97.0% FW: 278.56 N N+ PF6-
CDI [101385-69-7]
C7H6N4O N N N N
FW: 162.15 24375-1G-F 1g
O 24375-5G-F 5g
[530-62-1]
21860-5G 5g 24375-25G-F 25 g
21860-25G 25 g
2-Chloro-1,3-dimethylimidazolidinium hexafluorophosphate,
21860-100G 100 g
98%
CIP
1,1’-Carbonyl-di-(1,2,4-triazole), technical, >90% C5H10ClF6N2P
Cl
CDT FW: 278.56 N N+ PF6-
N N
C5H4N6O N N N N
[101385-69-7]
FW: 164.12
[41864-22-6]
O 420336-1G 1g
420336-5G 5g
21861-5G 5g
2-Fluoro-1,3-dimethylimidazolidinium hexafluorophosphate,
1,1’-Carbonyl-di-(1,2,4-triazole), ~90%
puriss., >98.5%
CDT
N N DFIH
C5H4N6O N N N N F
C5H10F7N2P
FW: 164.12 N+ PF6-
O FW: 262.11 N
[41864-22-6]
[164298-27-5]
C2956-5G 5g
17381-5G 5g
17381-25G 25 g
Oxalic acid diimidazolide, technical, >90% (NT)
C8H6N4O2 O O
FW: 190.16 N N
[18637-83-7]
N N

75749-5G 5g
75749-25G 25 g

To discuss how our expertise can benefit your next scale-up project or to obtain a quote,
contact your local Sigma-Aldrich office or visit www.safcglobal.com
 8

Phosphonium Salts (Benzotriazol-1-yloxy)tripyrrolidinophosphonium

Phosphonium salts are powerful and easy-to-use peptide coupling hexafluorophosphate, purum, >97.0%
PyBOP® N
reagents that allow in situ generation of active esters. After the N
C18H28N6OP · PF6 PF6-
recognition of chlorotris(dimethylamino)phosphonium as the N
N
FW: 520.39 O
activating species in the tris(dimethylamino)phosphine/CCl4 system [128625-52-5]
P+ N
N
and the importance of HOBt as an additive in peptide coupling,
Castro proposed BOP (benzotriazol-1-yloxy-tris(dimethylamino)
phosphonium hexafluorophosphate) as a suitable coupling 12805-1G-F 1g
reagent. Thereafter, various groups proved the efficiency of 12805-5G-F 5g
Coupling Reagents

BOP and it has become widely used.1,2 Since the utilization of 12805-25G-F 25 g
BOP involves the handling of the toxic and carcinogenic HMPA,
the viable alternative PyBOP has been developed where the (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium
dimethylamino groups are replaced by pyrrolidine substituents. hexafluorophosphate, 96%
PyBOP shows comparable performance to BOP, in some cases even PyAOP N
N
better.3 Numerous other variations of BOP have been reported C17H27F6N7OP2 N N PF6-
N
among which the HOAt analogue to PyBOP, PyAOP, excels FW: 521.38 O P+ N
especially in the coupling of sterically hindered amino acids.4 [156311-83-0] N

The halophosphonium compounds BroP or PyCloP are efficient

reagents when coupling N-methylamino acids or a,a-disubstituted 535303-1G 1g
amino acids.5 Recently, Goodman reported the new DEPBT 535303-5G 5g
(3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) with
superior performance as coupling reagent. It proved to be Bromotris(dimethylamino)phosphonium
especially suitable for PNA synthesis, where it yielded significantly hexafluorophosphate, purum, >98.0%
better results than even HATU.6,7 BroP H3C CH3
N
BrP[N(CH3)2]3PF6 H3C
References: (1) Hudson, D. J. Org. Chem. 1988, 53, 617. (2) Rivaille, P.; Gautron, J. P.; N P+ Br PF6-
Castro, B.; Milhaud, G. Tetrahedron 1980, 36, 3413. (3) Coste, J.; Le Nguyen, D.; Castro,
FW: 388.07 H3C
N
B. Tetrahedron Lett. 1990, 31, 205. (4) Carpino, L. A.; El-Faham, A.; Minor, C. A.; Alberi- [50296-37-2] H3C CH3
cio, F. J. Chem. Soc., Chem. Commun. 1988, 201. (5) Coste, J.; Frérot, E.; Jouin, P. J. Org. 18570-1G 1g
Chem. 1994, 59, 2437. (6) Li, H.; Jiang, X.; Ye, Y.-H.; Fan, C.; Romoff, T.; Goodman, M.
Organic Lett. 1999, 1, 91. (7) Tedeschi, T.; Corradini, R.; Marchelli, R.; Pushl, A.; Nielsen, 18570-5G 5g
P. E. Tetrahedron: Asymm. 2002, 13, 1629. 18570-25G 25 g

(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium Bromotris(dimethylamino)phosphonium
hexafluorophosphate, purum, >98.0% hexafluorophosphate, 98%
BOP, Castro’s reagent N H3C CH3 BroP H3C CH3
N CH3 N
C12H22F6N6OP2 N
PF6- BrP[N(CH3)2]3PF6 H3C
N P+ N CH3 N P+ Br PF6-
FW: 442.28 O
N
FW: 388.07 H3C
N
[56602-33-6] H C CH3
3 [50296-37-2] H3C CH3

12802-5G-F 5g 420107-250MG 250 mg

12802-25G-F 25 g
12802-100G-F 100 g Chlorotripyrrolidinophosphonium hexafluorophosphate,
>98.0%
(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium PyCloP
hexafluorophosphate, 97% C12H24ClN3P · PF6 N
N P+ Cl PF6-
BOP, Castro’s reagent H3C CH3 FW: 421.73
N N
C12H22F6N6OP2
N N CH3
PF6-
[133894-48-1]
N P+ N CH3
FW: 442.28 O
N 26564-1G-F 1g
[56602-33-6] H3C CH3
26564-5G-F 5g
226084-1G 1g
26564-25G-F 25 g
226084-5G 5g
Bromotripyrrolidinophosphonium hexafluorophosphate,
(Benzotriazol-1-yloxy)tripyrrolidinophosphonium >95.0%
hexafluorophosphate, 98% PyBroP®
PyBOP® N C12H24BrF6N3P2 N
C18H28N6OP · PF6 N
FW: 466.18 N P+ Br PF6-
N PF6-
FW: 520.39 O
N
[132705-51-2]
N
P+ N
[128625-52-5] N
18565-1G 1g
18565-5G 5g
377848-1G 1g
18565-25G 25 g
377848-5G 5g
3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one, 98%
s i g m a - a l d r i c h . c o m

