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I.

INTRODUCTION

Chemical synthesis is the execution of one or more chemical reactions in order to produce a
certain product; in relation to organic chemistry, organic synthesis is a branch of chemical
synthesis that deals with the construction of organic compounds, often times from inorganic
products (New World Encyclopedia 2017). In this exercise, Williamson Ether Synthesis (an SN2
reaction) will be employed to prepare 2-naphthoxyacetic acid, a phytohormone used as a plant
growth regulator on tomatoes and strawberries (Sigma-Aldrich 2017); further purification by
recrystallization will follow.

Williamson Ether Synthesis is an SN2 reaction between a deprotonated alcohol, or an "alkoxide",


and an alkyl halide that forms an ether (Ashenhurst 2014). SN2 is short for "substitution
nucleophilic bimolecular", and it is a substitution reaction featuring nucleophilic aliphatic
substitution at an sp3 carbon, which can be viewed as a Lewis acid-base reaction (see Figure
7.1.); for example, a halide present at the sp3 carbon can be replaced by another group, and the
carbon that bears the electonegative halide is partially positive due to the polarizaton of the C-L
bond, then it is attacked by the nucleophile (which seeks a a positively charged atom) for
electron donation, thus forcing the leaving group L to accept a pair of electrons from the
breaking bond.

FIGURE 7.1. Outline of nucleophilic aliphatic substitution.

Simultaneously with this, a carbon-nucleophile bond is formed and the carbon-leaving group
bond separates (Hardinger 2016); this type of mechanism can be seen in Figure 7.2.

FIGURE 7.2. An example of an SN2 reaction.

In Williamson Ether Synthesis, the nucleophile will be either a phenoxide or alkoxide ion that is
generated by the action of a base on phenol or alcohol, respectively. The base in question for
this exercise is aqueous sodium hydroxide or NaOH, and the amount of base to be used in
relation to the starting product (2-naphthol, in this case) should be carefully monitored and
checked stoichiometrically, as if too little is used, the reaction may proceed too slowly or the
conversion to the desired product might be too low; coversely, an excess of base could cause
participation in side reactions, lowering yields, or cause corrosion of reaction vessels (King,
Mitford and Hippler 2015).

Phenols, as a weak acid, react with NaOH to form a colorless solution containing sodium
phenoxide (see Figure 7.3.); in this reaction, the hydrogen ion has been removed by the strongly
basic hydroxide ion in the sodium hydroxide solution (Clark 2004).

FIGURE 7.3. Reaction of a phenol with aqueous sodium hydroxide.

Alcohols, on the other hand, are slightly weaker acids than water and much weaker than
phenols, so they require a strong base to be able to form alkoxide; as it is, alcohols react with
aqueous sodium hydroxide, breaking the bond between the hydrogen and oxygen atoms (see
Figure 7.4.) (Reusch 2013).

FIGURE 7.4. Reaction of an alcohol with aqueous sodium hydroxide.

Once a phenoxide or alkoxide has been formed, it will be able to react with a particular alkyl
halide, which is chloroacetic acid in this exercise (which should also not be dissolved in too much
water to prevent complete dissociation), in an SN2 reaction to create ether (see Figure 7.5.).
However, after the initial deprotonation, its conjugate acid is still present in the solution, and
therefore has the potential to react with the added alkyl halide; this can be prevented by
ensuring that the base used for deprotonation will be able to liberate hydrogen so that the
byproduct can bubble out or be vaporized by heat (Ashenhurst 2014).

FIGURE 7.5. An alkoxide reacts with an alkyl halide to form ether.

