Potential Test Question

A potential question I see that might be on our next test involves the Robinson Annulation.  The question asks: Draw the product of the Robinson Annulation from the given starting materials using -OH in H₂O.  This question appears in the problems at the end of Chapter 24.  See page 953, problem number 24.41, part D.

The starting materials are:

The product of this reaction will form a six-membered ring and three new carbon-carbon bonds.  First an enolate will form from the first starting material.  Then nucleophilic attack of the beta carbon and protonation occurs.  Next, an intramolecular aldol reaction will take place to form a beta-hydroxy ketone. Lastly, the material will be dehyrated to form the final alpha,beta-unsaturated ketone as follows.

An easy way to draw the product of this type of reaction is to place the alpha carbon of the compound that becomes the enolate next to the beta carbon of the alpha,beta-unsaturated carbonyl compound.  Then, join the appropriate carbons together so that a new six-membered ring forms. To better understand the Robinson Annulation reaction, see section 24.9 starting on page 936 of our textbook.  I think that a problem like this might about on our next exam because it incorporates topics that we have previously discussed and other reactions we have learned about in chapter 24.

Seminar Extra Credit Summary (for Lab)

Steven R. Meyers, Ph.D Assistant Professor,

Dept. of Pharmacology and Toxicology,

University of Louisville School of Medicine

Tobacco Smoking During Pregnancy – Biomarkers of Exposure & the

Relationship to Genetics

In the state of Kentucky, 30% of mothers smoke. This causes the baby to get less food and oxygen.  As a result, there are higher rates of miscarriage, still births, premature births, low birth weights, placenta previa, low IQ levels, ADHD, and infants dying of SIDS (Sudden Infant Death Syndrome).  If the child is exposed to second hand smoke during the first two years of life they may get ear infections, asthma or bronchitis, and pneumonia.

We know that tobacco smoke causes cancer, respiratory disease, cardiovascular disease, and cerebrovascular disease in adults. Children who are exposed to tobacco smoke have a 60% increase of having a lower respiratory disease.  There is also an increase risk of developing asthma, inner ear and other ear infections causing long-term hearing problems, and an increase risk of dying of SIDS.  There is no safe time for a mother to be exposed to tobacco smoke. Although there are no adverse effects during the first two weeks, it causes a difficulty attaching to the ovum.  During the third and eighth weeks embryonic development of organs and tissues can be damaged. The most common effect is cleft lip and cleft palate due to exposure to chemicals like the ones in tobacco smoke.  During the last stages of pregnancy functional defects and problems during birth can occur.

Biomarkers are needed because there are approximately 4000 chemicals in tobacco smoke. This is the leading cause of avoidable cancer death. Biomarkers are molecular, biochemical, or cellular alterations that are measurable in biological media such as human tissue, cells, or fluids.  The earlier the biomarker is detected, the more likely the disease will be stopped.  They can be found in metabolites in the body, DNA adducts, and gene mutations.  Biomarkers are selected by determining if it is related to the disease, if it appeared at a defined stage of disease, if it can be obtain non-invasively, if it can be modulated by eliminating exposure, if it provides specificity, sensitivity, and practicality, and if it is stable and easy to measure.

Amniotic fluid can be a biomarker during the first trimester because it protects the fetus. It is filled with urine from the fetus and can tell what the fetus has been exposed to.  During a study where women had an amniocentesis, 1-Hydroxypyrene and Benzo(a)pyrenes were detected and the levels increased as the amount of cigarettes smoked increased.  Hemoglobin can also be a biomarker of carcinogens and tobacco smoke exposure.

Since amino acids undergo nucleophilic substitution with electrophiles in tobacco chemicals, looking at the enzymes that are responsible for getting rid of chemicals in the body is a good place to find biomarkers.  If a person is null genotype they do not have the genes to make these enzymes and are at an increased risk of cancers.  These people often have much more benzo(a)pyrene in the body.  The enzyme N-acetyl transferases activate and deactivate aromatic and heterocyclic amines in the body. If a person does not have this enzyme, they are also at an increased risk.  Fetuses do not develop these enzymes until two years of age.

4-Aminobiphenyl is an aromatic amine that is a strong bladder carcinogen prominent in tobacco smoke.  It is one of the most carcinogenic chemicals in the smoke that we know of.  During a study, it was found that nonsmokers had a very small amount in their system, passively exposed mothers and babies had levels of this chemical, and in smokers the levels increased as the amount of cigarettes smoked increased. 