DEPBT O
O
C11H14N3O5P N
O
P O
CH3

FW: 299.22 N
N O
[165534-43-0] CH3

495964-5G 5g

To order: Contact your local Sigma-Aldrich office (see back cover),

or visit www.sigma-aldrich.com/order.
 9

Uronium and Guanidinium Salts
The special need of SPPS for rapid and highly efficient coupling
reagents led to the development of several new reagents starting
from BOP (Benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate). The HOBt (N-Hydroxybenzotriazole)
derived components HBTU and TBTU today belong to the
most widely used reagents for peptide coupling and feature
a broad application spectrum. HBTU and TBTU differ only by
their counterions hexafluorophosphate or tetrafluoroborate,
with greater stability in aqueous solvent mixtures allowing the
modification of proteins.8
The new thiouronium reagent TOTT (S-(1-Oxido-2-pyridyl)-
N,N,N’,N’-tetramethylthiuronium tetrafluoroborate) is ideally suited
for the rapid and high-yielding preparation of primary amides
when reacted with carboxylic acids and ammonium chloride.9
References: (1) Carpino, L. A. et al. Angew. Chem. Int. Ed. 2002, 41, 441. (2) Uhlmann,
E.; Peymann, A.; Breipohl, G.; Will, D. W. Angew. Chem. Int. Ed. 1998, 37, 2796. (3)
Kamencka, T. M.; Danishefsky, S. J. Chem. Eur. J. 2001, 7, 41. (4) Chen, S.; Xu, J. Tetrahe-
dron Lett. 1992, 33, 647. (5) Sabatino, G.; Mulinacci, B.; Alcaro, M.C.; Chelli, M.; Rovero,

Coupling Reagents
respectively. A comparison study showed that these anions have P.; Papini, A.M. Lett. Pept. Sci. 2002, 9, 119. (6) Pon, R. T.; Yu, S.; Sanghvi, Y. S. J. Org.
no significant influence on the coupling rate or racemization. Chem. 2002, 67, 856. (7) Knorr, R. et al. Tetrahedron Lett. 1989, 30, 1927. (8) Knorr, R.;
Trzeciak, A.; Bannwarth, W.; Gillessen, D. Peptides 1990, 62. (9) Bailin, M. A. et al. J.Org.
For a long time, the active HBTU and its family were believed Chem. 1999, 64, 8936.
to possess an uronium structure, but intensive studies provided
evidence for the formulation of guanidinium N-oxides.1 O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium
Nevertheless, by custom, they are still called uronium type hexafluorophosphate, purum, >98.0%
reagents. Unlike carbodiimides or phosphonium reagents, uronium HBTU
salts could form tetramethylguanidinium derivatives with free C11H16F6N5OP
N
N+ PF6-
amines. To circumvent this side reaction, excess reagent should FW: 379.24 N
N
be avoided and pre-activation of the carboxylic acid component is [94790-37-1] N+
recommended. O-
12804-1G-F 1g
Besides HBTU and TBTU, several other members of the uronium
family are worthy of attention. The 7-aza-analogue of HBTU called 12804-5G-F 5g
HATU (1-[Bis-(dimethylamino)methyliumyl]-1H-1,2,3-triazolo[4,5- 12804-25G-F 25 g
b]pyridine-3-oxide hexafluorophosphate) can be considered today’s
O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium
gold standard of peptide coupling reagents. It has been used for
tetrafluoroborate, 97%
difficult amide bond formation in solution and solid-phase (e.g., TBTU
PNAs) synthesis.2 It is especially superior for macrocyclization, C11H16N5O · BF4 N
N+ BF4-
fragment condensation, and the coupling of N-substituted FW: 321.08 N
amino acids. Danishefsky reported an impressive example for [125700-67-6]
N
N+
the application of HATU in a late step of the total synthesis of O-
Hemastatin with HATU simultaneously connecting two peptide 12806-5G-F 5g
macrocycles.3 12806-25G-F 25 g
12806-100G-F 100 g
H OTBS 12806-250G-F 250 g
TBSO HN N TrocHN
H
H N
O
O TESO CO2H O O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium
O N H
N N O
hexafluorophosphate, purum, >98.0%
H O N N N
O HO2C OTES O O
N H
O HATU
H N
NHTroc N NH OTBS C10H15F6N6OP N+ PF6-
TBSO H
FW: 380.23 N
N
[148893-10-1] N+
N
O-
1. Pb/Cd, THF, aq NH4OAc, 1.5 h
34 % for 3 steps 2. HATU, HOAt, DIEA, DMF, rt, 28 h 11373-1G 1g
3. TBAF, AcOH, THF, rt, 55 h 11373-5G 5g
11373-25G 25 g
H OTBS
N
TBSO
HN H HN O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium
H N H
O
O
O TESO O
O
O N
N hexafluorophosphate, 97%
N
N N O N O O
HATU
H O OTES N
O O OTBS C10H15F6N6OP N+ PF6-
N H
NH H NH FW: 380.23 N
N
TBSO H N
[148893-10-1] N N+
O-

445460-1G 1g
Scheme: Application of HATU in the simultaneous cyclization of two linked
peptide strands for the synthesis of Hemastatin.
445460-5G 5g
445460-25G 25 g
Substitution of HBTU’s dimethylamino groups by pyrrolidine
residues as in HBPyU leads to less racemization during peptide O-(Benzotriazol-1-yl)-N,N,N’,N’-bis(tetramethylene)uronium
coupling.4 Introducing an electron-withdrawing group into the hexafluorophosphate, purum, >98.0%
benzotriazole moiety enhances the reactivity. Accordingly HCTU HBPyU N
N
and TCTU show improved performance in difficult or hindered C15H20F6N5OP N
N+ PF6-
couplings and cyclizations when compared to HBTU.5 HCTU has FW: 431.32 O

also proven suitability for tandem oligonucleotide coupling on [105379-24-6] N

solid phase supports in a competitive study.6 TDBTU, TPTU, HOTU

and TOTU are recommended for fragment condensation and other 12809-1G-F 1g
critical cases leading to minimal racemization.7 12809-5G-F 5g
12809-25G-F 25 g
TSTU and HSTU are less efficient than their HOBt and HOAt
derived analogues. They compensate for the disadvantage

