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MAKARA, SAINS, VOL. 6, NO. 2, AGUSTUS 2002

THE NEW VARIANT OF THE SANDMEYER MODIFICATION REACTION BY IN-SITU GENERATED : SEMI-SYNTHESIS OF FROM

Wahyudi Priyono Suwarso and Aris Eka Utama

Jurusan Kimia, Fakultas Matematika dan Ilmu Pengetahuan Alam, Universitas , Depok, 16424

E-mail: [email protected]

Abstrak

Telah dilakukan modifikasi terhadap reaksi modifikasi Sandmeyer, dengan cara pembentukan formaldehida in- situ. Pembentukan formaldehida in-situ dilakukan melalui reaksi dalam dua fasa (fasa heterogen) antara 6,40 mL (0,10 mol) CH2Cl2 (fasa organik) dengan 40 mL 6,0 N larutan KOH-alkoholis (fasa air) dan 2,56 g tetrabutilammonium perklorat (sebagai katalis transfer fasa/PTC), pada suhu 400 C selama 4 jam.. Selanjutnya ke dalam campuran reaksi ditambahkan tetes demi tetes 5,9 mL guaiakol 1. Setelah penambahan guaiakol berakhir, reaksi dibiarkan berlanjut selama 1 jam, sehingga akan dihasilkan vanilil alkohol 10 sebanyak 25,3%., dalam bentuk kristal putih. Terhadap vanilil alkohol 10 yang dihasilkan, selanjutnya dilakukan reaksi oksidasi dalam dua fasa (fasa heterogen) dengan K2Cr2O7/H2SO4 pekat sebagai oksidator dan 18-crown -6 sebagai katalis transfer fasa, pada suhu ruang selama 5 jam., akan dihasilkan vanili 4 sebanyak 6,2% (dihitung dari substrat awal guaiakol 1).

Abstract

It has been carried out the modification of Sandmeyer modification reaction by in-situ generated formaldehyde. The in- situ generated formaldehyde has been performed via heterogeneous phase reaction between 6.40 mL (0.10 mol) CH2Cl2 as organic phase with 40 mL 6.0 N KOH-alcoholic solution as aqueous phase and 2.56 g tetrabutylammonium perchlorate as phase transfer catalyst (PTC) by 40o C for 4 hours. Furthermore, 5.9 mL (0.05 mol) guaiacol 1 is dropwised to add to the reaction mixture. After the addition of guaiacol 1 finished, then reaction is allowed to run for 1 hour, so that the white crystal of vanillil 10 can be produced in 25.3%. Followed by oxidation of vanillil alcohol 10 with mixture of K2Cr2O7/conc. H2SO4 solution as oxidator, and 18-crown ether-6 as phase transfer catalyst (PTC) in heterogeneous phase at the room temperature for 5 hours, can be afforded vanillin 4 in 6.2% (calculated from starting material 1).

Keywords: Guaicol, sandmeyer reaction, formaldehyde, vanillin

Introduction (glucovanillin) in the beans. Its is in the range of 2.0%. Vanillin can be found on the Since 100 years ago, vanillin has been used as in vanilla plant, especially from , and the foodstuff. Today vanillin is also still used as belongs to the family orchiedae. This species can grow very well in the region of Mexico, , Java flavoring in the foodstuff, for example as flavor in the -, candies-, ice cream- and biscuit industries. and Tahiti [1,2]. Vanillin is also used as perfumery based for soaps and [1]. Furthermore, since 1970, vanillin has The long and expensive processes in the vanillin been also used as intermediate for pharmaceutical extraction from vanilla beans, caused various qualities products, for example: aldomet, L-dopa and of vanillin products. Because in the last decade the trimethophin [2]. annually world demand of vanillin is always rapid increasing, therefore naturally vanillin can not cover In the nature, vanillin can be formed as those annually world demand. Based on the technological- and economical reasons, it is possible to

