MONITORING FLUORINATIONS......Selective direct fluorination for the synthesis of 2-fluoromalonate esters

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Optimisation and real time reaction monitoring of the synthesis of 2-fluoromalonate esters by direct fluorination using fluorine gas is reported. An assessment of green metrics including atom economy and process mass intensity factors, demonstrates that the one-step selective direct fluorination process compares very favourably with established multistep processes for the synthesis of fluoromalonates.





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 Scheme 2 Synthetic routes to 2-fluoromalonate esters.

There are three realistic, low-cost synthetic strategies available for the large scale manufacture of diethyl 2-fluoromalonate ester (Scheme 2) which involve reaction of ethanol with hexafluoropropene (HFP), halogen exchange (Halex)and selective direct fluorination processes. Other syntheses of fluoromalonate esters using electrophilic fluorinating agents such as Selectfluor™ are possible, but are not sufficiently commercially attractive to be considered for manufacture on the large scale.

A growing number of patents utilising fluoromalonate as a substrate for the synthesis of a range of biologically active systems have been published  For example, Fluoxastrobin (Fandango®), a fungicide marketed by Bayer CropScience that has achieved global annual sales of over €140 m since its launch in 2005, and TAK-733, an anti-cancer drug candidate, employ 2-fluoromalonate esters as the key fluorinated starting material (Scheme 1).

Scheme 1 2-Fluoromalonate esters used in the synthesis of Fluoxastrobin and TAK-733.

 Before a comparison of the green metrics between the three possible, economically viable large scale processes for the synthesis of fluoromalonate esters (Scheme 2) could be carried out, some primary goals for the optimisation of the process were targeted: complete conversion of the starting material is essential because it can be difficult to separate the starting material from the desired monofluorinated product by simple distillation; fluorine gas usage should be minimised because neutralisation of excess reagent could potentially generate significant amounts of waste; reduction in volumes of solvents used to reduce waste streams and overall intensification of the fluorination process and replacement and/or reduction of all environmentally harmful solvents used.

Conventional batch direct fluorination reactions of malonate esters were carried out in glassware vessels by introduction of fluorine gas, as a 10% or 20% mixture in nitrogen (v/v), at a prescribed rate via a gas mass flow controller into a solution of malonate ester and copper nitrate catalyst in acetonitrile using equipment described previously.

To better understand the relationship between fluorine gas introduction and rate of conversion, real time IR spectroscopic monitoring of the reaction was chosen as the most suitable technique. The use of the ReactIR technique was enabled by a sufficient difference in the carbonyl group stretching frequencies (1734 cm⁻¹ for diethyl malonate and 1775 cm⁻¹ for diethyl 2-fluoromalonate) and provided an in situ reaction profile (Fig. 1).

	Fig. 1 IR spectra of the fluorination reaction at 0% (light blue), 50% (dark blue) and 100% (red) conversions.

The real time reaction monitoring (Fig. 1 and 2) revealed that the reaction begins instantly upon initiation of fluorine introduction and the reaction conversion is directly proportional to the amount of fluorine gas passed into the reaction vessel. When the intensity of the fluoromalonate carbonyl peak (1775 cm⁻¹) reached a maximum, the introduction of fluorine gas was stopped and the crude reaction mixture was analysed by ¹H and ¹⁹F NMR spectroscopy. Complete conversion of the starting material was observed and diethyl fluoromalonate was formed with 93% selectivity after introducing 1.1 equivalents of fluorine into the reaction mixture. The small excess of fluorine explains the unexpectedly small amount of difluorinated side products B and C (4.5 and 2.5% respectively) which were the major impurities (6.5 and 9% respectively) when larger excess of fluorine gas (1.8 eq.) was used.

	Fig. 2 In situ monitoring of the fluorination of diethyl malonate.