To discuss how our expertise can benefit your next scale-up project or to obtain a quote,
contact your local Sigma-Aldrich office or visit www.safcglobal.com
 10

O-Benzotriazol-1-yl-N,N,N’,N’-bis(pentamethylene)uronium O-[(Ethoxycarbonyl)cyanomethylenamino]-N,N,N’,N’-
hexafluorophosphate, 98% tetramethyluronium tetrafluoroborate, purum, >98.0%
HBPipU N TOTU CN
N
C17H24F6N5OP N
C2H5O2CC(CN)=NOC[N(CH3)2]=N(CH3)2BF4 O O N+ BF4-
N+ PF6- N
FW: 459.37 O FW: 328.07 O N
[190849-64-0] N [136849-72-4]
02580-1G 1g
420271-1G 1g 02580-5G 5g
02580-25G 25 g
8
Coupling Reagents

O-(6-Chlorobenzotriazol-1-yl)-N,N,N’,N’-
tetramethyluronium hexafluorophosphate, purum, >98.0% O-[(Ethoxycarbonyl)cyanomethylenamino]-N,N,N’,N’-
HCTU N tetramethyluronium tetrafluoroborate, 98%
C11H15ClF6N5OP N TOTU CN
Cl N
N+ PF6- C2H5O2CC(CN)=NOC[N(CH3)2]=N(CH3)2BF4
FW: 413.69 O O
N
O N+ BF4-
[330645-87-9] N FW: 328.07 O N
[136849-72-4]
04936-5G-F 5g
382469-1G 1g
04936-25G-F 25 g
382469-5G 5g
04936-100G-F 100 g
N,N,N’,N’-Tetramethyl-O-(N-succinimidyl)uronium
O-(6-Chlorobenzotriazol-1-yl)-N,N,N’,N’- 8 hexafluorophosphate, purum, >99.0%
tetramethyluronium, purum, >98.0% HSTU O
TCTU N
C9H16F6N3O3P
N N O N+ PF6-
C11H15BClF4N5O Cl N FW: 359.21
N+ BF4-
FW: 355.53 O
[265651-18-1] O N
[330641-16-2] N
09668-1G 1g
78133-5G-F 5g 09668-5G 5g
78133-25G-F 25 g 09668-25G 25 g
78133-100G-F 100 g
N,N,N’,N’-Tetramethyl-O-(N-succinimidyl)uronium
O-(3,4-Dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N’,N’- tetrafluoroborate, 97%
tetramethyluronium tetrafluoroborate, purum, >99.0% TSTU O

TDBTU C9H16BF4N3O3
O N O N+ BF4-
C12H16BF4N5O2 O N+ BF4-
FW: 301.05
N N
FW: 349.09 [105832-38-0] O
N N
N
[125700-69-8] 385530-1G 1g
37345-1G-F 1g 385530-5G 5g
37345-5G-F 5g
37345-25G-F 25 g Dipyrrolidino(N-succinimidyloxy)carbenium , purum, >98.0%
HSPyU O

O-(2-Oxo-1(2H)pyridyl)-N,N,N’,N’-tetramethyluronium C13H20F6N3O3P N O N+ PF6-

tetrafluoroborate, purum, ≥ 99.0% FW: 411.28
O N
TPTU [207683-26-9]
O
C10H16BF4N3O2 O N+ BF4-
N 85971-1G 1g
FW: 297.06 N 85971-5G 5g
[125700-71-2]
85971-25G 25 g
37347-1G 1g
37347-5G 5g
S-(1-Oxido-2-pyridyl)-N,N,N’,N’- 8
37347-25G 25 g tetramethylthiuronium tetrafluoroborate, purum, >95.0%
TOTT O-
O-[(Ethoxycarbonyl)cyanomethylenamino]-N,N,N’,N’- C10H16BF4N3OS N+ S N+ BF4-
tetramethyluronium hexafluorophosphate, purum, >97.0% FW: 313.12 N
HOTU CN [255825-38-8]
C10H17F6N4O3P O
N
O N+ PF6- 94623-5G-F 5g
FW: 386.23 O N
94623-25G-F 25 g
02576-1G 1g
02576-5G 5g
02576-25G 25 g
s i g m a - a l d r i c h . c o m

To order: Contact your local Sigma-Aldrich office (see back cover),

or visit www.sigma-aldrich.com/order.
 11

Miscellaneous Coupling Reagents Propylphosphonic anhydride solution, technical, ~50% in

Propylphosphonic anhydride (T3P®)1 is a very efficient, non- DMF
C9H21O6P3
toxic coupling reagent especially suited for connecting sterically
FW: 318.18 O
hindered amino acids. A further advantage is the easy removal of P
[68957-94-8] O O
byproducts by extraction of the crude product with water.2 O P P
O
O
Mukaiyama introduced pyridinium reagents like 2-chloromethyl-
pyridinium iodide to peptide chemistry, which found application in 81801-25ML 25 mL
the synthesis of a b-lactam carbacepham skeleton.3
81801-100ML 100 mL

Coupling Reagents
Cyanuric chloride has been used for the preparation of acyl
chlorides, amides and peptides. The cyanuric chloride derivative 2-Chloro-1-methylpyridinium iodide, purum, >97.0% (AT)
CDMT (2-chloro-4,6-dimethoxy-1,3,5-triazine) yields highly reactive C6H7ClIN I-
esters with carboxylic acids that can then be used as powerful FW: 255.48 N+ Cl
acylating agents for amines and the less nucleophilic, alcohols.4 [14338-32-0] CH3
The activation is performed in presence of a base, preferentially 25270-25G 25 g
NMM (N-methylmorpholine). In situ NMM and CDMT form the
25270-100G 100 g
intermediate DMTMM. DMTMM can be isolated and used as
coupling reagent independently.5 In contrast to CDMT, DMTMM
2-Chloro-1-methylpyridinium iodide, 97%
does not require pre-activation of the carboxylic acid. The coupling
C6H7ClIN I-
efficiency of DMTMM in SPPS was found to be comparable to FW: 255.48 N+ Cl
PyBOP while racemization could be kept below the detection [14338-32-0] CH3
limit.6
198005-10G 10 g
References: (1) T3P is a registered trademark of Clariant. (2) Klose, J. et al. Chem. Com-
198005-25G 25 g
mun. 1999, 1847. (3) Berrien, J.-F.; Billon, M.-A.; Husson, H.-P. J. Org. Chem. 1995, 60,
2922. (4) Kaminski, Z. J. Synthesis 1987, 917. (5) Kaminski, Z. J.; Paneth, P.; Rudzinski, J. 198005-100G 100 g
J. Org. Chem. 1998, 63, 4248. (6) Falchi, A.; Giacomelli, G.; Porcheddu, A.; Taddei, M.
Synlett 2000, 275.
2-Chloro-4,6-dimethoxy-1,3,5-triazine, purum, >98.0%
CDMT NMM DMTMM CDMT Cl
O C5H6ClN3O2
Cl Cl- N N
THF, FW: 175.57 H3C CH3
O N+ O N O
N N rt, 30 min [3140-73-6]
+
N N 24320-5G-F 5g
MeO N OMe N 100 %
MeO N OMe 24320-25G-F 25 g