90 MAKARA, SAINS, VOL. 6, NO. 2, AGUSTUS 2002 91

OH OH OH OH

OCH3 OO OCH3 OCH3 OCH3 + NaOH (ox.) H2O/H + HOC CH

_1 HC CHO HO COONa O COONa

_234_ _

Figure 1. Semi-synthesis vanillin via Riedel reaction

flowed over the reaction. Subsequent OH OH hydrolysis of reaction product can be isolated vanillin 4, but unfortunately by this OCH3 OCH3 synthesis can be obtained isomers of KOH, CHCl3, vanillin (i.e. iso- and ortho vanillin, 5 and 6 , PTC respectively). d. Fries-rearrangement reaction [2,3,6]: _1 Fries-rearrangement reaction of guaiacyl CHO _4 acetate 7 catalyzed by Lewis acid, AlCl3, is reported to give good yield in vanillin 4. The oxidation of guaiacyl methyl keton 8 with p- Figure 2. Semi-synthesis vanillin via Reimer-Tieman nitrobenzene and decarboxylation reaction of vanillilformic acid 9 in dimethyl-p- toluidin can be resulted vanillin 4. e. Sandmeyer modification reaction [2,3]: conduct either semi- or/and full synthesis of vanillin. In this reaction, guaiacol 1 is reacted with Synthetical or unnatural vanillin has structure identic formaldehyde solution in acidic condition. with the natural vanillin, but rather different in its , The resulted vanillil alcohol 10 is then as well as its aroma, because in the natural vanillin oxidized with p-nitroso-N,N,-dimethylanilin contains another companied substances, so that the can be afforded vanillin 4. aroma of vanillin is more intens than the aroma of synthetical vanillin. As the most and cheap raw The actual Sandmeyer reaction [7] is a method to materials for the synthetical vanillin is lignosulfat, the synthesis aryl halides (F, Cl. Br and I) as well as aryl waste material from the industry [1]. nitril from anilin or its derivatives by diazotization of anillin or its derivatives with NaNO2/HCl. Subsequent Several methods for the synthesis of vanillin from reaction between intermediate diazobenzene or its guaiacol 1 are conducted via Riedel-, Reimer-Tieman- derivatives with Cu(I) halide or nitril can be produced and Gatterman reaction, Fries-rearrangement reaction, only one isomer halo or its derivatives as well as well as Sandmeyer modification reaction. as cyano benzene (benzonitril) or its derivatives. a. Riedel reaction [2,3]: In this reaction, guaiacol 1 is condensed with Normally, the organic reactions are carried out in the glyoxalic acid in the condition, homogenous phase, because in this phase the probability subsequent air oxidation and acidification of the substrates to meet or to collide with reactants are oxidation product, can be obtained vanillin 4. often, so that reaction can run smoothly. Otherwise, b. Reimer-Tieman reaction [4,5]: organic reaction can be done in the heterogeneous phase In this reaction, guaiacol 1 is reacted with (organic- and aqueous phase), for this reaction it is CHCl3 in base condition (KOH) and alcohol needed an capable agent to bring reactant from the () as co-solvent. To accelerate the aqueous- into organic phase, and then goes back to reaction, furthermore is used phase transfer aqueous phase. This agent connecting both phases is catalyst/PTC (i.e. 18-crown ether-6, called phase transfer catalyst (PTC). In order that a tetrabutylammonium perchlorate etc.). compound can be used as phase transfer catalyst, c. Gatterman reaction [2,3]: therefore this compound should have lipophylic- as well In this synthesis, guaiacol 1 is reacted with as hydrophilic skeleton or group in its structure. Phase hydrocyanic acid (HCN), whilst HCl gas is transfer catalyst can accelerate or make actually 92 MAKARA, SAINS, VOL. 6, NO. 2, AGUSTUS 2002