The effect of concentration of fluorine in nitrogen, reaction temperature, copper nitrate catalyst loading and concentration of malonate substrate in acetonitrile were varied to optimise the fluorination process (Table 1). Additionally, reactions described in Table 1 allowed an assessment of various factors that have a major influence on the environmental impact of the process such as solvent usage, reaction temperature and the amount and composition of waste generated. In each case 20 mmol (3.20 g) of diethyl malonate was used as substrate and the isolated mass balance of crude material obtained after work-up was recorded along with the conversion of starting material and yield of fluorinated products (Table 1).

Table 1 Fluorination of diethyl malonate ester using fluorine gas catalysed by Cu(NO₃)₂·2.5H₂O

Entry no.	T/°C	C malonate (mol L−1)	Catalyst (mol%)	F 2 in N2 (% v/v)	Conversion (1H NMR)	A/B/C ratio (19F NMR)	Isolated weight
1	0–5	1.0	10	10	100%	93.5/4.5/2	3.37 g
2	0–5	1.5	10	10	100%	94/4/2	3.30 g
3	0–5	1.0	5	10	97%	95/4/1	3.53 g
4	0–5	1.0	2.5	10	82%	95/4/1	3.51 g
5	RT	1.0	10	10	56%	97.5/1.5/1	3.33 g
6	0–5	1.0	10	15	85%	97.5/1.5/1	3.47 g
7	0–5	1.0	10	20	100%	94/3/3	3.50 g
8	0–5	2.0	5	20	52%	92/5/3	3.40 g

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In all cases, small quantities of side products were formed which were identified by ¹⁹F NMR and these originate from two different processes: 3,3-difluoromalonate is produced from enolisation of diethyl fluoromalonate which is much slower than enolisation of the diethyl malonate substrate, while the fluoroethyl fluoromalonate is postulated to form via an electrophilic process.

The data in Table 1 suggest that the concentration of the malonate ester substrate in acetonitrile has no apparent effect on the outcome of the reaction although solvent is required for these reactions because diethyl malonate does not dissolve the catalyst. Additionally, the use of high dielectric constant media, such as acetonitrile, have been found to be beneficial for the control of selectivity of electrophilic direct fluorination processes. For convenience, a 1.5 M concentration of malonate in acetonitrile was chosen as the optimal conditions which is approximately 5 mL solvent per 1 mL of diethyl malonate.

The concentration of fluorine gas, between 10–20% v/v in nitrogen, does not affect the selectivity of the reaction and the quality of the product either, as exemplified by the product mixtures obtained from reactions 1, 2 and 7 which have identical compositions. In contrast, carrying out fluorination reactions at room temperature rather than cooling the reaction mixture to 0–5 °C leads to increased catalyst decomposition which results in an insoluble copper species that on occasion blocked the fluorine gas inlet tube. In addition, without cooling, the exothermic nature of this fluorination reaction led to a slight reaction temperature increase (from 20 to 29 °C in a small scale laboratory experiment) resulting in loss of some solvent and some decomposition of the catalyst and product degradation.

Lowering the concentration of the copper nitrate catalyst led to a significantly slower reaction as would be expected and required the use of a larger excess of fluorine gas to enable sufficiently high conversion. For example, the reaction proceeded in the presence of only 2.5 mol% catalyst, but in this case 40% excess fluorine was required to reach 100% conversion.

Typical literature work-up procedures for direct fluorination reactions involve pouring the reaction mixture into 3 to 5 volumes of water and extracting the resulting mixture three times with dichloromethane. The combined organic fraction is typically washed with water, saturated sodium bicarbonate solution and dried over sodium sulfate before evaporation of the solvent to give the crude reaction product. We sought to improve the work-up to enable recycling of the reaction solvent and substitute the use of environmentally harmful dichloromethane in the reaction work-up stage. Upon completion of fluorine gas addition, acetonitrile was evaporated for reuse and then the residue was partitioned between ethyl acetate and water, the organic phase was washed with water, saturated Na₂CO₃ solution and saturated brine and dried prior to evaporation under reduced pressure. Modification of the workup procedure in this manner enables the recovery of acetonitrile and ethyl acetate and significantly reduces the amount of aqueous waste generated. When direct reuse of the recovered acetonitrile was attempted, a copper containing precipitate was formed presumably because of the high HF content of the solvent (0.63 M by titration). Therefore, before reuse of the solvent, HF must be removed. Stirring the recovered reaction solvent with solid Na₂CO₃ lowered the acid content to an acceptable level (0.04 M) and when a second fluorination reaction was carried out in the recovered, neutralised acetonitrile, no change in the fluorination reaction profile was observed.