Scheme: Reaction of CDMT with NMM to the powerful acylating agent

2-Chloro-4,6-dimethoxy-1,3,5-triazine, 97%
DMTMM.
CDMT Cl
C5H6ClN3O2
Propylphosphonic anhydride solution, 50 wt. % in ethyl N N
FW: 175.57 H3C CH3
acetate [3140-73-6] O N O
C9H21O6P3
FW: 318.18 375217-5G 5g
O
P
[68957-94-8] O O
O P P 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium
O
O chloride, purum, >98.0%
DMTMM O
431303-10ML 10 mL C10H17ClN4O3 N+ CH3 Cl-
431303-50ML 50 mL FW: 276.72
N N
[3945-69-5] H3C CH3
O N O
Propylphosphonic anhydride solution, technical, ~50% in
ethyl acetate 74104-1G-F 1g
C9H21O6P3 74104-5G-F 5g
FW: 318.18 O
P
[68957-94-8] O O
O P P
O
O

81799-10ML 10 mL
81799-50ML 50 mL
81799-250ML 250 mL

To discuss how our expertise can benefit your next scale-up project or to obtain a quote,
contact your local Sigma-Aldrich office or visit www.safcglobal.com
 12

New Unnatural Amino Acids Fmoc-D-b-Homophe-OH, purum, >97.0% (HPLC) 8

C25H23NO4 Fmoc
Unnatural amino acids are utilized as chiral building FW: 401.45 NH O
blocks, conformational constraints, molecular scaffolds, or [209252-16-4] OH
pharmacologically active compounds. They represent a nearly
18074-500MG-F 500 mg
infinite array of diverse structural elements for the development
of new therapeutic drugs. Small-molecule combinatorial libraries
Trans-2-(Boc-amino)-cyclohexanecarboxylic acid, 8
containing unnatural amino acid residues already show remarkable
impact on drug discovery processes. Novel short-chain peptide purum, >98.0% (TLC)
C12H21NO4 O OH
ligand mimetics with both enhanced biological activity and
FW: 243.3 H
N
improved proteolytic resistance are drug candidates in today’s R&D BOC
[209128-50-7]
pipelines of pharmaceutical companies. Sigma-Aldrich is pleased
to introduce 40 new additions to its unique and broad portfolio of 29293-1G-F 1g
more than 700 unnatural amino acids.
New Unnatural
Amino Acids

trans-2-(Fmoc-amino)-cyclohexanecarboxylic acid, 8
b-amino Acids purum, >98.0% (HPLC)
C22H23NO4 O OH
(cis)-3-Aminobicyclo[2.2.1]heptane-2-carboxylic acid 8 FW: 365.42 H
N
hydrochloride, purum, >98.0% (TLC) [381241-08-3] Fmoc

C8H13NO2 · HCl NH2 HCl

FW: 191.66 28319-1G-F 1g
OH
O
Z-DL-b-Homoalanine, purum, >98.0% (HPLC) 8
08356-1G-F 1g C12H15NO4 O
FW: 237.25 O NH O
4-Amino-nicotinic acid, purum, >97.0% (HPLC) 8 OH
C6H6N2O2 N
39599-1G 1g
FW: 138.12 OH
39599-5G 5g
[7418-65-7] NH2 O

11585-5G-F 5g Z-b-Homoala-OH, purum, >98.0% 8

C12H15NO4 O
cis-2-(Boc-amino)-cyclohexanecarboxylic acid, 8 FW: 237.25 O NH O
purum, >98.0% (TLC) [83509-88-0]
OH
C12H21NO4 O OH
FW: 243.3 H 61669-500MG-F 500 mg
N
BOC
[63216-49-9]

36314-1G-F 1g Phenylglycine Derivatives

cis-2-(Fmoc-amino)-cyclohexanecarboxylic acid, 8 2-(4-Boc-piperazino)-2-[2-(trifluoromethyl)phenyl] 8
purum, >98.0% (HPLC) acetic acid, purum, >95.0% (HPLC)
C22H23NO4 O OH
C18H23F3N2O4
FW: 365.42 H FW: 388.38 F3C
N
Fmoc OH
[194471-85-7] N
N O
BOC
29294-1G-F 1g
38903-500MG-F 500 mg
cis-2-Amino-2-methylcyclohexanecarboxylic acid 8
2-(4-Boc-piperazino)-2-phenylacetic acid, purum, 8
hydrochloride, purum, >98.0% (CHN)
C8H15NO2 · HCl
>97.0% (HPLC)
O OH
C17H24N2O4
FW: 193.67 NH2 HCl
FW: 320.38
[202921-88-8]
OH
N
30254-500MG-F 500 mg N O
BOC

cis-2-Amino-2-methylcyclopentanecarboxylic acid 8 16298-500MG-F 500 mg

hydrochloride, purum, >98.0% (CHN)
C7H13NO2 · HCl 3-(Trifluoromethyl)-DL-phenylglycine, purum, 8
HO O
FW: 179.64 >98.0% (HPLC)
[156292-34-1] NH2 HCl C9H8F3NO2 O
FW: 219.16
F3C OH
39927-500MG-F 500 mg [242475-26-9] NH2

cis-2-Aminocycloheptanecarboxylic acid 8 53636-500MG-F 500 mg

s i g m a - a l d r i c h . c o m

hydrochloride, purum, >98.0% (TLC)

C8H15NO2 · HCl HO O
Methyl 2-(4-Boc-piperazino)-2-(2-pyridyl)acetate, 8
FW: 193.67 purum, >95.0% (HPLC)
NH2 HCl
C17H25N3O4 BOC
N
FW: 335.4 N
N
11252-500MG-F 500 mg
O OCH3