VI. Discussion

2-naphthoxyacetic acid was prepared from 2-naphthol using the Williamson Ether Synthesis,
wherein an alkoxide ion (RO-) reacts with an alkyl halide through an SN2 mechanism (Carey
2000); this reaction also allows the formation of asymmetric ethers, or ethers with two different
R groups. As with all reactions, the nucleophile and electrophile must be taken into account,
along with the solvent and physical conditions such as temperature and pressure. Assuming
stable conditions, in Sn2 reactions the nucleophile should have an unstable negative charge,
however it should not be too basic as this may result in no attack on the electrophile, while the
said electrophile should have a net positive, polar charge and should not be sterically hindered
(Socratic 2014). The solvent, on the other hand, would preferably be nonpolar and aprotic; this
way, no solvent molecules would reduce the nucleophilicity or electrophilicity, and it would
ensure that the nucleophile attacks the electrophile.

Initially, 10% NaOH was added to 2-naphthol in order to deprotonate it and yield an alkoxide ion
(RO-), which acts as the nucleophile instead of the alcohol (ROH) due to the higher electron
density, resulting in a faster reaction (Ashenhurst 2014). The alkyl halide used in the experiment,
chloroacetic acid, is ideal due to it being a 1º-alkyl halide where elimination reactions are not a
possible side reaction (Reusch 2013), unlike secondary and tertiary alkyl halides wherein
elimination pathways become a concern, especially due to the alkoxide being a strong base. If
another alkyl halide with a longer parent chain, such as 4-chlorobutanoic acid for example (see
Figure 7.9.) were used instead of chloroacetic acid, the percentage yield of crude 2-
napthoxyacetic acid may decrease slightly due to the presence of more hydrogens, which
increases the chances of an electrophilic attack on the hydrogens instead of the electrophile
itself, possibly resulting in hydrochloric acid or water.

[FIGURE 7.9.] Appearance of 4-chlorobutanoic acid compared to chloroacetic acid.

The percentage yield for the crude product, presumably "2-naphthoxyacetic acid", was low at
0.6% (see Table 7.1.) due to the use of 10% NaHCO3 instead of saturated NaHCO3 solution
during the extraction of the organic layer, causing most of the 2-naphthoxyacetic acid to remain
in the discarded layer. Due to the low recovery, recrystallization was unable to be performed,
thus no data was gathered (see Table 7.1.). During characterization (see Table 7.2.), 2-naphthol
did not exhibit solubility in water or NaHCO3, while chloroacetic acid was the opposite, and the
resulting product was also soluble in both solvents, following the solubility of true 2-
naphthoxyacetic acid. In the FeCl3 test, only 2-naphthol reacted to form a dark green color (see
Table 7.3.), testing positively to the phenol group present (see Figure 7.10.).

[FIGURE 7.10.] Reaction of phenol with Fe3+.

However, upon determining the melting point through use of the Fisher-Johns apparatus, the
melting point of the recrystallized product was seen to be above 160 degrees C, greater than the
true melting point of 2-naphthoxyacetic acid at 156 deg C; this discrepancy could be due to
either systematic error or impurities in the acquired product with higher melting points than
that of the desired 2-naphthoxyacetic acid.

In differentiating phenols and alcohols, they are both very weak acids, however phenol is
sufficiently acidic for it to have recognizable properties. Phenols react with sodium hydroxide to
give a colorless solution containing sodium phenoxide, which can be seen in Equation 7.1.,
conversely they don't tend to give carbon dioxide (unlike majority of acids) when mixed with
sodium carbonate or bicarbonate solutions due to its low acidity (Clark 2004). With sodium
metal, phenol will react to give hydrogen gas, as acids do when crossed with reactive metals,
albeit phenol will react slowly due to its weak acidity (see Equation 7.2.).

[EQN 7.1.]

[EQN 7.2.]

Alcohols, on the other hand, when treated with NaOH, react to form an acid-base equilibrium
(see Equation 7.3.), and because most alcohols are slightly weaker acids than water, the left side
is favored (Reusch 2013); alcohols do not react with NaHCO3, however, due to being nearly
neutral and therefore unable to react with the basic bicarbonate solution. With sodium metal in
an alcohol like ethanol, for example, hydrogen gas is released and a colorless solution of sodium
ethoxide, an alkoxide, is left behind, as seen in Equation 7.4. (Clark 2003).

