1. INTRODUCTION:

Vilsmeier-Haack (VH) reaction is a method for acetyl or formyl group introduction onto organic compounds [1-7]. Formylated anilines are known for their various biological activities [8-11]. Green chemistry methods are simple and economically feasible [12-25]. Vilsmeier–Haack Bromination of Aromatic Compounds with KBr and N-Bromosuccinimide [26], benzamide and oxychloride using green mediated approaches was reported [27,28]. Surfactants and non conventional energy [29, 30] in the present investigation was investigated to achieve formylation of certain phenols with Vilsmeier-Haack reagents under solvent free conditions. These were also performed to explore the possibility to achieve formylation of certain phenols with Vilsmeier-Haack reagents using ultra sonics.

2. EXPERIMENTAL DETAILS:

The substrates and solvents were purchased from Aldrich or Merck.

2.1 General Procedure for Vilsmeier-Haack Synthesis in solvent free condition:

A centimolar (0.01mol) organic substrate (Phenols) and about 0.015 moles of VH reagent were taken in a previously cleaned mortar and grounded for about 20 t0 30 minutes. After completion of the reaction, as checked by TLC, the reaction mixture is treated with 5% sodium thio sulphate solution, followed by the addition of pet ether. The organic layer was separated, dried over Na₂SO₄ and evaporated under vacuum, purified with column chromatography using chloroform: n-hexane (8:2) as eluent to get pure product. This methodology has also been successfully used in both formylation reactions.

2.2 General Procedure for Vilsmeier-Haack Synthesis in microwave condition:

A centimolar (0.01mol) organic substrate (Phenols) and about 0.015 moles of VH reagent were taken in a previously cleaned beaker for about 2 t0 3 minutes. After completion of the reaction, as checked by TLC, the reaction mixture is treated with 5% sodium thio sulphate solution, followed by the addition of pet ether. The organic layer was separated, dried over Na₂SO₄ and evaporated under vacuum, purified with column chromatography using chloroform: n-hexane (8:2) as eluent to get pure product. This methodology has also been successfully used in both formylation reactions.

2.3. General Procedure for Vilsmeier-Haack Synthesis in ultrasonic radiation:

A centimolar (0.01mol) organic substrate (Phenols) and about 0.015 moles of VH reagent were taken in a previously cleaned conical flask for about 30 t0 45 minutes. After completion of the reaction, as checked by TLC, the reaction mixture is treated with 5% sodium thio sulphate solution, followed by the addition of pet ether. The organic layer was separated, dried over Na₂SO₄ and evaporated under vacuum, purified with column chromatography using chloroform: n-hexane (8:2) as eluent to get pure product. This methodology has also been successfully used in both formylation reactions. The reaction proceeds through scheme 4 and the results were cited in table 4.

3. RESULTS AND DISCUSSION:

Aromatic compounds such as Phenols derivatives underwent formylation under Vilsmeier- Haack conditions in good yields when treated with DMF/SOCl₂ under solution phase under classical conditions and sonicator and as well as solvent free conditions when the reactants are grounded in a mortar with a pestle for about 20-30 min. and in microwave for about 30 secs to 1 min. Phenols are used as substrates under different reaction conditions are shown as in Schemes –1 to 4. Tables1 to 4 show the yields obtained using different methods.The products were characterized by ¹H-NMR spectroscopy.

Scheme 1:

The reaction proceeds through scheme 2 and the results were cited in table 2. The reaction proceeds through scheme 3 and the results were cited in table 3. Good yields were obtained over corresponding solution phase reactions. The reaction is completed in 20-30 min under solvent free conditions in mortar and pestle and where as in microwave for only 30 secs to 1 min. where as in ultra sonics it took about 30 to 45 mins. Hence this green methodology could be employed in different VH reactions. The present finding is more advantageous over solution phase reaction. It is conducted with economically cheap and readily available reagents. Far less reaction times (about 12 times less than thermal reactions) coupled with enhanced reaction yields substantiate that the present work is very novel in the area of Vilsmeier-Haack synthesis.

