Aldrich

VOLUME 11 NUMBER 3 2011

Synthetic Reagents

Catalysis

Organometallics

Building Blocks

Specialty Synthesis

Stable Isotopes

Stockroom Reagents

Labware Notes

Potassium carbobenzyloxycyanamide: an efficient reagent for amine guanylation

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Introduction 3

Aldrich

Haydn Boehm, Ph. D.Global Marketing Manager: Chemical Synthesis

haydn.boehm@sial.com

Dear Fellow Chemists,

Welcome to the third installment of Aldrich ChemFiles for 2011, our complimentary quarterly innovation newsletter written by experts from Aldrich Chemistry Product Management and R&D.

Our aim is to keep you informed of the new Aldrich Chemistry products that facilitate the latest research methodologies and trends, and allow you to access key starting materials and reagents more efficiently.

As well as introducing all the latest innovations across all of our product lines, in 2011 each edition of Aldrich ChemFiles is themed to a product line. Aldrich ChemFiles Vol. 11, No. 3 will focus on our Synthetic Reagents product line. In this issue’s lead article, Troy Ryba, Product Manager, highlights our new ChiroSolv® EnantioPrep™ Kits which define scalable, optimized chiral resolution methods, to deliver pure enantiomers within a matter of days. Our “Synthetic Reagents” cover molecule is potassium carbobenzyloxycyanamide, which is an efficient reagent for amine guanylation.

Aldrich ChemFiles Vol. 11, No. 3 will also introduce the latest innovations across all of our product lines including new chiral catalysts and applications (Catalysis), chiral crotylsilanes and EZ-CrotylMixes (Organometallics), halogenated pyridines and aldehydes (Building Blocks), and new ionic liquids (Speciality Synthesis). I would also like to draw attention to Aldrich’s new normality and molarity calculators (acid and base molarity/normality, mass molarity, and solution dilution) which have been updated on our website at Aldrich.com/calculator and are now available as iPhone® and iPad® applications.

We hope that Aldrich ChemFiles will enable you to expand your research toolbox and advance your chemistry more effectively by implementing the latest innovative synthetic strategies.

Kind regards,

Dr. Haydn Boehm Global Marketing Manager: Chemical Synthesis

Sigma-Aldrich Corporation6000 N. Teutonia Ave.Milwaukee, WI 53209 USA

Editorial TeamHaydn Boehm, Ph.D.Wesley SmithDean LlanasSharbil J. Firsan, Ph.D.Weimin Qian

Production TeamCynthia SkaggsVincent ClarkChris LeinTom BeckermannChristian HagmannDenise de Voogd

Chemistry TeamLeslie Patterson, Ph.D.Aaron Thornton, Ph.D.Daniel Weibel, Ph.D.Josephine Nakhla, Ph.D.Ronaldo Mariz, Ph.D.Pietro Butti, Ph.D.Mark Redlich, Ph.D.Troy Ryba, Ph.D.Todd Halkoski Paula FreemantleMike Willis

Aldrich ChemFiles SubscriptionsTo request your FREE subscription to Aldrich ChemFiles visit Aldrich.com/chemfiles or contact your local Sigma-Aldrich office (see back cover).

Aldrich ChemFiles OnlineAldrich ChemFiles is also available in PDF format at Aldrich.com/chemfiles.

Aldrich Chemistry ProductsAldrich brand products are sold through Sigma-Aldrich, Inc.Sigma-Aldrich, Inc. warrants that its products conform to the information contained in this and other Sigma-Aldrich publications. Purchaser must determine the suitability of the product for its particular use. See reverse side of invoice or packing slip for addi-tional terms and conditions of sale. All prices are subject to change without notice.

To Place Orders or Contact Customer/ Technical ServicesContact your local Sigma-Aldrich office (see back cover).

Aldrich ChemFiles (ISSN 1933–9658) is a publication of Aldrich Chemical Co., Inc. Aldrich is a member of the Sigma-Aldrich Group. © 2011 Sigma-Aldrich Co. LLC.

Volume 11, Number 3

Table of ContentsSynthetic Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Organometallics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Building Blocks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Specialty Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Stable Isotopes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Stockroom Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Labware Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com

4

Synthetic ReagentsTroy Ryba, Ph.D.Product Managertroy.ryba@sial.com

Potassium Carbobenzyloxycyanamide: An Efficient Reagent for Amine Guanylation*

N CNK

O

O

carbobenzyloxycyanamide potassium salt

N CNK

Cbzor

L499994

Figure 1. Structure of Potassium carbobenzyloxycyanamide.

The reaction of amines with an activated carbodiimide represents a powerful method for the preparation of guanidines. A simple and efficient one-pot method for the synthesis of mono-protected guanidines is presented in Scheme 1. Treatment of this cyanamide with trimethylsilyl chloride generates a reactive N-silylcarbodiimide capable of guanylating a variety of amines. Typically the reaction is complete in 15 minutes for primary and secondary aliphatic amines at room temperature. Anilines are also reactive but require a little more time. This method is operationally simple, high yielding at room temperature, and adequate purification is usually achieved through aqueous acid / base work up which can remove excess amine or cyanamide, respectively.

NCN

K

TMSCl1.1 equiv.

1.1 equiv. MeCN, rt.

NCbz

N NH2

R1

R2CbzN

CbzN

SiMe3

NH

R2R1

NCbz

N NH2

R1

R2

NH

N NH2

R1

R2H2 (1 atm)

Pd/C MeOH

Eq. 1

Eq. 2

Scheme 1: Applications of potassium benzyloxycarbonylcyanamide

amine product yield (%)

NH2Me NH

Me NH2

NCbz

85%

time

NH

NH2

NCbz

N NH2

NCbzMe

Me

Me Me

N NH2

NCbz

N NH2

NCbz

O

NH

NH2

NCbz

NH

NH2

NCbzMeO

NH

NH2

NCbz

F

N NH2

NCbz15 min

15 min

15 min

15 min

15 min

88%

91%

NH2

NH

NH

NH

NCbz

NH2

NH

NH2

ONH

8 h 83%

16 h 73%

16 h

63%

NH

NH

Me

Me

Me

Me

NH2

MeO

NH2

NH2F

N NH2

NCbz

16 h

68%NH

MeMe

92%

90%

73%1 h

NH

NH2

NCbz

NH2

O2NO2N

91%

-- N.R

15 min

Figure 2. Examples of amine guanidinylation with potassium carbobenzyloxy-cyanamide.

References: Looper, R. E.; Haussener, T. J.; Mack, J. B.C; 2011, submitted.* Article provided courtesy of Prof. Ryan E. Looper, University of Utah.

NH3C

CH3

BH3

R H

O

R R

O

PEMB, AcOH

NH2,R rt

PEMB, AcOH

NH2,R 50 o C

R H

N

R R

N

R

H R

H

ExamplesAldehyde and Amine Conditions Product

% Yield in MeOH(% Yield Neat)

PhNH2

CHOPEMB, AcOH

MeOH, 25 oC

NH

Ph 72(80)

CHO

Pr2NH

PEMB, AcOH

MeOH, 25 oC PrN

Pr 0(96)

C4H9 CHO

PhNH2

PEMB

MeOH, 25 oC C4H9

HN

Ph92

(94)

O

PhNH2

PEMB, AcOH

MeOH, 25 oC

HN

Ph 92(93)

H3C C3H7

O

PhNH2

PEMB, AcOH

MeOH, 50 oC H3C C3H7

HNPh

74(94)

For more examples and experimental detailBurkhardt, E. R.; Coleridge, B. M. Tetrahedron Lett. 2008, 49, 5152.

5-Ethyl-2-methylpyridine borane (PEMB)725080

Select Substrate Scope

PEMB is a liquid Pyridine Borane Complex useful for reductive amination chemistry.

Advantageous Properties of PEMB:• Excellent for reductive aminations

• Mild reducing agent for imines and oximes

• Reaction with protic solvents is very slow

• Soluble in aromatic hydrocarbons, alcohols andether solvents

• Can be used solvent-free for reductive aminations

• Chemically effi cient: two-of-three hydrides are utilized

Add Aldrich to your research program. Aldrich.com/pemb

Contact Aldrich Chemistry for research quantities under 500 grams.

