Syntheses, Crystallization, and Spectroscopic Characterization of 3,5-Lutidine N-Oxide Dehydrate

Summary

Herein, we report the synthesis and crystallization of 3,5-lutidine N-oxide dehydrate by a simple protocol that differs from the classical synthesis of pyridine N-oxide. This protocol utilizes different starting material and involves less reaction time to yield a new solvated supramolecular structure, which crystallizes under slow evaporation.

Abstract

The synthesis of 3,5-lutidine N-oxide dehydrate, 1, was achieved in the synthesis route of 2-amino-pyridine-3,5-dicarboxylic acid. Ochiai first used the methodology for non-substituted pyridines in 1957 in a 12 h process, but no X-ray suitable crystals were obtained. The substituted ring used in the methodology presented here clearly influenced the addition of water molecules into the asymmetric unit, which confers a different nucleophilic strength in 1. The X-ray suitable crystal compound 1 was possible due to the stabilization of the negative charge in the oxygen by the presence of two water molecules where the hydrogen atoms donate positive charge into the ring; such water molecules serve well to construct a supramolecular interaction. The hydrated molecules may be possible for the alkaline system that is reached by adjusting the pH to 10. Importantly, the double methyl substituted ring and a reaction time of 5 h, makes it a more versatile method and with wider chemical applications for future ring insertions.

Introduction

Nowadays, scientists around the globe have been investing resources into the development of new synthetic routes for the functionalization of aromatic groups, which are known for low reactivity front to addition reactions^1,2,3. Pyridine, where a nitrogen atom substitutes a carbon atom, presents a similar chemical reactivity to analogue rings composed solely of carbon atoms³, and it usually undergoes a substitution mechanism rather than addition. N-oxides are distinctive by the presence of a donor bond between nitrogen and oxygen formed by the overlap of the nonbonding electron pair on the nitrogen with an empty orbital on the oxygen atom³. Particularly, pyridine N-oxides are Lewis bases, because their N-O moiety may act as an electron donor, and they may combine with Lewis acids forming the corresponding Lewis acid-base pairs. This property has an essential chemical consequence, because it can increase the nucleophilicity of the Lewis acids towards potential electrophiles and thus allow them to react under conditions where normally the reaction would not occur. Probably the most frequent use of such compounds is in various oxidation reactions where they act as oxidants⁴. Pyridine N-oxides and many of their ring-functionalized derivatives are recurrent molecules of biologically active and pharmacological agents⁵, and a clear spatial distribution by different spectroscopic tools has been established for some of them^6,7. In research on attaching different groups to the pyridine ring, scientists have tested various methodologies to produce an easy and conventional method, since isoxazolines requires a catalytic amount of base such as DBU in boiling xylene to form 6-substituted-2-aminopyridine N-oxides^8,9. A variety of pyridine derivatives were converted into their corresponding N-oxides in the presence of a catalytic amount of manganese tetrakis(2,6-diclorophenyl)porphyrin and ammonium acetate in CH₂Cl₂/CH₃CN^8,10. Other pyridines are oxidized to their oxides using H₂O₂ in the presence of catalytic amounts of methyltrioxorhenium^8,11, or by the addition of excess dimethyldioxirane in CH₂Cl₂ at 0 °C, which leads to the corresponding N-oxides^8,12,13,14. Bis(trimethylsilyl)peroxide in the presence of trioxorhenium in CH₂Cl₂ has been used for the synthesis of pyridine N-oxides^8,11. The synthesis of aminopyridine N-oxides involving acylation using Caro's acid (peroxomonosulfuric acid) has also been reported⁸. Nevertheless, the methodology reported here, and which uses part of the methodology reported by Ochiai¹, provides very good results with the use of cheaper and accessible reagents, H₂O₂ and glacial acetic acid. This practice is more suitable for use in large scale preparations that act on tertiary amines, it produces good yields in a reaction that only requires 30% hydrogen peroxide and glacial acetic acid in a temperature between 70-80 °C, and it uses a purification process that is available in most synthesis laboratories like distillation, without the use of catalyst or more expensive reagents¹. The literature reports that other methodologies also frequently involve time frames from 10-24 h and temperatures above 100 °C ^4,8, and the yield of well-formed crystals for X-ray analyses is rarely reported.