OH OH OH OH

OCH OCH OCH OHC OCH 3 3 3 3 1. HCN + + 2 . HCl g OHC 1 _ 5 6 CHO _ _ _4

Figure 3. Semi-synthesis vanillin via Gatterman reaction

OH OCOCH OH OH OH 3 OCH3 OCH3 OCH3 OCH3 OCH3 (CH3CO)2O AlCl3 (ox.) decarboxylation Pyridin dimethyl-- p toluidin

_1 _7 COCH3 CHO 8 O9 COOH _ _ _4

Figure 4. Semi-synthesis vanillin via Fries-rearrangement reaction

OH OH OH N(CH3)2

OCH3 OCH3 OCH3 HCHO, H+ p ---nitroso N,N dimethylanilin/HCl +

OH _1

CH2OH CHO NH2 4 _10_ _ __11

Figure 5. Semi-synthesis vanillin via Sandmeyer modification reaction

possible reaction between chemical species situated in e. higher yield of more pure products different phases. Typically, present in an aqueous f. easier workup medium or in solid form are g. modification of product selectivity reacted with substrates in organic, non polar solvent.. h. use of ordinary , PTC as a technique, provides many advantages which instead of aloxides, sodium amide, often include [8,9,10]: sodium hydride or other expensive bases a. milder reaction conditions because of enhanced rates and lower temperatures The type of phase transfer catalysts/PTC can be divided b. avoidance of conventional anhydrous into two groups [8,9,10]: solvents or expensives polar and protic 1. crown ether compounds, for example, 18- solvents crown ether-6 (18C6), dibenzo[18]-crown c. milder reaction conditions because of ether-6 (DB18C6), 15-crownether-5 enhanced rates and lower temperatures (15C5) etc. d. avoidance of conventional anhydrous 2. Quarternary -, phosphonium- solvents or expensives polar and protic and arsonium salts, for example, solvents tetrabutylammonium perchlorate, MAKARA, SAINS, VOL. 6, NO. 2, AGUSTUS 2002 93

_ + - NH2 NN Cl Cl

NaNO / HCl 2 CuCl

__12 __13 __14

CuCN,

CN

_15_

Figure 6. The actually Sandmeyer reaction

O O

O O O O OO

OO OO O O

O O O

18 _ crown ether _ 6 6 _ _ _ (18C ) dibenzo[18 ] crown ether 6 (DB18 6 ) 15 crown ether_ 515( 5 C C )

Figure 7. Example of Crown

_ + CE++ P S CER N organic phase where: CE = crown ether

RN = reactant_ + interphase CER N = complex between CE and RN _ S = substrate CE + RN CER+ N aqueous phase P = reaction product

Figure 8. The mode action of crown compounds in the phase transfer catalytic process

tetraphenylammonium bromide etc. transfer catalytic process generally can be described as follows [8,9,10]: The mode action of crown compounds in the phase