Table 1: Vilsmeier Haack Formylation Reactions with organic substrates (SOCl₂+DMF) in Solution phase Conditions

S.No.	SUBSTRATE	PRODUCT	Formylation
S.No.	SUBSTRATE	PRODUCT	at 60⁰C (Hrs)	Yield %
1	phenol	4- hydroxybenzaldehyde	6	87
2	p-cresol	2-hydroxy-4-methylbenzaldehyde	6	78
3	o-chloro phenol	4-hydroxy-3-chlorobenzaldehyde	6	74
4	p-Chloro- phenol	2-hydroxy-5-chloro benzaldehyde	6	72

Table 2: Vilsmeier Haack Formylation Reactions with organic substrates (SOCl₂+DMF) in Solvent less Conditions

S.No.	SUBSTRATE	PRODUCT	Formylation
S.No.	SUBSTRATE	PRODUCT	RT (mins)	Yield %
1	phenol	4- hydroxybenzaldehyde	30	67
2	p-cresol	2-hydroxy-4-methylbenzaldehyde	30	64
3	o-chloro phenol	4-hydroxy-3-chlorobenzaldehyde	30	68
4	p-Chloro- phenol	2-hydroxy-5-chloro benzaldehyde	30	64

Table 3: Vilsmeier Haack Formylation Reactions with organic substrates (SOCl₂+DMF)under Microwave conditions

S.No.	SUBSTRATE	PRODUCT	Formylation
S.No.	SUBSTRATE	PRODUCT	800w (secs)	Yield %
1	phenol	4- hydroxybenzaldehyde	30	78
2	p-cresol	2-hydroxy-4-methylbenzaldehyde	30	80
3	o-chloro phenol	4-hydroxy-3-chlorobenzaldehyde	30	96
4	p-Chloro- phenol	2-hydroxy-5-chloro benzaldehyde	30	81

Table 4: Vilsmeier Haack Formylation Reactions with organic substrates (SOCl₂+DMF)in ultra sonic Conditions

S.No.	SUBSTRATE	PRODUCT	Formylation
S.No.	SUBSTRATE	PRODUCT	RT (mins)	Yield %
1	phenol	4- hydroxybenzaldehyde	6	87
2	p-cresol	2-hydroxy-4-methylbenzaldehyde	6	78
3	o-chloro phenol	4-hydroxy-3-chlorobenzaldehyde	6	74
4	p-Chloro- phenol	2-hydroxy-5-chloro benzaldehyde	6	72

Table 5: Spectral Details of Vilsmeier Haack Formylation products obtained with organic substrates (SOCl₂+DMF) under solvent free conditions and solvent conditions

S.No	Substrate	Product	M⁺	IR(cm^-1)	NMR
1.	phenol	4-hydroxy-benzaldehyde	122	1650 (C=O)	d 9.8 (s, 1H, CHO) δ 5.14(s,1H,OH) δ6.8-7.9 (dd,4 H, Ar)
2.	p-cresol	2-hydroxy-4-methylbenzaldehyde	136	1690 (C=O)	d 9.9 (s, 1H, CHO) δ 5.10(s,1H,OH) d 2.55 (s, 3H, CH₃ ), δ7.94 (s, 1H, Ar ) δ 8.90 (d, 1H, Ar ) δ 8.40 (d, 1H, Ar )
3.	o-chlorophenol	4-hydroxy-3-chloro benzaldehyde	156	1680 (C=O)	d 9.8 (s, 1H, CHO) δ 5.14(s,1H,OH) δ7.94 (d, 1H, Ar ) δ 8.90 (d, 1H, Ar ) δ 7.80 (d, 1H, Ar )
4.	p-Chloro- phenol	2-hydroxy-5-chloro benzaldehyde	156	1670 (C=O)	d 9.8 (s, 1H, CHO) δ 5.12(s,1H,OH) δ 7.74 (s, 1H, Ar ) δ 8.90 (d, 1H, Ar ) δ 8.80 (d, 1H, Ar )

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Received on 28.11.2017 Modified on 29.01.2018

Asian J. Research Chem. 2018; 11(2):409-412.

DOI:10.5958/0974-4150.2018.00074.3