Upon completion of these optimisation studies, selective fluorination reactions of malonate esters were scaled up to 40 g scale in the laboratory without experiencing any change in product profile. Isolation of significant quantities of monofluoromalonate A crude product (99% yield, 95% purity) was achieved which could be used in the subsequent cyclisation processes described below without further purification or, if high purity material was required, could be purified by fractional vacuum distillation (bp. 102–103 °C, 18 mbar) to produce 99% pure material in 77% yield.

Related malonate esters were also subjected to direct fluorination using the optimised conditions established above. In the case of di-tert-butyl malonate, fluorination was carried out on 12 g scale. 100% conversion was reached after the introduction of 1.2 equivalents of fluorine gas and the desired product was isolated in 96% yield. The purity of the crude product was higher than 97% by ¹H and ¹⁹F NMR spectroscopy without any further purification and as expected, the only side product was the 2,2-difluorinated product (Scheme 3).

	Scheme 3 Fluorination of di-methyl and di-tert-butyl malonates.

Diethyl fluoromalonate large scale fluorination

Diethyl malonate (40.0 g, 0.25 mol) and copper nitrate hydrate (Cu(NO₃)₂·2.5H₂O; 5.81 g, 25 mmol) were dissolved in acetonitrile (200 mL) and placed in 500 mL fluorination vessel, cooled to 0–5 °C and stirred at 650 rpm using an overhead stirrer. After purging the system with N₂ for 5 minutes, fluorine gas (20% v/v in N₂, 80 mL min⁻¹, 265 mmol) was introduced into the mixture for 6 hours and 30 minutes. The reactor was purged with nitrogen for 10 minutes, the solvent removed in vacuo and the residue partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous phase was extracted once more with ethyl acetate (50 mL) and the combined organic layers were washed with saturated NaHCO₃ (25 mL) and brine (20 mL). After drying over sodium sulfate, the solvent was evaporated to leave diethyl 2-fluoromalonate (44.4 g, 99% yield, 95% purity) as a light yellow, transparent liquid. This crude product was distilled to afford high purity fluoromalonate (34.7 g, 77% yield, 99%+ purity) as a colourless liquid, bp. 102–103 °C (18 mbar), (lit.: 110–112 °C, 29 mbar), spectroscopic data as above.........N. Ishikawa, A. Takaoka and M. K. Ibrahim, J. Fluorine Chem., 1984, 25, 203–212 CrossRef CAS.

PAPER

 REF

 http://pubs.rsc.org/en/content/articlehtml/2015/gc/c5gc00402k

http://pubs.rsc.org/en/Content/ArticleLanding/2015/GC/c5gc00402k#!divAbstract

DOI: 10.1039/C5GC00402K (Paper) Green Chem., 2015, 17, 3000-3009

Fluorine gas for life science syntheses: green metrics to assess selective direct fluorination for the synthesis of 2-fluoromalonate esters†

Antal Harsanyi and Graham Sandford *
Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK. E-mail: graham.sandford@durham.ac.uk

Received 19th February 2015 , Accepted 17th March 2015

First published on the web 17th March 2015

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Optimisation and real time reaction monitoring of the synthesis of 2-fluoromalonate esters by direct fluorination using fluorine gas is reported. An assessment of green metrics including atom economy and process mass intensity factors, demonstrates that the one-step selective direct fluorination process compares very favourably with established multistep processes for the synthesis of fluoromalonates.