For quantities over 500 grams, contact BASF.

When you need a stable liquid Reductive Amination Reagent.

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TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com

6

ChiroSolv® EnantioPrep™ Kits Deliver Pure Enantiomers*

In 2007, Sigma-Aldrich began offering ChiroSolv Screening kits as useful tools to identify the optimal chiral resolution conditions for racemates. Very recently, Chirosolve, Inc. introduced ChiroSolv EnantioPrep Kits that provide scalable, optimized chiral resolution methods and that deliver pure enantiomers within a matter of days.

EnantioPrep is designed to obviate the obstacles analytical chemists face during the elaborate process of diastereomeric crystallization. It offers a well-established method to identify a comprehensive set of chiral separation options, deliver pure enantiomers, and define a scalable chiral separation. What sets EnantioPrep apart from other method development tools is the inclusion of ChiroSolv Screening Kits that allow for 384 unique reagent combinations to identify optimal separation conditions. It is an extremely time and resource efficient approach to chiral resolution that allows analytical chemists to skip over the hard part of finding an optimal or scalable method to achieving an enantiopure product.

Key Features:

•Four Screening Kits offer exhaustive screening to identify best separation conditions

•Purify Kits allow quick recovery of racemate

•Self-contained design of the product allows streamlined and consistent process for method development and to get pure enantiomer

•Very little amount of racemate is needed (0.5–4 g)

•Results within 2 weeks; up to 90% of theoretical enantiomer yield

Key Benefits:

•Fast delivery of isolated enantiomer at a target purity and yield needing minimal amount of racemate

•Cost-efficient method development through iterative crystallization accelerates the lead optimization and preclinical studies

•Consistent results provide solid basis for developing complete separation strategy

•Value-creating foundation builds differentiated patent estate

•Works with any racemate (acid, base, alcohol, aldehyde, ketone, amino acid, racemate with multiple chiral centers)

How do ChiroSolv Solutions Work?ChiroSolv EnantioPrep Kits use the method of diastereomeric crystal-lization, a process that chemically separates enantiomers in a racemic mixture by complexation with an enantiopure acid or base, resulting in a mixture of diastereomeric salts. These salts have different chemical and physical properties, which allow their separation. This well established technology competes favorably with newer techniques such as asymmet-ric synthesis, biocatalysis, enzyme resolution, kinetic resolution, or chiral chromatography.

One major advantage of diastereomeric crystallization is that the proce-dure scales up easily for manufacturing purposes. Today around 65% of chiral products are made using this technique.

Examples:

•Paroxetine is a selective serotonin reuptake inhibitor developed by Novo Nordisk’s subsidiary, Ferrosan, and licensed to GlaxoSmithKline. It is sold as the hydrochloride salt under the name Paxil® for the treatment of depression, anxiety, and obsessive–compulsive disorder. It is prepared by resolution using (–)-di-p-toluoyl-l-tartaric acid.

•Setraline is an antidepressant that inhibits the uptake of serotonin in the central nervous system and is sold by Pfizer under the name Zoloft®. Diastereomeric crystallization of the racemate by (R)-mandelic acid is used in its preparation.

•2-Amino-5-methoxytetralin is an intermediate in the synthesis of N-0923 (Nagase & Co., Ltd., Japan), a potent dopamine D2 receptor agonist, effective against Parkinson’s disease (currently in clinical trial). This intermediate is resolved by diastereomeric salt formation with (S)-mandelic acid. The undesired isomer is then racemized and reused in an iterative process.

•In the synthesis of AG-7404 (Pfizer), a key intermediate was resolved by (–)-norephedrine. The final compound was obtained by the combination of diastereomeric and enzymatic resolution.

How to Use ChiroSolv EnantioPrep Kits

Screen racemate against 384separation conditions

Recover racemate usingrecovery solution

Check purityand yield

Heat, Cool

Repeat until targetenantiomeric purity

is achieved

Purify racemate using thebest separation condition

Extract puri�edenantiomer ready

for testing

The experiment involves Three phases of work:

1. Screening: Racemate is screened against 384 different combinations of resolving agents and solvents. When the combination of the racemate, resolving agent, and solvent is heated together, diastereomeric salt of one enantiomer preferentially crystallizes out after cooling. The best combination of the reagent and solvent that offers the highest yield and enantiomeric enrichment for the target enantiomer is chosen to do further enrichment.

2. Recovery: After collecting all the material used during the screening process, which includes the racemate, resolving agents, and the solvents, this phase will treat it with our “recovery solution” that will separate out the racemate from the resolving agents in the form of two

Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.

7Synthetic Reagents

liquid layers. Using separatory funnel, these layers will be separated and the racemate (typically > 90%) will be recovered from the bottom layer

3. Purification: The goal of this phase is to identify how many recrystallization steps are required to get the enantiomeric purity needed. The end result should be a smaller quantity of enriched enantiomer (maximum yield: about 35% of the total racemate given).

EnantioPrep allows scientists to:

•Quickly screen a racemate against a comprehensive list of 384 resolving agent/solvent combination to identify all possible resolution conditions

•Recover the used racemate and proceed to purify it until target purity is achieved

•Define a step-by-step resolution method that can be scaled up to kilo quantities

This purification solution can be used for racemic acids, bases, alcohols, amino acids, aldehydes, and ketones.

EnantioPrep includes a set of four Acid or Base Series Screening Kits, Recovery Solution for acid or base racemate that recovers up to 90% racemate used during screening; and a self-contained Purification Package that allows incremental purification of enantiomer through simple steps.

Example Kit.

Each individual screening kit is in a disposable, ready-to-use, 96-vial, high-throughput format that allows the entire analysis to be performed inside the kit without removing any vials. The kit is made of polypropylene material that can withstand extreme temperatures (–20 to 120 °C), allowing the entire kit to be placed in a hot-water or ice bath without damage. The set of four screening kits offers unique 384 combinations of resolving agent/solvent combinations, so that a full set of separation conditions can be identified early on to help the rest of the research. Resolving agents are chosen with manufacturing use in mind; they are relatively inexpensive and recoverable in high yield after the resolution is complete. The high-throughput format allows scientists to explore the separation conditions in parallel and get results within 24 hours, which may otherwise take over two months.

When the Recovery Solution is added to the diastereomeric salts of the racemate and the resolving agents, it breaks the diastereomeric salt into neutral racemate that goes in the organic layer; while the resolving agents stay in the aqueous layer. Separating these two layers and removing the residual solvents from the organic layer returns the original racemate.

The Purification Package includes a filter funnel with vacuum adapter, enantiomer and filtrate collection bottles, spare filters, and pH paper. After recovering the racemate from Screening Kits (using the Recovery Solution), the resolving agent and solvent combination associated with best separation condition is selected to get incrementally purified salt of the target enantiomer until the required purity is achieved. Finally the enantiomer is extracted from the diastereomeric salt. In our experience, if you use 5 g of racemate during purification, depending on the number of recrystallization steps needed, you can get up to 2 g of pure enantiomer. The entire purification typically requires up to eight hours of hands-on work giving results within one week.

Types of KitsAcidThe acid screening kits include a distinct group of chirally pure acids and is used to resolve racemic bases and amino acids (some pre-processing is required for amino acids). Examples of resolving agents in the acid kits are:

•(–)-Camphoric acid

•(+)- and (–)-Camphorsulphonic acid

•(+)- and (–)-Dibenzoyltartaric acid

•(–)-Malic acid

•(+)- and (–)-Mandelic acid

•(+)-Lactic acid

•(+)- and (–)-Tartaric acid

BaseThe base screening kits include a distinct group of chirally pure bases or amines, and is used to resolve racemic acids, alcohols, aldehydes, and ketones (some pre-processing is required for the latter three). Examples of resolving agents in the base kits are:

•(–)-2-Aminobutanol

•(–)-Brucine

•(–)-Cinchonidine

•(+)-Cinchonine

•(+)-Dehydroabietylamine

•(+)- and (–)-Methylbenzylamine

•(+)-Quinidine

•(–)-Quinine

TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com

8

Case Studies with ChiroSolv® EnantioPrep™ SolutionChiroSolv EnantioPrep kits were used for two sample racemates:

•N-Benzyl-1-(4-methylphenyl)propane-2-amine (racemate had 70% S and 30% R isomer). Goal was to get over 90% purity for R isomer. This racemate was resolved by di-tolyltartaric (+) acid in 100% IPA.