94 MAKARA, SAINS, VOL. 6, NO. 2, AGUSTUS 2002

The crown compounds are a compound that has a hole cavity in the center of . The diameter of hole or phoshonium (Q+X-) the positive charge of molecule cavity of crown compound depends on the size of crown is already existing, so that its anion should be compound, for example, 18-crown ether-6 (18C6) and interchanged with anion of reactant (RN). The next step 15-crown ether-5 (15C5) has cavity diameter of 2.6 – for the catalyzing process alikes as for above described 3.2 Ao and 1.7 – 2.2 Ao, respectively. The certain crown compound. cathion that has diameter range closed to the diameter cavity of certain crown compounds can fill in or enter Application of this phase transfer to the type of precise in the cavity of these certain crown compound.. organic reaction as follow [8,9,10]: For example, K+ has cationic diameter of 2.66 Ao, can 1. substitution reaction fill good the cavity of 18-crown ether-6 (18C6), with a. simple nucleophilic displacement cavity diameter of 2.6 – 3.2 Ao , whereas Na+ with reactions, i.e. –S, -O, -N and C cathionic diameter of 1.90 Ao can be strong bonded by alkylation 15-crown ether-5 (15C5). The complex of macrocyclic b. nucleophilic aromatic substitution (SN) + - with cathion (CER N ) could still bind its anion in c. electrophilic aromatic substitution (SE) aqueous phase , and brings it to flash past the interphase 2. addition and condensation reaction into organic phase to react with substrate producing of 3. elimination reaction (E) reaction product (P). After reaction in organic phase 4. organometalic reaction takes place, then the complex of macrocyclic with 5. oxidation- and reduction reaction cathion could go back to flash past the phase border 6. micellaneous reaction (interphase) into aqueous phase. Thus, above mentioned processes are repeatedly again until no more substrate in Experimental Procedures organic phase presents. a. Synthesis vanillil alcohol 10 from guaiacol 1 The mode action of the onium salts (ammonium, Into three neck reaction flask equipped with phosphonium and arsonium) can be shown in this magnetic stirrer, Liebig cooler and thermometer are following picture [8,9,10]: placed 15.0 mL CH2Cl2, 40.0 mL solution of 6.0 M KOH-alcoholic and 2.56 g (0.015 mol) tetrabutylammonium perchlorate (TBAP). In opposite with crown compound, by the crown The mixture is stirred, if possible with velocity compound, first, cathion should be formed with a more than 750 rpm, and the condition of the presenting cathion, but in the quaternary ammonium or reaction flask is made in the (N2) atmosphere by flowing N2-gas into reaction flask. The reaction temperature is kept at 40o C for 4 hours, and then 5.9 mL (0.05 mol) guaiacol 1 is dropwised into mixture. After the last dropping of guaiacol 1, then the reaction is kept running for one hour. After the reaction finished, then cooled down to the room temperature, and acidified with HCl solution. The formed precipate is separated from its solution by decantation, and filtrate is then 3 times extracted with 20.0 mL CHCl3. The organic

fraction is dried over anhydrous Na2SO4, filtered off, and the dried solvent is vaporized under reduced pressure until Figure 9. Molecular model of 18C6 and its potassium Complex

+ + _ Q + P S + Q N organic phase where: Q+ = onium salt RN = reactant interphase RX = interchange between _QX and RN + Q N = new complex between + + _ onium salt and reactant QRN+ RX + Q N aqueous phase

Figure 10. The mode action of onium salts in the phase transfer catalytic process