19578-500MG-F 500 mg

To order: Contact your local Sigma-Aldrich office (see back cover),

or visit www.sigma-aldrich.com/order.
 13

Alanine Derivatives Boc-(R)-4-(3,4-difluorobenzyl)-L-proline, purum, 8

>97.0% (HPLC)
4-(Hydroxymethyl)-D-phenylalanine, purum, 8 C17H21F2NO4 OH
>97.0% (HPLC) FW: 341.35 F N O
C10H13NO3 HO NH2 F BOC
FW: 195.22 OH
40372-500MG-F 500 mg
O

43667-500MG 500 mg
Boc-(R)-4-[2-(trifluoromethyl)benzyl]-L-proline, 8
purum, >98.0% (HPLC)
Boc-3-(1,2,4-triazol-1-yl)-Ala-OH, purum 8 C18H22F3NO4 CF3
C10H16N4O4 O FW: 373.37 OH
FW: 256.26 N
N OH
HN N O
N BOC BOC

Amino Acids
New Unnatural
50996-500MG-F 500 mg 38455-500MG-F 500 mg

Boc-3-(1-pyrazolyl)-Ala-OH, purum, >97.0% (HPLC) 8 Boc-(R)-4-[4-(trifluoromethyl)benzyl]-L-proline, 8

C11H17N3O4 O purum, >98.0% (HPLC)
FW: 255.27 N
N OH C18H22F3NO4 OH
[21012-18-0] HN
BOC FW: 373.37 F3C N O
67387-500MG-F 500 mg BOC

01336-500MG-F 500 mg
Boc-4,5-dehydro-Leu-OH dicyclohexylamine salt, 8
purum, >96.0% (HPLC) Boc-(R)-a-(4-fluorobenzyl)-Pro-OH, purum, 8
C11H19NO4 · C12H23N O H >98.0% (HPLC)
N
FW: 410.59 OH C17H22FNO4 F
[87720-54-5] HN FW: 323.36
BOC
[706806-64-6]
11578-50MG 50 mg
OH
N
Fmoc-3-(1,2,4-triazol-1-yl)-Ala-OH, purum, 8 BOC O
>97.0% (HPLC)
67420-500MG-F 500 mg
C20H18N4O4 O

FW: 378.38 N
N OH
HN Boc-(R)-a-(4-tert-butylbenzyl)-Pro-OH, purum, 8
N Fmoc
>97.0% (HPLC)
53229-500MG-F 500 mg C21H31NO4
FW: 361.48
Fmoc-3-(1-pyrazolyl)-Ala-OH, purum, >97.0% (HPLC) 8
C21H19N3O4 O
FW: 377.39 N
N OH
OH
N
HN
Fmoc BOC O

51916-500MG-F 500 mg 39793-500MG-F 500 mg

L-a-Neopentylglycine, purum, >98.0% (TLC) 8 Boc-(R)-a-(4-trifluoromethylbenzyl)-Pro-OH, 8

C7H15NO2 O purum, >98.0% (HPLC)
FW: 145.2 OH C18H22F3NO4 CF3
[57224-50-7] NH2 FW: 373.37
73489-1G-F 1g
73489-5G-F 5g OH
N
BOC O

42004-500MG-F 500 mg
Proline Derivatives
N(R)-a-Allyl-proline hydrochloride, purum, 8 Boc-(R)-a-allyl-Pro-OH, purum, >98.0% (HPLC) 8
>98.0% (TLC) C13H21NO4
C8H13NO2·HCl FW: 255.31 OH

FW: 191.66 [144085-23-4] N

OH HCl BOC O
[177206-69-8] N
H O 06538-500MG-F 500 mg
06541-500MG-F 500 mg
Boc-(R)-a-benzyl-Pro-OH, purum, >99.0% (HPLC) 8
(S)-a-Allyl-proline hydrochloride, purum, >98.0% (TLC) 8 C17H23NO4
C8H13NO2 FW: 305.37
FW: 155.19 [706806-60-2] OH
OH
[129704-91-2] N
H
N
O BOC O

06594-500MG-F 500 mg 47079-500MG-F 500 mg

To discuss how our expertise can benefit your next scale-up project or to obtain a quote,
contact your local Sigma-Aldrich office or visit www.safcglobal.com
 14

Boc-(S)-a-(4-fluorobenzyl)-Pro-OH, purum, 8 Boc-(S)-a-allyl-Pro-OH, purum, >98.0% (HPLC) 8

>98.0% (HPLC) C13H21NO4
C17H22FNO4 F FW: 255.31 OH
FW: 323.36 [706806-59-9] N
BOC O
[706806-65-7]
06486-500MG-F 500 mg
OH
N
BOC O
Boc-(S)-a-benzyl-Pro-OH, purum, >97.0% (HPLC) 8
14931-500MG-F 500 mg C17H23NO4
FW: 305.37
Boc-(S)-a-(4-tert-butylbenzyl)-Pro-OH, purum, 8 [706806-61-3] OH
>98.0% (HPLC) N
C21H31NO4 BOC O

FW: 361.48 76896-500MG-F 500 mg

New Unnatural
Amino Acids

OH Miscellaneous
N
BOC O
(S)-6-Oxo-2-piperidinecarboxylic acid, purum, 8
39166-500MG-F 500 mg >97.0% (HPLC)
C6H9NO3
Boc-(S)-a-(4-trifluoromethylbenzyl)-Pro-OH, purum, 8 FW: 143.14 OH
O N
>98.0% (HPLC) [34622-39-4] H
O
C18H22F3NO4 CF3 36323-1G-F 1g
FW: 373.37 36323-5G-F 5g

OH 2-[2-(Boc-amino)ethoxy]ethoxyacetic acid 8
N
O dicyclohexylamine salt, purum, >98.0% (TLC)
BOC
C11H21NO6 · C12H23N H
05199-500MG-F 500 mg N
FW: 444.61 BOC
N
O
O
OH
H
O

14766-500MG-F 500 mg

8 Safe and Simple Application of Phosgene in Your Lab!

Phosgene Generation Kit
Phosgene is an extremely versatile reagent allowing easy access Advantages
to isocyanates, ureas, carbamates, carbonates, acyl and alkyl • Easy access to small quantities of phosgene
chlorides. As a dehydrating agent phosgene can also lead to
• Versatile chemistry where other reagents offer poor results
isocyanides, cyanides and carbodiimides.
• No transport or storage of liquid phosgene
In cooperation with BUSS ChemTech, Sigma-Aldrich now offers
a safe and reliable phosgene generation kit giving simple access • Production on demand of high purity gaseous phosgene
to small quantities of high-purity, gaseous phosgene exactly • Safe and reliable handling
when needed, while no transport and storage of liquid phosgene • Simple workup of reactions to obtain pure products
is necessary. The generator converts safe triphosgene into • Operation scale from mmol to industrial levels
phosgene on demand using a patented catalyst (U.S. patent
6,399,822 B1).
Test the suitability of the generators in your own laboratory today
with a starter kit and cartridges from Sigma-Aldrich. Solutions for the upscale to industrial production
levels are available at BUSS ChemTech.

