Structure Determination Using "F NMR A Simple Fluorination Experiment of Cinnamyl Alcohol Daniel J. deMendonca, Cheryl A. Digits, - Erin W. Navin, Tanya C. Sanders, and Gerald 6. ~ammond' University of Massachusetts Dartmouth, North Dartmouth, MA02747
High field NMR spectrometers are increasingly popular components of undergraduate laboratoly experiments. Traditionally, the use of FT-NMR in organic laboratories has been circumscribed to 'Hand nuclei. We want to expand the use of FT-NMR to other nuclei, particularly "F, through a n experiment that incorporates fluorine to a n organic molecule. To accomplish t h i s i n a n efficient manner we have developed a fluorination reaction suitable for a n honors organic laboratory or a n advanced organic preparations course. The focus of the experiment is the replace- Figure 1. Competing pathways in the nucleophilic fluorination of cinnamyl alcohol ment of a n allylic hydroxyl cohols. The difficulty in purifying structurally similar group with fluorine, via nucleophilic substitution, followed products derived from concurrent Ss2 and Ss2' mechaby "F NMR analysis of the resulting product. The novelty nisms in allylic systems, or the fastidious task of characof this approach rests upon the fact that displacement reterizing the resulting mixture of allylic halide isomers usactions of allylic alcohols, utilizing fluorinating agents, are ing proton NMR signals, are some of the reasons for the not found in organic chemistry laboratory manuals. few examples of allylic nucleophilic substitution in organic At the sophomore level the discussion of nucleophilic laboratory texts. The spectroscopic complexity of the 'H substitutions has been limited to classical experiments NMR spectrum of Ss2 and Ss2' derived products is comsuch a s the syntheses of alkyl halides via Ss1 or Ss2 dispounded when the substituted halide is NMR active. For placement of the hydroxyl group from simple aliphatic alexample, the extended multinuclear couplings that exist between protons and fluorine in a n allylic system impedes 'Author to whom correspondence should be addressed. a n easy identification of a mixture of 3-fluoro-l-phenyl-
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Journal of Chemical Education
Y ~ L . I . - , ~ - ~ ~ + ""*- ~ * ~ ~ ~ * ~ - ; ~ L u - ~ - - ~ '>
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Figure 2. 'H NMR of of allylic fluorides1 and 2 recorded on a 400 MHz spectrometer.
propene, 1, and 3-fluoro-3-phenylpropene, 2, using 'H NMR spectroscopy. I n our experiment, cinnamyl alcohol, dissolved i n methylene chloride, is added to diethylaminosulfur trifluoride2 (DAST) a t 0 "C (Fig. 1).DAST is a n efficient fluorinating agent for alcohols and some aldehydes and ketones ( I ) . The microscale reaction, carried out in a test tube, is shaken occasionally during 40 min, worked up and purified using a short silica-gel column. This reaction yields a mixture of cinnamyl fluoride 1, and its y-fluoro isomer 2. The procedure typically produces yields greater than 90%. Aglimpse of the 'H NMR spectrum of the resulting mixture of isomers (Fig. 2) shows a series of complex multiplets between 64.0-7.0, even a t high magnetic fields (400 MHz). The higher-order splitting pattern is due to homoand heteronuclear couplings between fluorine and the nonaromatic protons. This spectrum alone is insufficient to determine the percentage of n-fluorination and y-fluorination derived from S N a~n d S N ~mechanisms, ' respectively. Moreover, a physical separation of the isomers produced in the reaction is a daunting task due to their chemical similarities. However, a n analysis of the relative percentages of fluorinated isomers in the mixture can be determined effortlessly using "F NMR spectroscopy. The "F NMR spectrum of the same mixture (Fig. 3) is quite simple, showing