Paper

Fluorine gas for life science syntheses: green metrics to assess selective direct fluorination for the synthesis of 2-fluoromalonate esters

Antal Harsanyi^a and   Graham Sandford*^a  

*Corresponding authors

^aDepartment of Chemistry, Durham University, South Road, Durham, UK
E-mail: graham.sandford@durham.ac.uk

Green Chem., 2015,17, 3000-3009

DOI: 10.1039/C5GC00402K

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Arginine thioacid in synthesis of arginine conjugates and peptides

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Protected arginine thioacid enables convenient N-acylation with no detectable racemization. We report efficient syntheses of potentially biologically active arginine conjugates and novel arginine-containing di-, tri- and tetrapeptides in good yields without loss of chiral integrity.

Arginine thioacid in synthesis of arginine conjugates and peptides

Ravil N. Khaybullin,*^a   Siva S. Panda,^a   Saeid Mirzai,^a   Ellen Toneff,^a   Abdullah M. Asiri,^bc   C. Dennis Hall*^a and   Alan R. Katritzky^ab  

*Corresponding authors

^aCenter for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, USA
E-mail: ravilx84@gmail.com, charlesdennishall@gmail.com
Tel: +1-352-392-0554

^bCenter of Excellence for Advanced Material Research, King Abdulaziz University, Jeddah, Saudi Arabia

^c

Department of Chemistry, King Abdulaziz University, Jeddah, Saudi Arabia

RSC Adv., 2014,4, 55210-55216

DOI: 10.1039/C4RA04897K

 http://pubs.rsc.org/en/content/articlelanding/2014/ra/c4ra04897k#!divAbstract






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Synthesis, characterization and reactivity of a six-membered cyclic glycerol carbonate bearing a free hydroxyl group

Five- and six-membered cyclic carbonates have recently become popular as starting materials for the synthesis of polycarbonates via ring opening polymerization or synthesis of environmentally friendly non-isocyanate polyurethanes. In many cases a five-membered glycerol carbonate has been used in these applications. However, the simplest derivative of glycerol, a six-membered cyclic glycerol carbonate (5-hydroxy-1,3-dioxan-2-one), has not been reported so far. In this work, for the first time, we report a procedure for the synthesis of this monomer from glycerol. The product was characterized by ¹H NMR, ¹³C NMR, and FTIR spectroscopy and X-ray diffraction measurements. Further, the synthesis of bis(2-oxo-1,3-dioxan-5-yl) sebacate, a biscyclic six-membered carbonate, was described. The reactivities of 5-hydroxy-1,3-dioxan-2-one and its biscyclic ester derivative were investigated. No ring opening polymerization of both the monomers was observed, instead an isomerization to appropriate five-membered cyclic carbonates occurred. Unfortunately, the protection of the hydroxyl group 2with an ester type substituent does not protect it against isomerisation

Synthesis, characterization and reactivity of a six-membered cyclic glycerol carbonate bearing a free hydroxyl group

M. Tryznowski,*^a   Z. Żołek-Tryznowska,^b   A. Świderska^a and  P. G. Parzuchowski^a  

*Corresponding authors

^aFaculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
E-mail: tryznowski@ch.pw.edu.pl

^bFaculty of Production Engineering, Warsaw University of Technology, Narbutta 85, 02-524 Warsaw, Poland

Green Chem., 2015, Advance Article

DOI: 10.1039/C5GC01688F.......http://pubs.rsc.org/en/Content/ArticleLanding/2015/GC/C5GC01688F?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Paweł Parzuchowski

Warsaw University of Technology Faculty of Chemistry ul. Noakowskiego 3, 00-664 Warszawa, Poland Phone: +48 22 234 7317. E-mail: pparzuch@ch.pw.edu.pl

faculty of Chemistry, Warsaw University of Technology, Noakowskiego

//////faculty of Chemistry, Warsaw University of Technology, Noakowskiego







 Mozambique • Inhambane

more.......
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Scheme 1
Control experiments.
The ubiquitous oxazoles have attracted more and more attention in both industrial and academic fields for decades. This interest arises from the fact that a variety of natural and synthetic compounds which contain the oxazole substructure exhibit significant biological activities and antiviral properties. Although various synthetic methodologies for synthesis of oxazols have been reported, the development of milder and more general procedure to access oxazoles is still desirable.