Case Study Results Racemate Desired isomer purity Starting material Amount recovered # of recrystallization Amount of pure enantiomer

N-Benzyl-1-(4-methylphenyl)propane-2-amine R isomer, >90% purity 1.046 g 0.996 g (95%) 4 280 mg

N-Benzyl-1-(4-benzylphenyl)propane-2-amine R isomer, >90% purity 1.931 g 1.738 g (90%) 3 700 mg

After two recrystallizations, we were able to obtain 30% S and 70% R. Additional two recrystallizations yielded > 90% enrichment in R. The yield was over 90% of theoretical value.

•N-Benzyl-1-(4-benzylphenyl)propane-2-amine (racemate had 50% S and 50% R). Goal was to get over 90% purity of the R isomer. This racemate was resolved by S-acetylmandelic acid (+) in 90% IPA. After two recrystallizations, we were able to obtain 80% R and 20% S, with yield over 80% of theoretical value.

Representative Scope

DBU, Et3N 3HF, or Et3N 2HF* promoters:

R OH

XtalFluor-E or -M

+ promoter *substrates products

R H

O

R R

O

R OH

O

RS

O

CH3

R F

R H

R R

R F

O

RS F

F F

F F

O

OHRO

RO

RORO O

FRO

RO

RORO

XtalFluor reagents are crystalline dialkylaminodifluoro sulfinium tetrafluoroborate salts. They are useful for the deoxo fluorinationof hydroxyl and carbonyl moieties when used in conjunction with a promoter.*

Advantages of XtalFluor salts

Aldrich XtalFluor Reagents

H3C

H3CN=SF2 BF4 – –O N=SF2 BF4

+ +

719439 719447

XtalFluor-E® XtalFluor-M®

XtalFluor-E and XtalFluor-M are registered trademarks of OmegaChem Inc.

Multi-kilogram quantities available through Manchester Organics

Looking for a Safer Fluorinating Reagent?

Aldrich.com/xtalfl uors

References: (1) Beaulieu, F. et al. Org. Lett. 2009, 11, 5050. (2) L’Heureux, A. et al. J. Org. Chem. 2010, 75, 3401.

• Air-stable solids

• Enhanced thermal stability over DAST and other structurally similar deoxofl uorination reagents

• Broad substrate scope

• Predictable and high chemoselectivity

sh4078

Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.

9Synthetic Reagents

Facile and Rapid Chiral Resolution with ChiroSolv® EnantioPrep™ KitsThere are four Acid Series kits and four Base Series kits, available individually, or as the complete acid or base set. Each individual kit is in a ready-to-use, 96-vial, high-throughput format that allows the entire analysis to be performed inside the kit without removing any vials. The kit is made of polypropylene material that can withstand extreme temperatures (–20 to 120 °C), allowing the entire kit to be placed in an oven or ice bath without damage.

The kits can be supplied in two different formats, either as kits for solid racemates or kits for liquid racemates. The kits for liquid racemates provide calibrated quantities of a unique resolving agent and solvent combination in each vial. The racemate can then simply be added to start the screening process. The kits for solid racemates allow the researcher to dissolve the racemate into a volatile solvent and then dispense the resultant solution into each vial containing a resolving agent. The volatile solvent is evaporated and the prepared screening solvents are then dispensed from a separate plate into each vial.

Resolving agents are chosen with manufacturing use in mind; they are relatively inexpensive and recoverable in high yield after the resolution is complete. Using all four kits in an acid or base series, 384 resolving agent–solvent combinations can be explored for a single racemate. The high-throughput format allows scientists to identify within 24 hours the optimum resolution process which might otherwise take over two months.

ACID BASE12 solvents

384 combinations

8 Res

olving

Agents

Series 1

Series 2

Series 3

Series 4

Series 1

Series 2

Series 3

Series 4

96 vials

96 vials

96 vials

96 vials

96 vials

96 vials

96 vials

96 vials

0

5

10

15

20

25

16 32 48 96 144 192 240 288 336 384

No. of Resolving Agents

Manual Screening Screening with ChiroSolv Kits

No.

of D

ays

Requ

ired

Time Savings Using ChiroSolv Kits

TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com

10

Recap: How to Use ChiroSolv® Kits1. Choose the right kit type (Acid Series 1, 2, 3, 4 or Base Series 1, 2, 3, 4)

depending on the identity of the racemate.2. If the racemate is an alcohol, amino acid, aldehyde or ketone, you may

need to pre-process the racemate.3. Add 0.03 mmol of your racemate to each of the 96 vials. Depending on

the availability of the dispensing autostation and the racemate. type (liquid or powder), you may need to remove the seal on the vials. Note the seal is pierceable to accommodate direct injection of racemate by liquid dispensers.

4. In an oven or water bath, heat the rack along with its vials to 80 °C (optimal temperature for most of these experiments) or until the mixture becomes homogeneous.

5. Allow the kit to cool to ambient temperature. If required, further cool it to 4 °C or 0 °C to observe crystallization. Vials with crystals are considered positive results and should be examined further.

6. Often, more vials with positive results can be obtained using standard crystal initiation techniques. Vials with no crystals even after this effort are considered negative results.

7. Separate out the positive test results and note their alphanumeric identification.

8. Liberate the enantiomers from their diastereomeric salts and analyze by optical rotation. Typically, only one or two vials will show maximal optical purity.

Features•Eight types of ready-to-use disposable kits providing a total of 768

resolving agent–solvent combinations.

•Very little amount of racemate required (less than 3 mmol per kit).

•Concentrations of the resolving agents are calibrated to give accurate results and optimal crystallization.

•Pierceable seal allows easy racemate dispensing; vials held together by a plastic ring so that vials can be picked up and inspected together for crystal formation.

•Easy to follow, step-by-step instructions and results charts.

•Conveniently designed for easy robotic manipulations.

•Kits and vials have unique identification (barcode or alphanumeric) for cross-referencing.

•Long shelf life at room temperature (2 years).

Each rack has a unique barcode.

Each vial contains a unique combination of

resolving agent/solvent— 8 types of kits give 768 such

combinations.

Pierceable septa or foil seal for easy

robotic manipulation.

Plastic sleeve holds the vials together even when they are out of

the rack.

Each vial has a unique alphanumeric identification.

Rack, vials, and septa are chemically inert and can withstand –20 °C to 120 °C.

Extra septum mat provided in kits for

solid racemates.

Product Information for Liquid RacematesProduct No. Product Name/Description681431 ChiroSolv Resolving Kit, Acid Series 1681423 ChiroSolv Resolving Kit, Acid Series 2681415 ChiroSolv Resolving Kit, Acid Series 3699217 ChiroSolv Resolving Kit, Acid Series 4700363 ChiroSolv Resolving Kit, Complete Acid Series681407 ChiroSolv Resolving Kit, Base Series 1681393 ChiroSolv Resolving Kit, Base Series 2681377 ChiroSolv Resolving Kit, Base Series 3699241 ChiroSolv Resolving Kit, Base Series 4700371 ChiroSolv Resolving Kit, Complete Base Series

Product Information for Solid RacematesProduct No. Product Name/Description698881 ChiroSolv Resolving Kit, Acid Series 1699527 ChiroSolv Resolving Kit, Acid Series 2698873 ChiroSolv Resolving Kit, Acid Series 3699225 ChiroSolv Resolving Kit, Acid Series 4700398 ChiroSolv Resolving Kit, Complete Acid Series699233 ChiroSolv Resolving Kit, Base Series 1698938 ChiroSolv Resolving Kit, Base Series 2698946 ChiroSolv Resolving Kit, Base Series 3698954 ChiroSolv Resolving Kit, Base Series 4700401 ChiroSolv Resolving Kit, Complete Base Series

For more information, please visit Aldrich.com/chirosolv

Synthetic Reagents

Kits: A1, A2, A3, A4 or B1, B2, B3, B4

Analyze selected vials with crystals for specific rotation

Select vials with crystals & note their alphanumeric

identification

Unknown Racemate

Cool mixture 4 °C to 0 °C Yes

No

Cool mixture to ambient temp.