two major apparent multiplets centered a t d 169.77 ppm and 8211.02 ppm in a 1.7511.00 ratio, respectively. Upon close inspection, the resonance a t 6169.77 ppm (Fig. 3) shows a doublet split further into two sets of doublets which is consistent with the benzylic allylic fluorine in gfluoro isomer 2. The resonance a t 6211.02 ppm (Fig. 4) displays a triplet split further into two sets of doublets. This splitting pattern is compatible with the allylic fluorine in a-fluoro isomer 1. Thus, DAST fluorination of cinnamyl al3 cohol yields predominantly 2 via a S N ~pathway. ' This result can be compared nicely with peakintegration data obtained from GC-MS analysis of the mixture of isomers. Injecting a n aliquot into a GC-MS separates the mixture into two components, with retention times of 4.30 min. and 2.65 min., in 1.7511.00 ratio, and with almost identical mass fragmentation (see experimental section). The identity of the peaks cannot be established from the mass fragments alone hut the peak integration ratio is identical to the ratio of fluorine resonances obtained using 2Commercially available from Aldrich Chemical Company or PCR. Inc. 31n allvlic the re~lacementofthe hydroxyl group by fluorine , svstems , also may proceed via a cyclicSNi; mechanism producing the y-fluoro isomer 2. See ref. (1) pp 523-524. Volume 72 Number 8 August 1995
737
Figure 3. ' 9 ~NMR of a mixture of allylic fluorides1 and 2 recorded at 376.5 MHz.
NMR spectroscopv. Consequently, we can assim structure 2 to the compo~entwithlonger retention time. The c o m ~ l e t eexoeriment. e x c e ~ tFT-NMR data acauisition andAmanipuiation,can be completed within a three hour session. From a n educational standpoint t h e experiment described herein has unique features. The fluohnation of cinnamvl alcohol reauires onlv a mild fluorinatine aeent and so itprovides the'student with a n immediate contact with organofluorine chemistry. The allylic nucleophilic substitution typified bv our exoeriment will enhance the teaching of n&eophilic substitution in the laboratory, traditionally l i m i t e d t o S N a~n d S N substitutions. ~ To o u r knowledge, the svnthesis of allylic fluorides 1and 2 is hiththc under&;adunte organic laboratory. erto unknown Hecnuse the ratio of 1 to 2 cnnnot be determined direcllv using '11 NMR spectroscopy, but i t can be measured easily using "F S M R specrroscopy, the experiment gives the stud m t a first-hand experience of the uscfulnesi of N M R
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hMR ana 19F NMR spectra were recordeo bsng CDC as solvent 'F hMR SpeclrJn s referenced agalnsl inlernal CFCI, 'rl NMR spectrum against internal tetrarnethylsilane. Low-resolution El
mass spectrum was recorded on a Hewlett-Packard GC-MS 5970 with an ionization voltaae of 70 eV Peaks are reoorted as m/e (% intensity relative to basepeak)
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spectra of different nuclei. Furthermore, if a gas chromatography-mass spectrometer is available, the results from the spectroscopic examination can be complemented with a GC-MS study.
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Experimental procedure4 Caution: Carry out the procedure in a well-ventilated hood. DAST is a toxic, flammable and corrosive liquid that reacts violently with water.
A septum covered 10 x 100 mm test tube containing dry CHzClz (distilled over CaHd (1.5 mL) is cooled to 0 "C in a n ice water bath under inert atmosphere. DAST ( 0.15 mL, 1.15 mmol) is added via syringe. The mixture is swirled until homogeneous and allowed to cool for another 5 min. Next, a solution of cinnamyl alcohol (0.154 g, 1.15 mmol) in CHzClz (0.5 mL) is added dropwise with shaking. Shaking is continued occasionally over 40 min. The reaction mixture is quenched by transferring it slowly into a 15-mL centrifuge tube containing saturated aqueous NazCOs (2 mL). Caution: If done quickly, the addition of the reaction mix-
ture to aqueous Na,C03 can result in vigorous effervescence.
A slurry of silica-gel (70-230 mesh, 60 "J (0.75 g) in CHzClz (4 mL) is placed i n a micro column and conditioned
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