Name Mol. Formula MW or FW CAS No. Cat. No.

Cartridge for Phosgene Generation, Starter Kit 519782-1KT
Contains one 0.02 mole cartridge (#519758), hose connector with
sealing lips, Viton tubing, dosimeter badge, and instructions for use.
Cartridge for Phosgene Generation, 0.02 mole COCl2 98.92 75-44-5 519758-1PAK
519758-5PAK
s i g m a - a l d r i c h . c o m

Cartridge for Phosgene Generation, 0.05 mole COCl2 98.92 75-44-5 519766-1PAK
519766-5PAK

Visit sigma-aldrich.com for full details.

To order: Contact your local Sigma-Aldrich office (see back cover),

or visit www.sigma-aldrich.com/order.
 15

New Tools for Peptide PEGylation O,O’-Bis[2-(succinylamino)ethyl]polyethylene glycol 8

HOOCCH2CH2CONH(CH2
Circulatory half-life is a key success factor of new drugs. In CH2O)nCH2CH2NHCOCH2
O
H
O
N O OH
this respect, modification of potential candidates ranging CH2COOH HO O
n
N
H
O O
from non-peptidic molecules to peptides and proteins with Mr 6000
polyethyleneglycol chains (PEGs) offers numerous advantages. 14569-250MG 250 mg
PEGs are non-toxic, non-immunogenic, non-antigenic, highly
14569-1G 1g
soluble in water and FDA approved.1 The PEGylated conjugates
show a decreased degradation by metabolic enzymes and a
O,O’-Bis[2-(succinylamino)ethyl]polyethylene glycol 8
reduction or elimination of protein immunogenicity. Thus Pettit et
HOOCCH2CH2CONH(CH2
al. found a 50-fold enhancement of residence in the organism of O O
CH2O)nCH2CH2NHCOCH2 H
PEGylated IL-15 (Interleukin).2 CH2COOH HO
N
O
O
N
OH
n H
O O
Sigma-Aldrich is pleased to provide you with a continuously Mr 20000
growing and diverse portfolio of PEGs: 27 new products that will 14573-250MG 250 mg
help you improve the success of your drug discovery research. 14573-1G 1g
References: (1) Veronese, F. M.; Pasut, G. Drug Disc. Tod. 2005, 21, 1451. (2) Pettit, D.
K. et al. J. of Biol. Chem. 1997, 272, 2312. O,O’-Bis[2-(succinylamino)ethyl]polyethylene glycol 8

Peptide PEGylation
New Tools for
HOOCCH2CH2CONH(CH2
O O
tert-Butyl 12-amino-4,7,10-trioxadodecanoate 8 CH2O)nCH2CH2NHCOCH2 H
N O OH
C13H27NO5 CH2COOH HO O
n
N
H
O O
FW: 277.36
O Mr 3000
H2N O
O O O
[252881-74-6] 14567-250MG 250 mg
83060-1G-F 1g
83060-5G-F 5g Hycron linker 8
C17H31BrO6
O
O,O’-Oxydiethylene-diglycolic acid 8 FW: 411.33 O O
[166668-33-3] Br O O O
C8H14O7
O O
[13887-98-4] O O 96823-1G-F 1g
HO O OH
96823-5G-F 5g
92893-50ML 50 mL
92893-250ML 250 mL O,O’-Bis(2-aminoethyl)octadecaethylene glycol, 8
>95% (oligomer purity)
{2-[2-(Fmoc-amino)ethoxy]ethoxy}acetic acid, 8 C40H84N2O19
FW: 897.1 H2N O
purum, >95.0% O
18
NH2

C21H23NO6
O
FW: 385.41 H
N O 06703-1G-F 1g
[166108-71-0] Fmoc O OH

95003-500MG-F 500 mg O,O’-Bis(2-carboxyethyl)dodecaethylene glycol, 8

>95% (oligomer purity)
2-[2-(2-Methoxyethoxy)ethoxy]acetic acid, 8 C30H58O17 O
FW: 690.77 O OH
technical, >90% HO O
12
O
CH3(OCH2CH2)2OCH2CO2H
O
FW: 178.18 O O 94704-1G-F 1g
H3C O OH
[16024-58-1]
64732-250ML 250 mL O-Methyl-undecaethylene glycol, >95% 8
64732-1L 1L (oligomer purity)
HO(CH2CH2O)11CH3
FW: 516.62 O H
Methoxypolyethylene glycol 5,000 maleimide, 8 H3C O
11
[114740-40-8]
BioChemika, >90%
[99126-64-4] O 16603-500MG-F 500 mg
N O
O
O
n
O
O-Methyl-heptaethylene glycol, >95% 8
(oligomer purity)
63187-1G 1g
HO(CH2CH2O)7CH3
63187-5G 5g FW: 340.41 O H
H3C O
7
[4437-01-8]
O,O’-Bis[2-(succinylamino)ethyl]polyethylene glycol 8
HOOCCH2CH2CONH(CH2 41749-1G-F 1g
O O
CH2O)nCH2CH2NHCOCH2 H
N O OH
CH2COOH HO O
n
N Octaethylene glycol, >95% (oligomer purity) 8
H
O O
Mr 10000 HO(CH2CH2O)8H
FW: 370.44 HO
O
H
14571-250MG 250 mg [5117-19-1] 8

14571-1G 1g
15879-1G-F 1g
15879-5G-F 5g

To discuss how our expertise can benefit your next scale-up project or to obtain a quote,
contact your local Sigma-Aldrich office or visit www.safcglobal.com
 16

O-(2-tert-Butyloxycarbonylethyl)dodecaethylene 8 O-[2-(Fmoc-amino)-ethyl]-O’-(2-carboxyethyl) 8
glycol, >95% (oligomer purity) polyethylene glycol 3000
C31H62O15 H
O O
FW: 674.81 HO
12 Fmoc
N
O
O OH
n
O O