Heat mixture to 80–100 °C

Ready to Use Disposable Kit

Need a MolarMatic™ Measuring Cylindersfor your Acid solutions?

Aldrich MolarMatic Measuring Cylinder

Our MolarMatic graduated measuring cylinder allows you to add concentrated acid to the desired molarity line. Simply pour the measured acid into one liter of water, and your 1 M, 2 M, or 3 M solution is prepared.

• No calculations

• No struggling for the correct cylinder

Convenient Dual-Scale Graduated Cylinder• Class A, 350-mL cylinders

• Graduated in 5.0-mL increments; calibrated "to deliver"

• 1 to 3 Molar scale on opposite side

• Eliminates repetitive molar calculations and potential errors

• Set contains one of each cylinder in plastic storage case

Acid Type Cat. No.

Acetic acid Z683728

Hydrochloric acid Z683736

Nitric acid Z683744

Sulfuric acid Z683752

Set of four Z683760

Save time. Add Aldrich.Aldrich.com/molarmatic

75634

TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com

12

CatalysisRonaldo Mariz, Ph.D.Product Managerronaldo.mariz@sial.com

ZACA Catalyst: Enabling Flexible Asymmetric Synthesis Through Carboalumination of Terminal AlkenesSince the seminal work of Nobel laureate Ei-ichi Negishi using ZACA catalyst (719072),1 the zirconium catalyzed asymmetric carboalumination reaction (ZACA reaction) of terminal alkenes has allowed highly flex-ible design for the syntheses of chiral organic compounds. For instance, proper treatment of the carboaluminated intermediate from inexpensive allyl alcohol gives rise to versatile building blocks through a one-pot procedure which can undergo further Pd-catalyzed functionalization (Scheme 1).2

H3O+

Me

HO IMe

TBSO I

TBSCl, DMA

(-)-ZACA catalyst - (R)-product(+)-ZACA catalyst - (S)-product

* *80%82%

Me

TBSO* CH2

Me

TBSO*

CO2Me

MeMe

TBSO*

TMS

Me

TBSO* Me

O

[Pd] [Pd]

[Pd] [Pd]

HOCH2

1) Me3Al (2.5 eq)2) 719072 (5 mol%) MAO (1 eq)

Me

Me2AlO AlMe2

I2(2.5 eq) Me

Me2AlO I

Scheme 1: One-pot procedure for the synthesis of versatile protected and unprotected 3-iodo-2-methyl-1-propanol via ZACA reaction.

Probing its flexibility, Negishi’s group has demonstrated that when followed by vinylation the ZACA reaction can be sequentially used to construct multiple stereogenic centers. This methodology furnishes an elegant entry to deoxypolypropionate, residues present in many natural products with interesting medicinal properties and biological activity such as doliculide (Scheme 2).2,3

CH2

Me

TBSO

1) (i) (+)-ZACA; (ii) Pd-cat.vinylation2) (i) (+)-ZACA; (ii) O2

Me

TBSO

MeMe

OH

52%1) NaH, BnBr2) TBAF3) Dess-Martin oxid.4) EtO2CCH=PPh3

77% (4 steps)

Me MeMe

OBnEtO2C

steps

(R) (S) (S)

MeMe

O

O

OHMe

Me

Me

MeN

O

NH

OHI

HO

doliculide

(S)

(S)

(R)

Scheme 2: Sequential ZACA reaction to construct multiple stereogenic centers.

References: (1) (a) Kondakov, D. Y.; Negishi, E. J. Am. Chem. Soc. 1995, 117, 10771. (b) Kondakov, D. Y.; Negishi, E. J. Am. Chem. Soc. 1996, 118, 1577. (2) Liang, B.; Novak, T.; Tan, Z.; Negishi, E. J. Am. Chem. Soc. 2006, 128, 2770. (3) Negishi, E. ARKIVOC 2011, viii, 34.

H3C

H3CCH3

CH3

CH3H3C

Cl Zr Cl(-)-ZACA catalyst

719072

For a list of zirconium catalysts available from Aldrich Chemistry, visit Aldrich.com/zirconium

Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.

13Catalysis

p-Tol-BINASO: A Highly Active and Selective Ligand for Rhodium-Catalyzed Asymmetric Conjugated Addition The rhodium-catalyzed asymmetric 1,4-addition reaction has emerged as a powerful tool for the formation of C-C bonds over the last decade.1 Recent reports by the group of Prof. Dorta at the University of Zürich showed excellent results by using a C2-symmetric bis-sulfoxide ligand based on the binaphthyl moiety. High activity and selectivities were en-countered in the addition of boronic acids to α,β-unsaturated cyclic esters and ketones under mild conditions when applying rhodium p-Tol-BINASO complex (Scheme 1).2

1.1 eq. ArB(OH)2

[(p-Tol-BINASO)]RhCl]2(1.5 mol% Rh)

KOH (50 mol%)toluene/H2O (10/1)

40 °C

+X

O

X

O

Ar*

2.0 h98% yield, 90% ee

CH3

1.0 h60% yield, 99% ee

1.5 h93% yield, 99% ee

1.0 h94% yield, 97% ee

1.5 h93% yield, 99% ee

1.0 h91% yield, 97% ee

Ar =F

CH3 CF3

Cl F

1.0 h55% yield, 97% ee

OMe

1.0 h97% yield, 96% ee

1.5 h86% yield, 98% ee

1.5 h90% yield, 98% ee

Ar =

CH3 Cl

F

0.5 h99% yield, 96% ee

O

Ph

O

Ph

3.0 h98% yield, 66% ee

O

O

Ph

1.0 h98% yield, 91% ee

O

2-naphthyl

1.0 h, 98% yield, 94% ee (1:1 cis:trans)

H3C

1.0 h92% yield, 99% ee

1.0 h99% yield, 90% ee

1.0 h89% yield, 96% ee

Ar =

1.0 h90% yield, 95% ee

OMe

1.0 h99% yield, 98% ee

O

2-naphthyl

H3C

Scheme 1: Rhodium-catalyzed 1,4-addition of boronic acids to α,β-unsaturated esters and ketones using p-Tol-BINASO.

While an excess of boronic acid was required for most systems used for this transformation, the ligand enabled coupling of ortho, meta, and para substituted aryl boronic acids using only 1.1 equivalents of the nucleo-phile. In addition, only 1.5 mol% of rhodium is needed instead of the 3 mol% normally required to preform the reaction in short time at a mild 40 °C, which is in contrast to the higher temperatures frequently applied.

References: (1) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829. (2) (a) Mariz, R.; Luan, X.; Gatti, M.; Linden, A.; Dorta, R. J. Am. Chem. Soc. 2008, 130, 2172. (b) Burgi, J.; Mariz R.; Gatti, M.; Drinkel, M.; Luan, X.; Blumentritt, S.; Linden, A.; Dorta, R. Angew. Chem. Int. Ed. 2009, 48, 2768. (c) Mariz, R.; Bürgi, J.; Gatti, M.; Drinkel, E.; Luan, X.; Dorta, R. Chimia 2009, 63, 508. (d) Mariz, R.; Poater, A.; Gatti, M.; Drinkel, E.; Burgi, J.; Luan, X.; Blumentritt, S.; Linden, A.; Cavallo L.; Dorta, R. Chem. Eur. J. 2010, 16, 14335.

