Synthesis of Ethyl ß-Naphtholate (Nerolin)

A. Introduction
This procedure is for the preparation of nerolin, a perfume, and scent fixative. It is an alkyl aryl ether and is prepared here using the Williamson ether synthesis.

ß-naphthol, a weak acid, reacts with potassium hydroxide to form potassium ß-naphtholate:



The ß-naphtholate anion then reacts with ethyl iodide by an SN2 mechanism to give ethyl ß-naphtholate:



B. Reagents
8g of potassium hydroxide (corrosive!)
6mL of ethyl iodide
10g of ß-naphthol
100mL of methanol (anhydrous)

CAUTION: methanol is highly flammable, and poisonous



reagents

C. Equipment
250mL RBF
condenser (cold water cooled)
heating mantle
magnetic stirrer (optional)
600mL beaker
7cm Buchner funnel
suction flask
vacuum source
25mL Erlenmeyer flask

D. Procedure
Set up the 250mL RBF and condenser for reflux as shown in the photo below. The use of magnetic stirring is optional. However, it assists in mixing the reactants prior to boiling, and mitigates the mild bumping that occurs in the latter part of the reflux period.


2 hour reflux

Place the methanol, ß-naphthol, KOH, and ethyl iodide in the 250mL RBF. Heat to boiling and reflux for 1.5 to 2 hours.

E. Workup
Fill the 600mL beaker to the 300mL mark with cracked ice. Then pour the hot reaction product onto the ice and stir well. The nerolin will precipitate as shown in the photo below:


precipitated nerolin on ice

When the ice has melted collect the nerolin by vacuum filtration using the Buchner funnel. Crude nerolin (~5g) is shown in the photo below:


crude nerolin

Recrystallize the nerolin from methanol. You should get some glistening pure white plates as shown in the photo below:


recrystallized nerolin

F. Results
The recrystallized nerolin shown above had a melting point of 36°C. The literature value is 37-38 °C. My yield was only 0.32g.

G. Discussion
Nerolin is used in perfumery and as a fixative in soaps. Fixatives reduce the evaporation rate of other added volatile scents.

One source of the discoloration in the crude nerolin was likely the homemade ß-naphthol, as it is also off-color. During the recrystallization there was a large amount of contamination that precipitated out first. I carefully removed the upper crystals which looked to be quite pure as shown in the photo above. I then attempted to harvest more pure crystals from the heavy residue but was not successful.

I’m not sure why the yield of nerolin is so low. Perhaps steric hindrance plays a part as the ß-naphtholate anion is quite bulky. I should also mention that I accidentally used 150mL of the solvent methanol instead of 100mL, which would reduce the concentration of the reactants.

This is a simple procedure and you are rewarded with a most delightful smelling compound. It smells so good you will not want to wash it off your hands. I detect notes of vanilla and citrus.

H. Reference
This procedure is a 2X scale paraphrase of a college hand-out obtained in 2003.

Quote: Originally posted by reckless explosive

Could ethyl bromide be used in place of the ethyl iodide as long as its in the same stoichiometric amounts?

Quote: Originally posted by sbbspartan

Is that how you made your ß-naphthol Magpie?

Funny, I didn't even realize the thread you listed was the same one I was looking at.

You use the same source of methanol as I do too. I like HEET, it's easy to get and cheap...

Good prep!

I too, recently finished the preparation of 2-ethoxynaphthalene via a slightly alternate procedure (that I more or less made up entirely as modifications of this prep). Instead of KOH, I elected to use sodium methoxide produced freshly as base. My starting 2-naphthol was somewhat less pure than Magpie's, melting from 118-120C (uncorr, lit. value 123C). This is pictured below.



A 250ml RBF was charged with a stirbar and 75ml of methanol (HEET, distilled to remove the fraction of a percent of oily high-boiling material). 1.33g (0.058mol) of fresh sodium, cut into thin sticks to speed reaction was added and stirring started. The methanol became quite warm as the sodium rapidly dissolved to an ever-so-slightly hazy solution of NaOMe in methanol.