MAKARA, SAINS, VOL. 6, NO. 2, AGUSTUS 2002 95

the over saturated condition is reached. The over the of OH-group of chloromethanol could be saturated solution is allowed to crystallize at room abstracted by hydroxyl ion (OH-), and at the same time temperature, until the white crystal of vanillil the chlor anion (Cl-) could leave the molecule alcohol 10 formed. The white crystal of vanillil (elimination process) to form formaldehyde, as shown alcohol 10 is then dried in the desiccator. in the Figure 13: b. Oxidation of vanillil alcohol 10 to vanillin 4 Into three neck reaction vessel equipped with In this reaction, tetrabutylammonium perchlorate used magnetic stirrer, Liebig cooler and thermometer are as phase transfer catalyst played importance role to - placed 1.18 g K2Cr2O7 in 10 mL H2O, 5.0 mL bring the hydroxyl ion (OH ) from aqueous phase into concentrate H2SO4 and 0.8 g 18-crown ether-6. The organic phase, so that this anion could react with reaction mixture is stirred with velocity more than CH2Cl2 as intermediate substrate as well as organic 750 rpm for one hour, and then solution of 1.54 g solvent to form formaldehyde. The reaction between in (0.01 mol) vanillil alcohol 10 in 20 mL CHCl3 is situ generated formaldehyde with guaiacol 1 could be dropwised into the mixture, whilst the reaction classified as electrophilic aromatic substitution reaction temperature is kept to room temperature. After last (SE). As the results from the negative mesomeric or drooping of vanillil alcohol solution, the reaction is conjugate (-M) effect of phenoxyl group is stronger than allowed running for 5 hours. After the reaction negative mesomeric effect of phenolic- as well as finished, then neutralized with 3.0 M KOH-solution methoxyl group in the guaiacol 1, so that this phenoxyl (controlled by universal pH-paper indicator). The group could activate the benzene ring to the formed precipate is separated from its solution, and electrophilic aromatic reaction, and dirigents the the solution is extracted 2 times with 20 mL CHCl3. entering electrophil (formaldehyde) into the ortho- The organic phase is then dried over Na2SO4 or/and para position from the position of phenoxyl anhydrous, filtered off, and the solvent is group. The activated benzene ring could be stabilized by evaporized under reduced pressure until the over its structure resonans toward the electrophilic saturated condition reached. The over saturated substitution reaction. solution is then allowed to crystallize at room temperature until the formation of a white crystal with specific aroma of vanillin 4. By the regulation of reaction temperature can be achieved the needed reaction product, so that by this Result and Discussion reaction, the reaction temperature is kept to allow by 40o C with the aim that electrophil (formaldehyde) should In situ generated formaldehyde from CH2Cl2 and KOH enter into para position, because first, para position has solution as well as catalyzed by phase transfer catalyst lower energy than ortho position, and second, para represented two steps of reaction. The first step of this position has smaller steric hindrance as well as wider reaction is called as a nucleophilic bimolecular reaction space than ortho position. Also by this reaction could be - (SN2) between CH2Cl2 and hydroxyl anion (OH ) [7]. obtained p-hydroxymethyl guaiacol or vanillil alcohol CH2Cl2 is weak acid and weaker than CHCl3, 10 as a major product after acidification with acid eventhough one of its chlor atom (Cl) can be replaced solution. Vanillil alcohol 10 is white crystal with o o by hydroxyl ion (OH-) under phase transfer catalysis to of 115 C (Lit.[2]: 116 C), and the yield form the chloromethanol The second step of this of this product is 25.3%. Its IR-spectrum showed reaction is bimolecular elimination reaction (E2). existence of strong band of OH-group. From (CH3OH) has base property, but if into this benzylalcohol in comparison with the band of OH- molecule is introduced one chlor atom, then its base group in the guaiacol 1. property could change into weak acid property, so that

H H HH H H - - C Cl + OH HO C Cl HO C + Cl Cl Cl Cl

Figure 11. The first step of proposed mechanism of the modified Sandmeyer modification reaction

96 MAKARA, SAINS, VOL. 6, NO. 2, AGUSTUS 2002

+ The last step reaction in this work is oxidation reaction because K2Cr2O7/H has stronger oxidazing power than of vanillil alcohol 10 to vanillin 4. In the previous work KMnO4 [11], it was successful to cleavage oxidize the propenyl The reaction temperature is kept to the room group in the 16 into functional temperature with the aim to prevent the formed group of vanillin 4 with neutral KMnO4 solution by aldehyde group not to subsequent oxidize to carboxylic using 18-crown ether-6 as phase transfer catalyst for this group (). The formation of aldehyde group oxidation reaction in the heterogeneous phase condition. can be viewed at its IR- spectrum by appearance of -1 KMnO4 as strong oxidator can be used in the three strong band at ν = 1674 cm , indicated the vibration of + conditions: neutral- (KMnO4), acidic- (KMnO4/H ) as carbonyl group from aromatic aldehyde. The yield of - well as basidic (KMnO4/OH ) condition. this oxidation reaction has been not satisfied yet (24% from vanillil alcohol 10), therefore in the next In this work will be tried to oxidize vanillin alcohol 10 work this yield should be optimized. Normally, the by using K2Cr2O7 in acidic (concentrate H2SO4) aroma of the synthetical vanillin is not so intens than the condition as oxidator in the heterogeneous phase related naturally vanillin. catalyzed by 18-crown ether-6 as phase transfer catalyst. + K2Cr2O7/H is chosen as oxidator in this work because The overall oxidation reaction of vanillil alcohol 10 to should be oxidized to , the reaction product (vanillin) can be shown in the therefore there is needed a stronger oxidation agent, and Figure 17.