Aldrich Chemistry is pleased to offer researchers this promising chiral sulfoxide ligand.

S

S

OO

CH3

CH3

(P,S,S)-p-Tol-BINASO

726443

S

S

OO

CH3

CH3

(M,S,S)-p-Tol-BINASO

726443726435 726443

For a list of chiral catalysts and ligands available from Aldrich Chemistry, visit Aldrich.com/asymmetriccatalysis

Takasago Ligands and Complexes: Excellence in Catalysis Technology Now at Reduced PricesThe research team at Takasago International Corporation has developed excellence in catalysis through continuous improvements for over a quarter century. This work has translated into cutting edge catalysis technology for many chemical transformations with special emphasis on asymmetric synthesis (Scheme 1).

R1 R2

O

R1 R2

OH

R1 R2

NH2or

R1 R3

R2

R1 R3

R2

R2

R1 NR3

R3

R2

R1X

O

n

CO2t-Bu X

O

n

CO2t-BuF

X = O, NH, NR

R1 H

O

R1

OH

O

H

CN

R1 R2

O

R1 R2

OH

R3

R3 = vinyl, aryl

NR1

R2

R3

XR3

HN

R1 R2

+

Reduction of ketones toalcohols or amines

Arylation and vinylationof ketones

Reduction of Alkenes Cyanomethylation

Fluorination Conversion of allylamine to aldehydes

or

B(OH)2Ar

or

ArR3

Buchwald-Hartwig Amination and Suzuki cross-coupling

Scheme 1: Examples of reactions performed by Takasago ligands and complexes.

TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com

14

Aldrich Chemistry is pleased to offer the over 70 Takasago ligands and complexes at reduced prices.

PPh2PPh2

693065

PPh2PPh2

O

O

O

O

692395

CH3

P(t-Bu)2

711179

PPh2PPh2

692387

OMePPh2

693537

CH3

PCy2

702943

P(t-Bu)2

CH3

693383

PCy2

CH3

702951

OP PPh PhPh Ph

692344

O

O

O

O

P

PRu

NH2

H2N

R R

R RPh

Ph

Cl

ClR =

CH3

CH3

693200

For a complete list of Takasago ligands and complexes, visit Aldrich.com/takasagocatalysts

New Palladium Catalysts and Precursors for Cross-coupling Reactions

N N

Pd

N

Cl

Cl Cl

CH3H3C

CH3

H3C

H3C CH3

H3C

CH3

732117

P

PdNH2Cl

H3CO

OCH3

t-Bu OCH3

704946

Pd NH2

Cl

Pi-Pr

i-Pr

i-Pr

704954

Pd NH2

Cl

P t-But-Bu

i-Pr

i-Pr

i-Pr

708739

P

PdNH2Cl

O

O

t-Bu OCH3i-Pr

i-Pr

707589

P

Pd

H3CO

OCH3

i-Pr

i-Pr

i-Pr

NH2

Cl

718750

A comprehensive list of palladium catalysts and precursors for cross-coupling reactions is available from Aldrich Chemistry in a useful application guide format, Aldrich.com/pdapplicationguide

Need Chemical Compounds for Your Research?Let us supply the chemicals so you can concentrate on the science!

Aldrich® Custom Packaged Reagents

AldrichCPR provides pre-weighed, application ready building blocks and screening compounds, allowing you to focus on discovery rather than the tedious process of sourcing, procurement, and preparation.

Provide your list of MFCD numbers, CAS numbers, CNC IDs, structures, and/or vendor and product numbers, and Aldrich Chemistry will source, package, and send your chemicals to you.

Aldrich.com/CPRAldrichCPR@sial.com

76758

Continually introducing new and innovative Boronic Acid Surrogates to meet your research needs, our vast line of organotrifluoroborates feature:

•Air and moisture stability

•Less prone to protodeboronation

•Stability to common and harsh reagents, and reaction conditions

From the latest product innovations to the widest selection of solvents on the market, your research will move forward faster when you add trustworthy products, services, and information from Aldrich Chemistry.

Add Aldrich to your research program.

When you need a Trifluoroborate for your cross-coupling.

Aldrich.com/tfb

681342

BF3KBr

662984

BF3K

711144

NH

N

BF3K

729299

BF3KBr S

720747

BF3K

CH3

CH3

720682

BF3K

CH3

H3C

723797

BF3KS

728837

BF3K

NCI

728810

KF3B N

N OCH3

710075

FF

F

S

B

NH+

-

710083

CH3

BF3

NH

N

723916

BF3K

CH3H2C

76253

TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com

16

OrganometallicsAaron Thornton, Ph.D.Product Manageraaron.thornton@sial.com

EZ-CrotylMix: A Comprehensive Solution to the Enantioselective Crotylation of AldehydesEnantioselective crotylation reactions have been the focus of an enormous amount of effort within the field of organic synthesis. This reaction’s ability to form C-C bonds, as well as set adjacent stereocenters, has been critical to the construction of numerous complex molecules. The first general approach to this transformation was disclosed by Professor H.C. Brown and co-workers in 1986, in the form of their chiral crotylborane methodology (Scheme 1).

CH3

B CH3

2

CH3

B

2CH3

CH3

B

2CH3

CH3

B

2

CH3

Scheme 1: Brown’s chiral crotylboranes.

Despite the fact that Brown’s methodology has been the method of choice for the past 20 years, significant shortcomings remain. Of particular importance is the inherent diastereofacial bias of certain chiral aldehydes that is often difficult, or even impossible, to overcome. Also, the Brown method is hampered by the use of somewhat impractical synthetic techniques, including the use of harshly basic organometallic species, air and moisture sensitive Lewis acids, and the need for low temperature manipulations.

The group of Professor James Leighton previously developed reagents for the enantioselective crotylation of aldehydes based on the use of their chiral crotylsilanes (Scheme 2).1

NSi

N

H

H

Br

Br

CH3Cl

733180

NSi

N

H

H

Br

Br

CH3Cl

733083

NSi

N

H

H

Br

Br

Cl

CH3

733199

NSi

N

H

H

Br

Br

Cl

CH3

733075

Scheme 2: Leighton’s crotylsilane reagents.

While these reagents have made significant strides in addressing many of the previously mentioned shortcomings of the Brown method, still an overall lack of substrates that undergo productive reaction with these reagents significantly limits their application (Scheme 3).

BnOO

H

733180

CH2Cl2, 0 o CBnO

OH

CH3

BnOOH

CH3

733199

CH2Cl2, 0 o C

82 % yield96 % ee

83 % yield99 % ee

PhCH3

O

H

CH3

O

H

SiOH3CH3C

PhPh 733199

or733180

733199

or733180

No Reaction

Scheme 3: Representative examples of successful and unreactive substrates.

Based on the knowledge that Lewis acids may be used to catalyze the reaction of similar allylboranes with aldehydes by binding to one of the boronate oxygen atoms, the Leighton group hypothesized that a similar strategy may be useful for activating their crotylsilane reagents. Now, with the addition of just 5 mol% Sc(OTf )3, the enantioselective crotylation of previously unreactive aldehydes may now be performed with excellent yield and enantioselectivity (Scheme 4). Importantly, this new method utilizes air-stable crystalline solids that can easily be weighed out and manipulated at room temperature.2

PhCH3

O

H

733075

5 mol% Sc(OTf)3CH2Cl2, 0 oC

PhCH3

OH

CH3

87% yield94% ee

PhCH3

OH

CH3

733083

5 mol% Sc(OTf)3CH2Cl2, 0 oC

87% yield91% ee

Scheme 4: Sc(OTf )3 catalyzed enantioselective aldehyde crotylation.

Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.

17Organometallics

To further increase the utility of this method, the Leighton group has shown that simply premixing the chiral crotylsilane reagent and Sc(OTf )3 leads to a versatile reagent that simplifies reaction set-up even further. This bench-stable reagent, termed EZ-CrotylMix, can now be used for the enantioselective crotylation of previously unreactive substrates, with the crotylation of α-methylcinnamaldehyde yielding the desired product in 89 % yield with 92 % ee (Scheme 5).