[EQN 7.3.]

R–O–H + Na(+) OH(–) R–O(–) Na(+) + H–OH

[EQN 7.4.]

Applying the Williamson Ether Synthesis, synthesizing benzyl t-butyl ether from benzyl alcohol
and t-butanol is not feasible, as an SN2 reaction will not take place. However, if the benzyl
alcohol can be converted to a benzyl halide, such as benzyl bromide through terabromethane
and triphenylphosphine (Lee and Hwang 2004), then the halide can be displaced with t-butanol
in an SN2 mechanism.

VII. Summary and Conclusion

The Williamson Ether Synthesis, an SN2 mechanism, was used to prepare 2-naphthoxyacetic acid
from 2-naphthol.

10% NaOH deprotonated 2-naphthol in order to yield an alkoxide, which acts as the nucleophile,
and the alkyl halide, chloroacetic acid, acts as the electrophile. The resulting crude product
however, was low at 0.6% (see Table 7.1.) due to the use of 10% NaHCO3 instead of saturated
NaHCO3, causing most of the 2-naphthoxyacetic acid to remain in the discarded layer, and so
recrystallization could not be performed. Following group data, the recrystallized product was
then subject to solubility and FeCl3 tests, where the data followed that of true 2-
naphthoxyacetic acid (see Tables 7.2. and 7.3.); however, the melting point of a recrystallized
product was taken to be above 160 deg C whereas the literature value for 2-naphthoxyacetic
acid is 156 deg C (see Table 7.1.), the difference in melting points may be either a systematic
error or due to the presence of impurities.

VII. References

A. Books

CAREY F.A. 2000. Organic Chemistry. 4th Edition. New York City, USA: McGraw-Hill Companies.

B. Journals

LEE J.C., HWANG E.Y. 2004. An International Journal for Rapid Communication of Synthetic
Organic Chemistry 34(16): 2959-2963.

C. Web Sources

ASHENHURST J. 2014. The Williamson Ether Synthesis. Retrieved October 17, 2017, from:
https://www.masterorganicchemistry.com/2014/10/24/the-williamson-ether-synthesis/

CLARK J. 2003. Alcohols and sodium. Retrieved October 31, 2017, from:
http://www.chemguide.co.uk/organicprops/alcohols/sodium.html

CLARK J. 2004. The acidity of phenol. Retrieved October 17, 2017, from:
http://www.chemguide.co.uk/organicprops/phenol/acidity.html

HARDINGER S. 2016. Illustrated Glossary of Organic Chemistry - SN2 Mechanism. Retrieved


October 17, 2017, from: http://www.chem.ucla.edu/~harding/IGOC/S/SN2_mechanism.html

KING S.W., MITFORD R.R., HIPPLER J.G. 2015. Process for making ethers from alkoxide anions or
precursors of alkoxide anions. Retrieved October 17, 2017, from:
https://www.google.com/patents/US8957256

NEW WORLD ENCYCLOPEDIA. 2017. Organic Synthesis. Retrieved October 17, 2017, from:
http://www.newworldencyclopedia.org/entry/Chemical_synthesis#Organic_synthesis

REUSCH W. 2013. Alcohol Reactivity. Retrieved October 17, 2017, from:


https://www2.chemistry.msu.edu/faculty/reusch/virttxtjml/alcohol1.htm

SIGMA-ALDRICH. 2017. 2-napthoxyacetic acid. Retrieved October 17, 2017, from:


http://www.sigmaaldrich.com/catalog/product/sigma/n3019?lang=en&region=PH

SOCRATIC. 2014. What factors affect SN2 reactions? Retrieved October 31, 2017, from:
https://socratic.org/questions/what-factors-affect-sn2-reactions