H H H HO H _ H H H _ HO + O C OC OC + + H H 2O Cl Cl Cl

Figure 12. The second step of proposed mechanism of the modified Sandmeyer modification reaction

_ OH OH O O O O OCH OCH OCH OCH3 OCH3 OCH3 3 3 3 _ _ H O + OH 2

1 _

Figure 13. Activated benzene ring toward the electrophilic substitution reaction (SE)

_ O O O OH

OCH3 OCH3 OCH3 H H+ + CO H _ H HCH2O CH2OH CH2OH __10

Figure 14. The last step in the electrophilic substitution reaction (SE)

MAKARA, SAINS, VOL. 6, NO. 2, AGUSTUS 2002 97

OH OH

OCH 3 OCH3 KMnO4 / PTC 40o C

CHO

4 __16 cis or/and trans _

Figure 15. The oxidation of isoeugenol 16 to the vanillin

OH OH

OCH3 OCH3 + K2Cr2O7 / H, PTC RT

CH2OH CHO 10 4 __ _

Figure 16. The oxidation of benzylalcohol 10 to the vanillin

OH OH

OCH3 OCH 3 3 18C6 + K Cr O +4 H SO 3 + K SO + Cr (SO ) + 7 2 2 7 2 4 RT 2 4 2 4 3 H2O

CH2OH CHO 10__ _4

Figure 17. The overall reaction of benzylalcohol 10 to the vanillin 4

Conclusion 2. The phase transfer catalyzed oxidation reaction + of vanillil alcohol with K2Cr2O7/H in From this work can be drawn two conclusions : heterogeneous phase could produce vanillin in 1. The in situ generated formaldehyde in 24.4% (or 6.2% from starting material, heterogeneous phase catalyzed by phase guaiacol) transfer catalyst (PTC) could become new alternative for semi-synthesis vanillin from References guaiacol (new variant of Sandmeyer modification reaction). The yield of vanillil [1] F.W. Wells, M. Billot, Perfumery and Flavoring alcohol with this reaction method is 25.3% Synthetics, 2nd ed., Elsevier Publ. Co., New York 1967. 98 MAKARA, SAINS, VOL. 6, NO. 2, AGUSTUS 2002

[2] I. Kirk, F. Othmer, Encyclopedia of Chemical [7] K.T.C. Vollhardt, N.T. Schore, Organische Technology, 3rd ed., John Wiley & Sons, Chemie, VHC Verlagsgesellschaft-mbH, New York, 1977. Weinheim, Germany, 1995. [3] J. Kroschwitz, Kirk-Othmer, Encyclopedia of [8] E..V. Dehmlow, S.S. Dehmlow, Verlag Chemie, Chemical Technology, Wiley Interscience Basel 1980. Publication, New York, 1986. [9] E.V. Dehmlow, E. Weber, Merck-Schuchardt, [4] W. Priyono Suwarso, Suyanto, 2nd ITB-UKM Mainz, West Germany (1989). Joint Seminar on Chemistry, ITB, Bandung [10] C.M. Stark, C. Liotta, Phase Transfer Catalysis: (1995). Principle and Techniques, Academic Press, New [5] W. Priyono Suwarso, E. Budianto, I. Jayadi, York, London, 1978. Makara, Seri Sains 6 (2002) 70. [11] W. Priyono Suwarso, Synthesis Vanillin I: Semi- [6] W. Priyono Suwarso, B. Siahaan, 2nd National Synthesis Vanillin from by Using Seminar on Chemistry at Chemical Industrial Photochemical and Phase Transfer Catalyst Era in Indonesia University of Gadjah Mada, (PTC) Methods, Second Malaysian International Yogyakarta, 1997. Conference on Essential Oils and Aroma Chemicals (SMIC-EOAC), Kuala Lumpur, Malaysia (1990).