CH3

O

H

SiOH3CH3C

PhPh

CH3

OHSiOH3CH3C

PhPh

CH3

85% yield97% ee

(R,R)-trans EZ-CrotylMix(737674)

CH2Cl2, r.t.

PhCH3

O

H PhCH3

OH

CH3

89% yield92% ee

(S,S)-cis EZ-CrotylMix(737666)

CH2Cl2, r.t.

Scheme 5: EZ-CrotylMix for the enantioselective crotylation of aldehydes.

Aldrich Chemistry has now teamed with Prof. Leighton to make these powerful reagents commercially available. These reagents show a number of advantages over previously developed crotylation products, including:

•Crystalline solids that can be weighed in air on the benchtop

•Provide excellent reactivity and selectivity

•Have a truly broad substrate scope

To learn more about Leighton’s EZ-CrotylMix reagents available from Aldrich Chemistry, visit Aldrich.com/ezcrotylmix

References: (1) Hackman, B. M.; Lombardi, P. J.; Leighton, J. L. Org. Lett. 2004, 23, 4375. (2) Kim, H.; Ho, S.; Leighton, J. L. J. Am. Chem. Soc. 2011, 133, 6517.

Chiral Crotylsilanes and EZ-CrotylMixes from Aldrich

NSi

N

H

H

Br

Br

CH3Cl

733180

NSi

N

H

H

Br

Br

CH3Cl

733083

NSi

N

H

H

Br

Br

Cl

CH3

733199

NSi

N

H

H

Br

Br

Cl

CH3

733075

NSi

N

H

H

Br

Br

CH3Cl

Sc(OTf)3

25 737674

NSi

N

H

H

Br

Br

CH3Cl

Sc(OTf)3

25 737682

NSi

N

H

H

Br

Br

Cl

CH3

Sc(OTf)3

25 737666

NSi

NCH3

Cl

Br

Br

H

H

25

Sc(OTf)3

737658

TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com

18

Building BlocksMark RedlichProduct Managermark.redlich@sial.com

Halogenated PyridinesPyridines continue to be extremely popular building blocks for synthetic chemists across a number of disciplines. The pyridine moiety is found in a wide range of synthetic targets with applications in catalysis, drug design, molecular recognition, and natural product synthesis. Halogenated pyridines in particular are attractive building blocks for various cross-cou-pling methodologies. Aldrich Chemistry offers these useful halogenated pyridines for your research.

New Halogenated Pyridines

N SH

NO2

724793

N CF3

F

730181

N Br

Cl

725188

N F

NH2

728675

N Br

F

723339

N Br

HO

725072

N F

NH2

720232

N Br

F F

733997

N Br

Br

725196

N NO2

Cl

714585

N NH2F 725064

NBrNH2

O 714526

N

NH2

Cl

725056

N

Br

O OH

714658

N

NH2F

732176

N

ClO2N

Cl 724297

N

BrO2N

Cl 730157

N

FCl

NH2 714631

New Halogenated Pyridines — continued

N

NH2Br

F 722391

N

BrF3C

Cl 728748

N

CH3F

Br 731072

N

BrF3C

F 733237

N

F

Br

OH

O

722448

For a complete list of available halogenated pyridines available from Aldrich Chemistry, visit Aldrich.com/hal-pyr

New Aldehydes

S

Br

O

H

716553

N

S Cl

Cl

H

O 724300

H

O

CH 725021

I

OCH3

H

O

729450

H

O

F

F

Cl 728985

O

H

H3CO

715778

H

O

Cl 715786

Cl

H

O

725722

NN

OCH3

H3C

H

O

732508

NN

Br

H3C

H

O

732494

For a complete list of available aldehydes available from Aldrich Chemistry, visit Aldrich.com/aldehyde

Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.

19Building Blocks

Other New Building Blocks

• O CH3

OH3C

714984

S

Cl

O

734454

S

Br CN

731315

NN

Br

CH3

CH3

715344

NN

O OCH3

730203

N

N

Cl

HN

732095

N

N

CF3

NH2 709131

N

N

ClH2N

732281

N

N

Cl

H2N 732133

O

N

N

Cl

Cl

Cl

728772

N

N

NH2

Br OCH3

732125

NH

Cl

I 707120

HN

N NH

O

731935

O

OI

732842

O

OICl

732869

O

OIBr

732877

For a comprehensive list of building blocks available from Aldrich Chemistry, visit Aldrich.com/bb

To discover Microreactor Technology & Flow Chemistry

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• Improve product profiles, purities, and yields of your products

• Perform scale-independent synthesis from mg to kg in a single day

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• Handle unstable or hazardous materials (even explosives) safely

• Minimize the time frame for process development

Improve safety and cost. Add Aldrich.

Aldrich.com/mrt76072

TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com

20

Specialty SynthesisPietro Butti, Ph.D.Product Managerpietro.butti@sial.com

Ionic Liquids: A Smart AlternativeEnvironmentally low-impact alternatives, sustainable processes, industrial ecology, and efficiency are some of the topical words which are directing the development of the new generation of technologies and products.1 Therefore, the importance of compounds coming from renewable feed-stock or enabling high levels of recycling is growing exponentially. These compounds are seen as promising materials able to replace compounds produced with fossil fuel sources, hence reducing our global dependence upon them.2

NNR' R'' N

R

R

NR''' R'

R''

R

PR''' R'

R''

Figure 1: Commonly used ionic liquids aprotic cations.

NTf2

PF6

BF4

OTf

CH3COO

NO3 Br

CF3COO

Cl

Water Miscibility

Figure 2: Commonly used ionic liquids aprotic anions.

Ionic liquids have been recognized and developed by scientists from academia and the chemical industry as new green(er) chemicals.3 Even if they are not always the “greenest choice”, 4 ionic liquids, a group of salts that exist as liquids at relatively low temperatures (<373 °K) (Figures 1 and 2), have gained overwhelming interest over the past decades (Chart 1). They offer unique sets of properties, often difficult to achieve with any other compounds. Some of these properties are chemical and thermal stability, non-flammability, and low vapor pressures.5

Publications per Years

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

19901991

19921993

19941995

19961997

19981999

20002001

20022003

20042005

20062007

20082009

2010

Year

Num

ber o

f Pub

icat

ions

Chart 1: Number of SciFinder® hits containing the words “Ionic Liquids” from 1990 to 2010. Red total number of publications, Gray filtered through patent applications.

This class of compounds opens up a variety of opportunities in many dif-ferent applications. For example, chemical processing and fine chemicals synthesis such as the BASIL™ process (Scheme 1).6

N

NR2PCl

EtOH NH

N

Cl-+ +R2POEt

Recycle

Scheme 1: Preparation of alkoxyphenylphosphines (R2POEt) with the BASIL process.6

Another example is the olefin metathesis, published by Grela and co-workers in 2007 (Scheme 2).7

TsNTs

N

H2C CH2CH3 CH3

O

Ru

CH3

H3C

Cl

Cl

NMesMesN

N

PF6

Up to >98% Conversion5 Cycles

5 mol%,

BMIM PF6 (70956)Tol, 3h, 25°C

Scheme 2: Recyclable catalytic system for a model metathesis reaction.7

Ionic liquids are also used in polymer and biopolymer processing as enabling technology to utilize cellulose.1,8 In electrochemical applications and in metal processing9 they offer unprecedented prospects for metal deposition. Furthermore, they can be used in nuclear fuel processing.10 They lead to new opportunities in separation processes, or their tune-able properties can be exploited to prepare engineering fluids or other high-performance materials. Ionic liquids are also used in analytical chemistry11 (Supelco’s GC capillary column SLB-IL series) and biomedical applications.12 These examples highlight just a few of the large number of potential applications in which this class of extraordinary compounds can be used.

Publications per Years

Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.