7.21g (0.050mol) of the aforementioned (and pictured) mostly-pure 2-naphthol was added to this methoxide solution, rapidly dissolving to a dark brown solution. A liebig condenser was placed atop the RBF as a reflux condenser. After stirring for ~5 minutes, 10.92g (0.10mol) of Ethyl Bromide (I don't reccomend this. Just get some iodide. The reflux period is way too long with bromide unless you're making mol quantities.) was poured down the condenser into the reaction mixture, and the condenser was topped with a CaCl2 drying tube.

Very gentle reflux was maintained for 26 hours (arbitrary, based on the advice of Nicodem in the 2-naphthol thread, I did not have TLC plates to monitor with) The reaction mixture remained at ~50C during the entire period and at no time was the condenser permitted to rise above 20C through addition of ice to the recirculating water bath. The color of the reaction mixture lightened over the reflux period, but remained brown.



The reaction mixture was then brought to a vigorous boil for 5 minutes with the condenser removed in order to expel excess EtBr and any ethereal byproducts. The hot reaction mixture was poured into 300ml of ice water containing 2g of NaOH to help dissolve any unreacted naphthol. Initially, the mixture was a milky off-white suspension, but with stirring the 2-naphthol slowly "curdled" and sank to the bottom of the beaker leaving a cloudy, but decidedly translucent supernatant.



This solid was vacuum filtered and washed with 100ml of distilled water. It is highly hydrophobic. Air is drawn through the solid for some time and it dries fairly easily, providing 7.41g of crude 2-ethoxynaphthalene as a tan powder (86% yield).

An attempt was made to purify this material by recrystallization from dry methanol, which failed. 90% methanol, 10% water was then tried, which also gave a dark brown oil. I ended up reprecipitating with icewater, but the emulsion did not "curdle" like the first time and it remained white and milky with some chunks of tan material at the bottom. An attempt at vacuum filtration did not separate the emulsion and the medium frit plate plugged completely after a portion of "milk" was drawn through. DCM was added to the emulsion and stirred vigorously, but the "milk" remained. It was found that adding a few grams of NaCl caused the emulsion to break and the aqueous phase to clear. The DCM phase was boiled down, transferred to a 50ml RBF with stirbar and completely stripped of DCM under vacuum.

Disregard the above italics if repeating this preparation and simply transfer the crude 2-ethoxynaphthalene to a 50ml RBF with a small stirbar. The crude material is vacuum distilled with a short path stillhead. An air condenser is suitable for this scale, but ~40C water should be used for any larger amount.



The bulk of the material passes over at 170C (~30torr) with some forerun in the 160C range and is collected as a very slightly yellow oil that freezes in the reciever to a crystalline solid. Yield is 6.31g (73% yield from 2-naphthol, 85% recovery) of 2-ethoxynaphthalene as a white crystalline solid melting at 33-34C (uncorr. lit, 36-37C).



It has a powerful scent reminiscent of a more floral, sweeter version of methyl benzoate that is otherwise hard to put a finger on. At extremely high concentrations (nose right up to the bottle) it seems to have a disagreeable fecal smell. This could be impurity, but it would not surprise me seeing as how indole, which is floral at low concentrations is fecal at any decent concentration. Nerolin may activate the same receptors, but with different affinities.

It might be possible to properly recrystallize the material at this point and improve the m.p, but I'm sick of working with it after the first recrystallization failures.

[Edited on 10-26-13 by UnintentionalChaos]

Quote: Originally posted by vulture

Question: Why the specific warning for methanol? I'd be more weary of exposure to alkylbromides and iodides.

2-Ethoxynaphthalene using ethanol and sulfuric acid

I want to present another alternative synthesis and workup for 2-ethoxynaphthalene, which avoids alkyl halides.

The preparation comes from an article by Gattermann from the late 19th century.^[1]

Chemicals:
2.5 g 2-naphthol
2.5 mL absolute ethanol
1 g 98 % sulfuric acid
MTBE
Sodium hydroxide
Sodium sulfate for drying

For the pad:
Cyclohexane
Silica gel 60 A, 40-63 µm

Procedure:
The 2.5 g of 2-naphthol were dissolved in the ethanol (2.5 mL) in a 25 mL flask, then the 1 g of 98 % sulfuric acid was added carefully. This addition is quite exothermic. A reflux condenser is added and the mix is refluxed for 4 hours by using an oil bath at 145 °C.

Then, the flask is allowed to cool a bit and the contents are dumped into 50 g of icewater, which is then extracted with 30 mL of MTBE in two portions. (I'm sure diethyl ether would work just as well if not better.) The organic layers are combined.