08453-500MG-F 500 mg
669717-100MG 100 mg
669717-500MG 500 mg
Methoxypolyethylene glycol 5,000 acetic acid, 8
BioChemika, >80%
Octacosaethylene glycol 8
O HO(CH2CH2O)28H
H3C O
O
n
OH FW: 1251.49 HO
O
H
28

70718-1G-F 1g
672351-500MG 500 mg
70718-5G-F 5g
70718-25G-F 25 g
O-(2-Mercaptoethyl)-O’-methyl-hexa(ethylene glycol) 8
C15H32O7S
Methoxypolyethylene glycol 5,000 propionic acid, 8
New Tools for
Peptide PEGylation

FW: 356.48 H3C O

O SH
BioChemika, >80% 6

H3C O OH
672572-250MG 250 mg
O
n
O
O-(2-Carboxyethyl)-O’-(2-mercaptoethyl) 8
88908-1G-F 1g heptaethylene glycol
88908-5G-F 5g C19H38O10S O
88908-25G-F 25 g FW: 458.56 HO O
O
SH
7

N-Boc-2,2’-(ethylenedioxy)diethylamine, purum, 8 672688-250MG 250 mg

>95.0%
C11H24N2O4 O-(2-Aminoethyl)-O’-[2-(Boc-amino)ethyl] 8
FW: 248.32 H2N O BOC
O N polyethylene glycol 3000
H
[153086-78-3]
H2N O BOC
O N
89761-1G-F 1g n H
89761-5G-F 5g
671150-500MG 500 mg
N-Boc-4,7,10-trioxa-1,13-tridecanediamine, purum, 8
O-(2-Aminoethyl)-O’-[2-(Boc-amino)ethyl] 8
>97.0%
C15H32N2O5
polyethylene glycol 10000
O BOC
FW: 320.42 H 2N O O N
H H2N O BOC
O N
n H

93113-1G-F 1g
671363-100MG 100 mg
O-(2-Aminoethyl)-O’-[2-(Boc-amino)ethyl] 8 671363-500MG 500 mg
polyethylene glycol 5000

H2N O BOC
O N
n H

671266-100MG 100 mg
671266-500MG 500 mg

Monthly Chemistry E-Newsletter

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To order: Contact your local Sigma-Aldrich office (see back cover),

or visit www.sigma-aldrich.com/order.
 17

Fluorous Peptide Synthesis Fluorous side-chain

protecting group
PG
Fluorous-phase chemistry offers new synthesis and separation Fluorous R2
strategies for the synthesis of peptides in solution or in SPPS. acid- or base-labile PG OH
N-protecting group N Fluorous
Orthogonal to other purification procedures, Fluorous Solid- H
O coupling
Phase Extraction (F-SPE), fluorous HPLC or fluorous liquid-liquid Activation
reagents
extraction require an additional but greatly simplifying workup of
the final products. The necessary fluorous tags can be introduced Deprotection
by using pre-tagged reagents or through the use of tagging
compounds at various stages of peptide synthesis (see scheme).
PG
O R2 O
Some recent examples of fluorous peptides synthesis include the H H
N PG N
peptide synthesis on fluorous supports by Mizuno et al.,1 the PG O N
H
O
solid-phase peptide synthesis with fluorous capping by Kumar and R1 O R1
PG PG
Montanari2, or the application of fluorous N-protecting groups in
peptide synthesis by Overkleeft et al.3
References: (1) Mizuno, M. et al. Tetrahedron Lett. 2004, 45, 3425. (2) Kumar, K.; Capping
Montanari, V. J. Am. Chem. Soc. 2004, 126, 9528. (3) Overkleeft, H. S. et al. Tetrahedron Fluorous
Lett. 2003, 44, 9013. Cleavage
purification tags

Fluorous
FINISHED PEPTIDE
cap-tags

Synthesis
Fluorous Peptide
Fluorous Peptide Coupling Tools Fluorous Protecting Groups

2-Chloro-4,6-bis[3-(perfluorohexyl)propyloxy]- 8 2,7-Bis(1H,1H,2H,2H-perfluorooctyl)-9- 8
1,3,5-triazine fluorenylmethoxycarbonyl-chlorid
C21H12ClF26N3O2 Cl C31H17ClF26O2
F3C(F2C)5 (CF2)5CF3
FW: 867.75 N N FW: 950.88
F3C(F2C)5 O N O (CF2)5CF3
O
672378-1G 1g Cl O

672262-1G 1g
4-(3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluorooctylthio) 8
phenol, >97% 2-[(4,4,5,5,6,6,7,7,7-Nonafluoro-1,1-dimethylheptyloxy)-
C14H9F13OS OH
carbonyloxyimino]-2-phenylacetonitrile
FW: 472.26
C18H15F9N2O3 O
FW: 478.31 NC N
O O (CF2)3CF3
S

(CF2)5CF3

43893-1G-F 1g 01382-1G-F 1g
43893-5G-F 5g
2-[(4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluoro-1,1-
4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10- 8 dimethylnonyloxy) carbonyloxyimino]-2-phenylacetonitrile
Heptadecafluorodecylthio)phenol, >97% C20H15F13N2O3 O
NC N
C16H9F17OS OH
FW: 578.32 O O (CF2)5CF3

FW: 572.28

S 11807-1G-F 1g
11807-5G-F 5g
(CF2)7CF3

40829-1G-F 1g 2-[(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-Heptadecafluoro-1,1-
40829-5G-F 5g dimethylundecyloxy)carbonyloxyimino]-2-phenylacetonitrile
C22H15F17N2O3
FW: 678.34 O
NC N
[350716-42-6] O O (CF2)7CF3

55118-1G-F 1g
55118-5G-F 5g

To discuss how our expertise can benefit your next scale-up project or to obtain a quote,
contact your local Sigma-Aldrich office or visit www.safcglobal.com
 18

N-[4-(3,3,4,4,5,5,6,6,6-Nonafluorohexyl) 4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodecyl)-
benzyloxycarbonyloxy]succinimide benzyl alcohol, >98.0%
C18H14F9NO5 O C17H11F17O
O OH
FW: 495.29 N
FW: 554.24
O O
[356055-77-1] F3C(F2C)7
O
F3C(F2C)3
19563-1G-F 1g
00246-1G-F 1g 19563-5G-F 5g