Reactively, various N-oxide derivates are used to adequately activate the lutidine ring, in either a nucleophilic or electrophilic way. The nucleophilic or electrophilic factor is affected by the substituents. With the pyridine ring being the electron-withdrawing groups, the main factor is the nucleophilic characteristic¹. The free N-oxide compounds are rarely isolated as suitable crystals for X-ray analysis due to the delocalized charge in the aromatic ring. However, the solvation factor is critical to stabilize the negative density of the oxygen¹⁵.

Protocol

1. Reaction

1. Place in a fume hood an opened round 100 mL flask with 0.5 mol (29.8 mL) glacial acetic acid and add 0.051 mol (5.82 mL) of 3,5-dimethylpyridine and 5 mL of H₂O₂ (35%). Keep the mixture reaction under constant magnetic stirring, at an inner temperature of 80 °C for 5 h.
2. After the reaction time, cool the flask to 24 °C with ice (do not expose the acetic acid gases to the ice), and plug it to a high vacuum distillation unit for 90-120 min to remove excess acetic acid.
   Caution: Do not use hot material. Wait until the glassware reaches a manageable temperature. This will also avoid vapors entering the top of the distillation unit.
3. Add distilled water (10 mL) twice to ensure the removal of any trace of acetic acid and to concentrate the mixture much as possible.

2. Basicity Adjustment and Extraction

1. Dissolve in bi-distillated water the isolated viscous and transparent product and use a potentiometer to adjust the pH to 10 with pure solid Na₂CO₃.
2. Place carefully the solution in a 250 mL separation funnel and extract it 5 times with 250 mL of CHCl₃ to improve the yield. Recover the organic layer and dry it over solid Na₂SO₄ for 30 min maximum, which will contain the product. If necessary, re-extract the aqueous phase with the desired amount of CHCl₃.
   Caution: CHCl₃ may cause drowsiness and dizziness; handle with care and inside a fume hood.
3. Remove the solvent under reduced pressure with a high vacuum distillation unit, until the formation of a very hygroscopic clear beige crystalline powder (70%).

3. Crystallization Process

1. Dissolve 4.3 g of the crystalline powder in 50 mL of cold high performed liquid chromatography (HPLC) grade diethyl ether. Vacuum filter the solution to remove any trace of solid starting material or even dust. Pour the filtrate into a glass Petri dish, leaving it to slow evaporate at 4 °C in a laboratory fridge.
2. Ensure that after two days, clear colorless crystals are obtained. Then measure the melting point, which should be in the range of 310-311 K.

4. Analysis of 3,5-Lutidine N-oxide Dehydrate

1. Remove the crystals that are formed, of prismatic shape and colorless, by decantation from the flask's walls for further X-ray analysis. If not immediately used, keep the crystals in diethyl ether to avoid crystal hydration.
2. Dissolve 0.010 g of 3,5-lutidine N-oxide dehydrate in 0.4 mL of CDCl₃ to perform NMR H¹ and C¹³ analysis to prove the effectiveness of the procedure.

Results

The protocol is essentially an extension of Ochiai's technique¹. However, lower temperature and less time are applied. This simple method can be used to obtain a versatile ligand, which is a substituted pyridine N-oxide derivate. To confirm the formation of 1, NMR ¹H and ¹³C analysis are preferred to test the effectiveness of the procedure.

The chemical shif...

Discussion

The protocol presented here is a conventional method to link an oxygen atom to the nitrogen atom of the 3,5-lutidine as a functionalization method of substrates. This technique is also well established to yield X-ray suitable dehydrated crystals (Figure 5, pictures taken with a DSC-HX300 Cyber-shot Sony camera). As far as we are concerned, not many reports have described the production of such crystals¹⁶. Many compounds grow ideal crystals for X-ray analysis when they are chelated...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
3,5-lutidine	Sigma-Aldrich	L4206-500ML
Glacial acetic acid	Fermont	3015
Hidrogen peroxide (35%)	Sigma-Aldrich	349887-500ML
Na2CO3 anhydrous	Productos Químicos Monterrey	1792
Na2SO4 anhydrous	Alfa reactivos	25051-C
CHCl3	Fermont	6205
Ethyl eter	Mercury Chemist	QME0309
Distilled water	Comercializadora Química Poblana	not-existent