Initially, compound A, formed by the substitution reaction of 1a with 2a, which can be transformed following two pathways: (a) I⁺, generated by the oxidation of iodine, could oxidize A to radical intermediate B, which eliminates one molecular of CO₂ to generate radical C, which is further oxidized to imine Dor its isomer E. Subsequently, F is obtained by intramolecular nucleophilic addition of E. Finally, the desired product (3a) is given by deprotonation and oxidation of F; (b) G is formed from the oxidation of A. Then 3a is obtained through H, I, J, K following a process similar to path a.

Scheme 2
Plausible mechanism.

General procedure for the synthesis of polysubstituted oxazoles

1a (105.8 mg, 0.7 mmol), 2a (99.5 mg, 0.5 mmol), I₂ (50.8 mg, 0.2 mmol), DMA (2 mL) and TBHP (70% aqueous solution, 1 mmol) were placed in a tube (10 mL) and sealed with a thin film. Then the reaction mixture was stirred at 25°C for 4 h, heated up to 60°C and stirred at this temperature for another 4 h. After that, the resulting mixture was cooled to the room temperature, diluted with water, extracted with ethyl acetate. The organic phase was washed with saturation sodium chloride solution, dried and filtrated. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column separation (petroleum ether:ethyl acetate = 10:1) to give 3a(154.7 mg, 70%) as light yellow solid, mp = 70–72°C.
2,5-diphenyloxazole (3a) [1]
Synthesized according to typical procedure and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give light yellow solid (154.7 mg, 70%), mp = 70-72 °C.

1H NMR (300 MHz, CDCl3): δ 8.12-8.09 (m, 2 H), 7.72-7.69 (m, 2 H), 7.50-7.40 (m, 6 H), 7.35-7.24 (m, 1 H).

13C NMR (75 MHz, CDCl3): δ 161.3, 151.4, 130.4, 129.0, 128.9, 128.5, 128.1, 127.6, 126.4, 124.3, 123.6.

HRMS (APCI-FTMS) m/z: [M + H]+ calcd for C15H12NO: 222.0913, Found: 222.0911.

The scope of the reaction. Standard conditions: 0.7 mmol of amino acids (1a-1h), 0.5 mmol of2a-2j, 0.1 mmol of I₂, 1 mmol of TBHP, 2 mL of DMA, were stirred at 25°C for 4 h then slowly raised to 60°C for 4 h. Catalysts amount and isolated yields were based on 2.

Metal-free synthesis of polysubstituted oxazoles via a decarboxylative cyclization from primary α-amino acids

Yunfeng Li, Fengfeng Guo, Zhenggen Zha and Zhiyong Wang^*

• *Corresponding author: Zhiyong Wang zwang3@ustc.edu.cn

Zhiyong Wang

Department of Chemistry, Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China

Sustainable Chemical Processes 2013, 1:8  doi:10.1186/2043-7129-1-8
The electronic version of this article is the complete one and can be found online at:http://www.sustainablechemicalprocesses.com/content/1/1/8

ADDITIONAL SPECTRAL DATA FROM NET

WANG Zhiyong（汪志勇）

Ph.D., University of Science and Technology of China (USTC) (1992); M.S., USTC (1989); B.S., Anhui Normal University (1982).


Professor of Chemistry
Department of Chemistry
School of Chemistry and Materials Science
University of Science and Technology of China
Hefei, Anhui 230026, P. R. China
Tel: 86-551-63603185
Fax: 86-551-63603185
E-mail: zwang3@ustc.edu.cn
Personal Homepage:
http://staff.ustc.edu.cn/~zwang3/default.htm

• RESEARCH INTERESTS
  Research in our group will focus on the general areas of reaction development and chemical synthesis. Our studies will be driven by the discovery of new and useful catalysts. By virtue of the developed organic reactions various organic ligands are synthesized and used as probes in biological progress. Brief summaries of three research directions illustrating these objectives are shown below:
  1) The preparation of heterogeneous catalysts;
  2) The theoretical calculation for the mechanism of organic reactions;
  The application of organic ligands as probes or inhibitors to explore the molecular mechanism of HIV transcription.
  PUBLICATIONS
  http://www.researcherid.com/rid/F-7955-2010