15 g of sodium hydroxide was dissolved using 50 mL of water, left to cool and then used to wash the MTBE extract in two portions. Three phases are observed: An aqueous bottom layer, above that a brown oil and above that a slightly brown MTBE layer. Only the top MTBE layer is retained. On standing the brown oil solidifies into a glittering plate-like solid, it is 2-naphthol.

The MTBE is dried over anhydrous sodium sulfate, then removed in a simple distillation using a water bath. The residual liquid froze in the fridge.
Yield 2.19 g (73 %) of slightly brownish 2-ethoxynaphthalene.



Analysis:
A TLC (silica 60 F₂₅₄, glass backed) was done using 9/1, v/v, n-hexane/ethyl acetate as the eluent. Visualized with 250 nm UV (2-ethoxynaphthalene shows a blue fluorescence) and by staining with Hanessians stain (developed at 250 °C with a heatgun). Approximate R_f values are 0.21 for 2-napthol and 0.70 for 2-ethoxynaphthalene. The product contains traces of 2-naphthol and another unknown impurity at an R_f of about 0.29.


Left lane: 2-Naphthol.
Middle lane: The brown oil.
Right lane: Final MTBE extract before evaporation.
Between the lanes co-spots of the adjacent lanes.
Left image under 250 nm UV, right one after staining with Hanessians stain.

Further workup:
The product was padded with cyclohexane. A glass frit with a diameter of about 2 cm and a height of about 10 cm (called a "filter tube, according to Allihn", example from Roth) was filled with a slurry of silica gel (60 A, 40-63 µm) in cyclohexane. This was put onto a filtration flask with a vacuum pump attached. Then the product was dissolved in about 20 mL of cyclohexane, added onto the column, the solvent was run into the silica and it was eluted using about 80 mL of cyclohexane. In the end the column was pulled mostly dry with the vacuum. All the brown and yellow impurities stay within 1 cm of the top, the filtrate is colorless. The cyclohexane is recovered by distillation, a vacuum is applied at the end to remove the last amount of cyclohexane, the residual liquid freezes into a white solid in the fridge.

After drying in air, the white solid weighs 1.97 g (66 % based on 2-naphthol).



Discussion:
Washing the MTBE with sodium hydroxide is supposed to remove most unreacted 2-naphthol. If the 2-naphthol that precipitated out was included, the yield based on unrecovered 2-naphthol would likely be considerably higher.
The padding eluent was chosed by suggestion of CorrosiveChemistry, who I'd like to thank here. I'm quite happy with how it turned out.

The original paper also mentioned the same method works for the methyl ether. In this case they heated to 125 °C, but they do mention that it is beneficial to work "under the pressure of a small mercury column". So some slight pressure seems to help in the case of the methyl ether. Maybe it could work without?

Literature:
[1] - L. Gattermann, Justus Liebigs Ann. Chem. 1888, 244, 29-76. https://doi.org/10.1002/jlac.18882440104

[Edited on 29-11-2023 by Diachrynic]

Quote: Originally posted by Metacelsus

Alzheimer's researchers who abbreviate amyloid-beta as Aß are making asses of themselves, see for example: https://pubmed.ncbi.nlm.nih.gov/11145990/

Literally

Questions about synthesis of 2-Ethoxynaphthalene using ethanol and sulfuric acid

Quote: Originally posted by AvBaeyer

I have executed the same reaction under several conditions including that reported by Diachrynic and have never achieved a yield in excess of 35% of crystalline 2-ethoxynaphthalene melting at 34-36 C. My reactions were all run using 5.0 g of 2-naphthol (mp 120-121 C), undenatured absolute ethanol and 96% sulfuric acid (by titration). I use hexane to extract the product from the work up mixture. The crystalline product is isolated directly from the hexane extract after a brine wash, drying, and evaporation of the hexane. I can recover about 85% of the unreacted 2-naphthol which is extremely difficult to filter.

Quote: Originally posted by Fery

Damn the longer carbon chain the lower m.p., some kind of unexpected anomaly.

Quote: Originally posted by Texium

Not really. That’s a pretty typical trend for molecules like this. Longer “greasier” alkyl chains attached to aromatic compounds tend to disrupt the crystal structure and lower the melting point.