21Specialty Synthesis

References: (1) Pinkert, A.; Marsh, K. N.; Pang, S.; Staiger, M. P. Chem. Rev. 2009, 109, 6712–6728. (2) Xie, H.; King, A.; Kilpelainen, I.; Granstrom, M.; Argyropoulos, D. S. Biomac-romolecules, 2007, 8, 3740. (3) Keskin, S.; Kayrak-Talay, D.; Akman, U.; Hortacsu, O. J. of Supercritical Fluids, 2007, 43, 150–180. (4) Jessop, P. G. Green Chem., 2011, article in press DOI: 10.1039/C0GC00797H (5) Zhu, S.; Wu, Y.; Chen, Q.; Yu, Z.; Wang, C.; Jin, S.; Ding, Y.; Wu, G. Green Chem., 2006, 8, 325. (6) Maase, M. Multiphase Homogeneous Catalysis, 2005, 2, 560–566. (7) Rix, D.; Caïjo, F.; Laurent, I.; Gulajski, L.; Grela, K.; Mauduit, M. Chem. Commun., 2007, 3771–3773. (8) Maase, M.; Massonne, K.; Uerdingen, E.; Vagt, U.; ChemFiles, 2006, 6(9), 3 (9) Abbott, A. P.; Frisch, G.; Hartley, J.; Ryder, K. S. Green Chem., 2011, 13, 471–481. (10) Nash, K. L; Lumetta, G. J. Advanced Separation Techniques for Nuclear Fuel Reprocessing and Radioactive Waste Treatment. 2011, 1. (11) Soukup-Hein, R. J.; Warnke, M. M.; Armstrong, D. W. Annual Rev. Anal. Chem., 2009, 2, 145–168. (12) Elliott, G. D.; Kemp, R.; MacFarlane, D. R.; Plechkova, N. V.; Rogers, R. D.; Seddon, K. R. Ionic Liquids: From Knowledge to Application. 2009, 6, 95–105.

For a complete list of ionic liquids, available from Aldrich Chemistry, visit Aldrich.com

N+

H3C CH3

PF6–

713198

N+

H3C CH3

Br–

713171

N+

H3C CH3

BF4–

713163

N+

H3C CH3

SO

ON–F3C S CF3

O

O 713155

CH3N+

H3C

I–

713139

CH3N+

H3C

PF6–

713120

CH3N+

H3C

O SO

OCF3

727725

N+

N

CH3

CH3

CH3

BF4–

713023

N+

N

CH3

CH3

CH3

PF6–

713015

N+

H3CCH3

PF6–

713090

N+

H3CCH3

BF4–

713082

N+

H3C

SO

ON–F3C S CF3

O

OCH3

713074

N

N+CH3

I–

CH3 713031

N

N+CH3

CH3

I–

713066

N

N+CH3

CH3

I–

713058

N

N+

N– SSO

OCF3

O

OF3C

CH3

CH3

711705

SO

ON–F3C S CF3

O

OCH3N+

CH3

CH3

H3C

713007

N+I–

CH3

CH3 713112

N+

CH3

BF4–

713104

N NH3C

H2C

I 727717

N NH3C

H2C

CNCN

N 727709

N NH3C SO

ON–F3C S CF3

O

O

H2C

727695

N NH3CCH3

O

ONH2

727911

N NH3CCH3

OH 728527

O SO

O

FF

FF

N NH3CCH3

727687

N NH3CCH3

O

OCH3

NH2 727903

N NH3CCH3

O

O

HO 726257

NCH3

CH3 CH3

SO ON–

CF3

SCF3

O OH3C

727989

NCH3

H3C

CH3

OCH3

SO ON–

CF3

SCF3

O O

727679

N

N+

N–S

S

OOCF3

OOCF3

CH3

CH3 727954

TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com

22

Aldrich NMR SolventsChallenge Us… And See Why Our Quality is Unsurpassed!

High quality NMR solvents are essential for satisfying the most rigorous demands of NMR-based research and analyses. At Aldrich, we are pas-sionate about providing this high level of quality to our customers and work continuously to meet these requirements. We offer the widest range of NMR solvents with the highest isotopic enrichment available along with excellent chemical purity. We consistently review and im-prove our methods for solvent purification and for the reduction of water content in our already high quality NMR solvents. All of our NMR solvents undergo thorough quality control testing during the manufacturing and packaging processes to verify the product quality is preserved.

Most deuterated NMR solvents readily absorb moisture. To minimize the chance of water contamination, use carefully dried NMR tubes and handle NMR solvents in a dry atmosphere.

How to Obtain a Nearly Moisture-free Surface1. Dry glassware at ~150 °C for 24 hours and cool under an inert atmosphere.

2. Rinse the NMR tube with the deuterated solvent prior to preparing the sample. This allows for a complete exchange of protons from any residual moisture on the glass surface.

3. For less demanding applications, a nitrogen blanket over the sample prepara-tion setup may be adequate.

How to Avoid Sources of Impurities and Chemical Residues1. Use clean, dry glassware and PTFE accessories.

2. Use a vortex mixer instead of shaking the tube contents. The latter action can introduce contaminants from the NMR tube cap.

3. Residual chemical vapor from equipment can be a source of impurities; residual acetone in pipette bulbs is a common example.

How to Remove Solvent Residue1. Protonated solvent residue can be removed by co-evaporation.

2. Use a small quantity of the desired deuterated solvent, a brief high vacuum drying (5–10 min), and then prepare the NMR sample.

3. Solvents such as chloroform-d, benzene-d6, and toluene-d8, also remove residual water azeotropically.

How to Avoid TMS Evaporation1. Extended storage of TMS-containing solvents can lead to some loss of TMS.

Storing these solvents in Sure/Seal™ bottles virtually eliminates such a loss.*

2. Purchase TMS-containing solvents in single-use ampules.* To dispense the product from Sure/Seal™ bottle or septum vials, use standard syringe needle techniques. For details and recommended procedures, please refer to Aldrich Technical Bulletin AL-134 or visit our Web site at Aldrich.com.

Use and Handling of NMR Solvents

Aldrich Chemistry also offers unparalleled convenience and service. Our award-winning website allows for quick product searching, easy ordering, and a wealth of valuable tools and information to aid your research efforts. We also offer on-site stocking programs for NMR solvents so they are avail-able to you for immediate use. If you have technical questions, you can feel comfortable knowing our knowledgeable and well-trained technical service specialists can answer your toughest questions.

Try our NMR Solvents today to see their high quality for yourself.

For a complete listing of all NMR-related products and information, visit Aldrich.com/nmr

Stable IsotopesLeslie Patterson, Ph.D.Product Managerleslie.patterson@sial.com

Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.

23Stable Isotopes

Specialty NMR Solvents Aldrich Chemistry offers a wide range of high purity deuterated solvents for the NMR community. In addition, we also offer various specialty solvents for more demanding applications. Whether you need the high-est enriched deuterium oxide available, or solvents with a reduced HOD peak, we have what you need.

“Special HOH” SolventsWhen customers requested NMR solvents with a suppressed HOD peak we listened, and developed NMR solvents called “Special HOH”. These solvents have an HOD peak which is less than 1% of the HOH peak, to minimize potential exchange with an analyte. “Special HOH” solvents also meet our standard water specification for NMR solvents.

1H-NMR Spectrum of DMSO-d6 “Special HOH”

Anhydrous NMR SolventsWhen water content is of paramount concern, try our anhydrous solvents that contain reduced levels of water.

“Extra” Enriched D2OWith an enrichment of 99.994 atom % D, this is the highest enriched deuterium oxide available.