  WANG Zhiyong, Professor

  Name: Zhiyong Wang（汪志勇） Born: June, 1962, Anhui, P. R. China Address: Department of Chemistry, University of Science and Technology of China, 230026 Hefei, P. R. China Tel: 86-551-63603185 Fax: 86-551-63603185 E-mail: zwang3@ustc.edu.cn EDUCATION AND RESEARCH EXPERIENCE 　1978-1982 B.S., Anhui Normal University 　1982-1986 Lecturer, South Anhui Agricultural College, China 　1986-1989 M.S., University of Science and Technology of China 　1989-1992 Ph.D., University of Science and Technology of China 　1992-1997 Lecturer, Associate Professor, University of Science and Technology of China 　1997-1999 Research Fellow, Tulane University & Brandeis University 　1999-Now Professor of Chemistry, University of Science and Technology of China RESEARCH INTERESTS 1) Organic reactions in aqueous media and development of synthetic methodology; 2) Supramolecular assembly under the control of organic ligands; 3) Drug design on the base of PCAF bromodomain. CURRENT RESEARCH PROJECTS 1) Organic reactions in water mediated by nano-metals and its application in asymmetric synthesis, National Natural Science Foundation (2004-2006) 2) Crystal Engineering under control of organic ligands, Foundation from Education Department of Anhui Province (2003-2005) REPRESENTATIVE PUBLICATIONS 1) C-F. Pan, M. Meze, S. Mujtaba, M. Muller, L. Zeng, J-M. Li, Z-Y. Wang,* M-M. Zhou* “Structure-Guided Optimization of Small Molecules Selectively Inhibiting HIV-1 Tat and PCAF Association” J. Med. Chem., 2007, 50, 2285 2) Y. Xie, Z-P. Yu, X-Y. Huang, Z-Y. Wang,* L-W. Niu, M-K. Teng, J. Li “Rational Design on the MOFs Constructed from modified Aromatic Amino Acids” Chem. Eur. J., 2007, 13, 9399 3) Z-H. Zhang, C-F. Pan, Z-Y. Wang* “Synthesis of chromanones: a novel palladium-catalyzed Wacker-type oxidative cyclization involving 1,5-hydride alkyl to palladium migration” Chem. Commun, 2007, 4686 4) Y. Xie, Y. Yan, H-H. Wu, G-P. Yong, Y. Cui, Z-Y. Wang*, L. Pan, J. Li “Homochiral Metal-organic Coordination Networks from L-Tryptophan” Inorg. Chim. Acta., 2007, 360,1669 5) Y. Xie, H-H. Wu, G-P. Yong,, Z-Y. Wang*, R. Fan , R-P. Li, G-Q. Pan, Y-C. Tian, L-S. Sheng, L. Pan, J. Li “Synthesis, Crystal Structure, Spectroscopic and Magnetic Properties of Two Cobalt Molecules Constructed from Histidine” J. Mol. Struct., 2007, 833, 88 6) Z-H. Zhang, Z-Y. Wang* “Diatomite-Supported Pd Nanoparticles: An Efficient Catalyst for Heck and Suzuki Reactions” J. Org. Chem., 2006, 71, 7485 7) Z-H. Zhang, Z-G. Zha, C-S. Gan, C-F. Pan, Y-Q. Zhou, Z-Y. Wang*, M-M. Zhou* “Catalysis and Regioselectivity of the Aqueous Heck Reaction by Pd(0) Nanoparticles under Ultrasonic Irradiation” J. Org. Chem., 2006, 71, 4339

Hefei, Anhui China

////Metal-free,  Synthesis,  Oxazoles,  Oxidation,  Decarboxylative cyclization,  α-amino acids

Synthesis of 2-dimethylaminomethyl-cyclohexanone hydrochloride

++

EtOH, HCl

Synthesis of 2-dimethylaminomethyl-cyclohexanone hydrochloride

Reaction type:	reaction of the carbonyl group in aldehydes, Mannich reaction
Substance classes:	ketone, aldehyde, amine
Techniques:	heating under reflux, stirring with magnetic stir bar, evaporating with rotary evaporator, filtering, recrystallizing, heating with oil bath
Degree of difficulty:	Easy