N-[4-(3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluorooctyl) 1-(4-Methoxyphenyl)-1-[4-(1H,1H,2H,2H- 8
benzyloxycarbonyloxy] succinimide perfluorodecyl)phenyl]-1-phenylmethyl chloride
C20H14F13NO5 O C30H20ClF17O
O
FW: 595.31 N FW: 754.91
[556050-48-7] O O
[865758-37-8]
O Cl
F3C(F2C)5 F3C(F2C)7

05656-1G-F 1g
05656-5G-F 5g OCH3

672149-1G 1g
N-[4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodecyl)
benzyloxycarbonyloxy]succinimide 1,1-Di-(4-methoxyphenyl)-1-[4-(1H,1H,2H,2H- 8
C22H14F17NO5 O perfluorodecyl)phenyl]methanol, 97%
O
FW: 695.32
Fluorous Peptide
Synthesis

N C31H23F17O3 OCH3
O O
[556050-49-8] O FW: 766.49
F3C(F2C)7
[865758-47-0]
14944-1G-F 1g OH
F3C(F2C)7
14944-5G-F 5g

4-(4,4,5,5,6,6,7,7,7-Nonafluoroheptyloxy)benzyl alcohol OCH3

C14H13F9O2 672696-1G 1g
OH
FW: 384.24
F3C(F2C)3 O
Diisopropyl(3,3,4,4,5,5,6,6,6-nonafluorohexyl)silane, >95%
01452-1G-F 1g C12H19F9Si
FW: 362.35 Si H

4’-(4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononyloxy)benzyl [356056-13-8] F3C(F2C)3

alcohol 18976-1G-F 1g
C16H13F13O2
OH
FW: 484.25 Diisopropyl(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)silane,
F3C(F2C)5 O
>95%
67772-1G-F 1g C14H19F13Si
67772-5G-F 5g FW: 462.37 Si H
[356056-14-9] F3C(F2C)5

4-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11- 00454-1G-F 1g
Heptadecafluoroundecyloxy)benzyl alcohol 00454-5G-F 5g
C18H13F17O2
OH
FW: 584.27 Diisopropyl(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadeca-
F3C(F2C)7 O
fluorodecyl)silane, >95%
97071-1G-F 1g C16H19F17Si
97071-5G-F 5g FW: 562.38 Si H
[356056-15-0] F3C(F2C)7

4-(3,3,4,4,5,5,6,6,6-Nonafluorohexyl)benzyl alcohol, >95% 04537-1G-F 1g

C13H11F9O 04537-5G-F 5g
OH
FW: 354.21
F3C(F2C)3

08431-1G-F 1g

4-(3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluorooctyl)benzyl alcohol,
>97.0%
C15H11F13O
OH
FW: 454.23
[356055-76-0] F3C(F2C)5

16638-1G-F 1g
s i g m a - a l d r i c h . c o m

16638-5G-F 5g

To order: Contact your local Sigma-Aldrich office (see back cover),

or visit www.sigma-aldrich.com/order.
 19

Fluorous Proteomics Reagents Fluorous Separation Media

N-Succinimidyl 4,4,5,5,6,6,7,7,8,8,9,9,9- 8 FluoroFlash® SPE Cartridges, 2 grams, 8 cc tube,
tridecafluorononanoate, purum, >97.0% 40 μm particle size
C13H8F13NO4 O
O

FW: 489.19 N 14196-1EA-F 20 pieces

F3C(F2C)5 O
O
FluoroFlash® SPE Cartridges, 5 grams, 10 cc tube,
41687-5MG 5 mg
40 μm particle size
41687-25MG 25 mg
00866-1EA-F 10 pieces
N-Succinimidyl 4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11- 8
heptadecafluoroundecanoate, purum, >98.0% FluoroFlash® SPE Cartridges, 10 grams, 60 cc tube,
C15H8F17NO4 O
40 μm particle size
O
FW: 589.2 N
[852527-45-8] F3C(F2C)7 O
08967-1EA-F 5 pieces
O

73028-5MG 5 mg
FluoroFlash® SPE Cartridges, 20 grams, 60 cc tube,
73028-25MG 25 mg
40 μm particle size
4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononyl azide, 8 08966-1EA-F 2 pieces
purum, >97.0%

Synthesis
Fluorous Peptide
C9H6F13N3 FluoroFlash® SPE Cartridges, 20 grams, 60 cc tube,
FW: 403.14 F3C(F2C)3 N3
40 μm particle size
[852527-60-7]
77983-5MG 5 mg 06961-1EA-F 5 pieces
77983-25MG 25 mg
FluoroFlash® TLC Plates with F254 indicator,
4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11- 8 dimension 5 cm x 10 cm
Heptadecafluoroundecyl azide, purum, >97.0%
C11H6F17N3 16888-1EA-F 10 pieces
FW: 503.16 F3C(F2C)5 N3
[852527-61-8] FluoroFlash® Silica Gel, ~40 μm particle size
97087-5MG 5 mg 08965-1EA-F 100 g
97087-25MG 25 mg

Fluorous separation using solid-

N-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11- 8
phase extraction: a mixture
Heptadecafluoroundecyl)maleimide, purum, >97.0% of a nonfluorous dye (blue)
C15H8F17NO2 O
and a fluorous dye (orange)
FW: 557.2 F3C(F2C)5 N are loaded on a fluorous
[852527-40-3] sorbent (see left-hand test
O
tube). The nonfluorous dye
40889-5MG 5 mg can be washed with aequeous
40889-25MG 25 mg methanol (middle test tube).
The fluorous dye remains on
N-(4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononyl) 8 the sorbent until the elution
iodoacetamide, purum, >98.0% with a fluorophilic wash (e.g.
C11H9F13INO with pure methanol, right hand
H test tube).
FW: 545.08 F3C(F2C)5 N
I
[852527-50-5] O

51526-5MG 5 mg
51526-25MG 25 mg

N-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11- 8
Heptadecafluoroundecyl)iodoacetamide, purum, >98.0%
C13H9F17INO H
FW: 645.09 F3C(F2C)6 N
I
[852527-48-1] O The fluorous products are manufactured by Fluorous Technologies, Inc.. U.S. patents
6,156,896; 5,859,247; 5,777,121 and 6,673,539 may protect use of these compounds.
55266-5MG 5 mg FluoroFlash® is a registered trademark of Fluorous Technologies, Inc.
55266-25MG 25 mg

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