For additional information visit Aldrich.com/nmr or contact:

Stable Isotope Technical ServicePhone: (937) 859-1808 (800) 448-9760 (US and Canada) Fax: (937) 859-4878 E-mail: isosales@sial.com

11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 –0.5ppm

2.5 2.4ppm

3.3ppm

HOH

DMSO-d6 residual peak

HOD

Deuterium oxide, Extra, 99.994 atom % D613398-10G serum bottle 10 g613398-50G serum bottle 50 g

Acetonitrile-d3, 99.8 atom % D, Anhydrous (water < 10 ppm)569550-10X1ML ampule 10 x 1 mL

Benzene-d6, 99.6 atom % D, Anhydrous (water < 10 ppm)570680-50G glass bottle 50 g

Chloroform-d, 99.8 atom % D, Anhydrous (water < 10 ppm)570699-50G glass bottle 50 g

Dimethyl sulfoxide-d6, 99.9 atom % D, Anhydrous (water < 50 ppm)570672-50G glass bottle 50 g569585-5X1ML ampule 5 x 1 mL569585-10X1ML ampule 10 x 1 mL

Methanol-d4, 99.8 atom % D, Anhydrous (water < 50 ppm)570729-50G glass bottle 50 g569534-5X1ML ampule 5 x 1 mL569534-10X1ML ampule 10 x 1 mL

Toluene-d8, 99.6 atom % D, Anhydrous (water < 10 ppm)570710-50G glass bottle 50 g

Acetonitrile-d3, 99.8 atom % D, "Special HOH"699543-10G glass bottle 10 g699543-25G glass bottle 25 g699543-50G glass bottle 50 g

Dimethyl sulfoxide-d6, 99.9 atom % D, "Special HOH"612324-25G glass bottle 25 g612324-50G glass bottle 50 g612324-100G glass bottle 100 g716731-10x0.75ML ampule 10 x 0.75 mL716731-10ML serum vial 10 mL716731-50ML serum vial 50 mL

Data acquired on a Varian 400 MHz instrument.

TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com

24

Stockroom ReagentsTodd HalkoskiMarket Segment Manager, Solvents and Reagentstodd.halkoski@sial.com

Sigma-Aldrich® is a Leading Global Supplier and Manufacturer of High Quality, Stockroom and Essential Research Products We specialize in providing the most comprehensive product range and widest selection of purity grades to fulfill your particular application needs.

•Solvents — As a leading supplier of high-purity, research grade solvents, we have the solvent to meet your exact needs

•Acids and Bases — From ACS grade to TraceSELECT® Ultra for the ultra trace analysis level down to ppb and ppt.

• Routine Organic and Inorganic Reagents

• Adsorbents, Filter Aids, and Drying Agents

You will also find several programs that offer unique solutions to help control your costs. One may be right for you!

National Association of Scientific Materials Managers (NAOSMM)Sigma-Aldrich is a proud partner of NAOSMM and its members receive savings on a wide range of Sigma-Aldrich Chemistry products.

Supply Rewards™ ProgramGet rewarded for choosing Sigma-Aldrich. Earn rewards for your team, your community, or yourself, every time you purchase selected products from Sigma-Aldrich. With over 1,500 eligible common laboratory products to choose from, earning reward points couldn't be easier.

New Lab Start-Up ProgramGet your new lab set up in an easy and economical way. Your lab is eligible for the program if:

• You are starting a new lab

• You are moving to a new location

• You have received your first research grant

To learn more, visit Aldrich.com/stockroom

By always listening, Sigma-Aldrich delivers.Monthly Savings from Sigma-Aldrich

Easy-to-find site offers monthly savings on Chemistry, Life Science, Analytical, and Labware products.

United States Aldrich.com/offers

Europe Aldrich.com/offerseu

For specific country discounts, visit us at Aldrich.com

The Sigma-Aldrich Pressure-Temperature Nomograph allows you to quickly and easily estimate boiling points at various pressures. Interactive controls simplify calculations to improve the efficiency of your distillation or evaporation process.

Pressure Conversion Tab: Use the built-in Pressure Conversion Calculator to convert among five units of pressure using either numeric values or scientific notation.

Temperature Conversion Tab: Quickly calculate temperature conversions without leaving the Nomograph.

Printable: Need a hard copy to take with you? Simply right-click and select 'print'.

Aldrich.com/nomograph

Stockroom Reagents

Need a Molarity Calculator for your Acid/Base solutions?

Aldrich Normality and Molarity Calculator

Features• Calculates molarity for known acids and bases

• Calculates solutions of a solid reagent

• Dilutes a solution of known molarity

• Gets results at the click of a button

• Runs on your iPhone® and iPad® mobile digital devices

Benefits• Saves time over hand calculations

• Increases accuracy of calculations

Easy-to-Use 1. Select Acid or Base from drop down menu

2. Density, FW, and Wt. % will auto-populate

3. Input desired volume and concentration

4. Click on “Calculate”

Add Aldrich to save time and access the Normality and Molarity Calculator atAldrich.com/calculator

iPhone and iPad are trademarks of Apple Inc., registered in the US and other countries. 76070

76070 ALD Molarity Calc ad_R.indd a 7/29/2011 2:22:51 PM

TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com

26

Labware NotesPaula FreemantleProduct Managerlabware@sial.com

Aldrich® Rotary Evaporator Replacement Glassware•Cross-referenced with Buchi part numbers

•Plastic-coated and uncoated versions

•Jointed flasks compatible with most evaporators

This heavy-duty glassware is designed to fit Buchi rotary evaporators and is cross-referenced with Buchi part numbers to aid in selection. The condensers and flasks are available in non-coated glass for maximum resistance to solvents and heat, and with poly coating for extra protection from breakage. The jointed flasks and splash-guard adapters will fit most brands of rotary evaporators. Note that 35/20 and 35/25 spherical joint components are interchangeable.

Premium quality glassware, widest range, low cost

•Condenser Assemblies and Components

•Drying Flasks with Indents

•Evaporating Flasks, Pear-Shape

•Large Evaporator Flasks

•Receiving Flasks Adapters

•Receiving Flasks

•Splash Guard Adapters

•Vapor Duct Tubes

To see the complete range of products or to place orders, visit Aldrich.com/evapglass

Z682055

Z515515

Z549193

Z682187

Z682713

Z682829

Z682918

Z682411

Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.

27Labware Notes

News and Innovation

Aldrich® FKM sleeve stopper septaThese new septa are made from fluoroelastomer FKM which is highly resistant to a broad range of solvents. An elastomer study done at Sigma-Aldrich compared the solvent compatibility (resistance) of FKM and EPDM rubber (Figure 1). A Sealability Factor was determined for each elastomer. The lower the number the more compatible the rubber is with a solvent.

Z569941 10/30 jointsZ569968 14/20 joints, 2, 4, and 8 oz Aldrich bottlesZ569976 15/25 joints, 10, 32, 40 oz, 1 L Aldrich bottles,

125 mL, 1 L Sure/Seal bottlesZ569984 24/40 joints, 64, 80 oz, and 1 gal Aldrich jugs

Aldrich Rotary Evaporator Adapter SetThis versatile adapter connects jars and bottles to the vapor tube of a rotary evaporator. Precision machined from durable, chemically inert glass-filled PTFE. The unique, “universal fit” threaded connection adapts to any suitable cap. Simply insert the threaded shaft of the adapter through a 16 mm diam-eter holed cap and secure by hand-tightening the PTFE gasket and nut. Attach the other end of the adapter to the vapor tube via standard taper joint and clip. Set includes one 58 x 400 mm diameter holed cap and a solid top cap with PTFE liners, and a 200 mL borosilicate glass jar.

Z723169-1EA 24/40 joint Z723177-1EA 29/32 joint

Julabo® Economy Series Refrigerated/Heating Circulators•Compact design

•Temp. range -20 to 100 °C

•0.35 bar pump pressure

•15 L/min pump flow

•Cooling capacity 120 W, at 0 °C

•200 W, at 20 °C

•Heater capacity 2 kw

•Bath opening W × L × D 15 cm × 16 cm × 13 cm

•Overall W × L × H 20 cm × 36 cm × 56 cm

•Volume 4.5 L

Z557285-1EA 115 VAC Z653209-1EA 230 VAC

Figure 1

Sealability FactorThe lower the number the higher the compatibility

0500

10001500200025003000350040004500

Diethyl ether

Dichloromethane

Benzene

Cyclohexanes

Diisopropylamine

Fluoroelastomer FKM

EPDM rubber

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