Equipment

	round bottom flask 25 mL			reflux condenser
	suction filter			suction flask
	heatable magnetic stirrer with magnetic stir bar			rotary evaporator
	exsiccator with drying agent			oil bath

Instruction (batch scale 100 mmol) 

Equipment 

100 mL round bottom flask, reflux condenser, Buechner funnel (Ø 5.5 cm), suction flask, 

heatable magnetic stirrer, magnetic stir bar, rotary evaporator, desiccator, oil bath 

Substances 

cyclohexanone (bp 156 °C) 9.82 g (10.3 mL, 100 mmol) 

paraformaldehyde (mp 120-170 °C) 3.60 g (120 mmol) 

dimethylammonium chloride 8.16 g (100 mmol) 

hydrochloric acid (conc.) 0.4 mL 

ethanol (bp 78 °C) 64 mL 

acetone (bp 56 °C) 180 mL 

Reaction 

9.82 g (10.3 mL, 100 mmol) cyclohexanone, 3.60 g (120 mmol) paraformaldehyde, 8.16 g 

(100 mmol) dimethylammonium chloride and 4 mL ethanol are filled in a 100 mL round 

bottom flask with reflux condenser and magnetic stir bar. 0.4 mL conc. hydrochloric acid are 

added and the mixture is heated under stirring for 4 hours under reflux. 

Work up 

The hot solution is filtered in a round-bottom flask and the solvent is evaporated at the rotary 

evaporator. The residue is dissolved in 20 mL ethanol under heating. At room temperature 

70 mL acetone are added to the solution. For complete crystallization the solution is stored 

over night in the freezer compartment. The crystallized crude product is sucked off over a 

Buechner funnel (Ø = 5.5 cm) and dried in the desiccator over silica gel. 

Crude yield: 15.6 g; mp 149-150 °C 

For further purification the crude product is again dissolved in about 40 mL ethanol under 

reflux and at room temperature 110 mL acetone are added. The crystallization is completed in 

the freezer compartment. The product is sucked off and dried in the desiccator. 

Yield: 14.7 g (76.7 mmol, 77%,); mp 156-157 °C 

Comments 

To verify a complete crystallization, the mother liquor is stored in the freezer compartment. 

No product should crystallize any further.

Simple evaluation indices

Atom economy		not defined
Yield		76	%
Target product mass		1.45	g
Sum of input masses		54	g
Mass efficiency		27	mg/g
Mass index		37	g input / g product
E factor		36	g waste / g product

1H-NMR: 2-Dimethylaminomethyl cyclohexanone hydrochloride
500 MHz, CDCl3
delta [ppm]	mult.	atoms	assignment
1.35	m	1 H
1.54	m	1 H
1.73	m	1 H
1.82	m	1 H
2.05	m	1 H
2.37	m	2 H	6-H (ring)
2.41	m	1 H
2.67	d	3 H	N-CH3
2.74	m	1 H
2.77	d	3 H	N-CH3
3.09	m	1 H	N-CH2
3.57	m	1 H	N-CH2
11.88	m	1 H	N-H
7.26			CHCl3

13C-NMR: 2-Dimethylaminomethyl cyclohexanone hydrochloride
125 MHz, CDCl3
delta [ppm]	assignment
24.70	C5
27.70	C3
33.88	C4
41.75	CH3
42.26	CH3
44.99	C6
46.69	C2
56.80	-CH2-N-
209.58	C1 (C=O)
76.5-77.5	CDCl3

IR: 2-Dimethylaminomethyl cyclohexanone hydrochloride
[Film, T%, cm-1]
[cm-1]	assignment
3068, 3020	N-H valence
2932, 2858	C-H valence
1698	C=O valence, ketone

http://kriemhild.uft.uni-bremen.de/nop/en/instructions/pdf/4008_en.pdf