After all of these studies, it can be seen that there is a correlation of the amount a mother smokes affecting her baby.  It is also observed that the more chemical compounds found in babies, the less they weigh.  The final study showed that there was no difference in African Americans to Caucasians but the amount if Hispanics was much lower in mothers and in the babies.  The birth weights of Hispanic babies were also greater than African Americans and Caucasians.  Overall, this presentation showed that mothers should not smoke during of after pregnancy because the effects are very dangerous and harmful to the baby.

Hell-Volhard-Zelinsky Halogenation

The Hell-Volhard-Zelinsky halogenation reaction halogenates carboxlyic acids at the alpha carbon.  Treatment with bromine and a catalytic amount of phosphorus leads to the selective α-bromination of carboxylic acids. PBr₃ replaces the carboxylic OH with a bromide, resulting in a carboxylic acid bromide. The acyl bromide can then tautomerize to an enol, which will readily react with bromine to brominate a second time at the α position. 

Now that I have introduced what the HVZ halogenation reaction is, let's examine a specific example. This reaction was used in the invention of Cycloalkane Carboxaldoxime Carbamates, which are used as pesticides. The compounds can be prepared via the alpha halogenation of cyclic carboxylic acids under slightly modified Hell-Volhard-Zelinsky conditions (Step I) followed by esterification to give the cyclic alpha halocycloalkanecarboxylic acid ester. The active halogen is easily displaced with sodium alkyl mercaptide in alcohol to yield the alkylthio ester. Hydrolysis of the ester followed by reacting the hydrolyzed product with thionyl chloride gives the reactive acid chloride which is transformed into the aldehyde. Further reaction of the aldehyde with hydroxylamine hydrochloride in base gives the corresponding oxime which in turn can be carbamoylated with suitable reagents to form the final insecticidal agent.

Sources:

http://www.google.com/patentshl=en&lr=&vid=USPAT3721711&id=9yMuAAAAEBAJ&oi=fnd&dq=hell+volhard+zelinsky+halogenation&printsec=abstract#

http://en.wikipedia.org/wiki/Hell-Volhard-Zelinsky_halogenation

Ester: Gamma-Valerolactone

Gamma-Valerolactone

(http://toxicopoeia.com/chemistry/molecules/GVL-sm.png)

Gamma-valerolactone is one of the more common lactones. This compound is a colorless liquid and is used in the perfume and flavor industries because of it's herbal odor.¹ It is also a constituent of crude pyroligneous acid, in dye baths (coupling agent), brake fluid, cutting oils and as a solvent for adhesives, insecticides and lacquers.² Recently, it has been said that gamma-valerolactone is a promising "green" liquid fuel. This compound is derived from furfural:

 (http://www.alanwood.net/pesticides/structures/furfural.gif)


Basic Information
Melting Point: -31°C
Boiling Point: 207-208°C
Water Solubility: Miscible
Density: 1.03 g/mL
Irritant to eyes, respiratory system, and skin


I had a difficult time finding a reaction where gamma-valerolactone was converted to another carboxylic acid derivative. I did find a reaction where gamma-butyrolactone, which is very similar, was converted to alpha-tetralone. I found this on the organic synthesis website provided by Dr. Mullins. In the notes it states that replacing the butyrolactone with 120 grams of gamma-valerolactone in an otherwise identical procedure yields 150–160 grams (79–84%) of 4-methyl-1-tetralone.³ Here is the link so you can see what I'm talking about:
http://orgsyn.org/orgsyn/default.aspformgroup=basenpe_form_group&dataaction=db&dbname=orgsyn

Thanks for reading!


Sources:
1. http://en.wikipedia.org/wiki/Gamma-Valerolactone

2. http://www.erowid.org/chemicals/ghv/ghv_info2.shtml
3.http://orgsyn.org/orgsyn/default.aspformgroup=basenpe_form_group&dataaction=db&dbname=orgsyn

Grignard Reagent Synthesis

The following is a synthesis that involves a Grignard reagent during part of the reaction to yield the final product of  Tris(2-PerFluorohexylethyl)tin hydride:

The Grignard reagent is used in step B of the sythesis to yield Tris(2-perfluorohexyl ethyl)phenyl tin.

This compound is made by frist dissolving Phenyltin trichlorid in dry benzene in a 100-mL, round-bottomed flask under argon at room temperature. The solution is slowly added to a 500-mL, three-necked flask containing the Grignard reagent at room temperature over 1 hour, while stirring.. The reaction mixture is heated at reflux overnight in an oil bath at 50°C, removed from the bath, and allowed to stand at ambient temperature for 4.5 hours, with stirring. The reaction mixture is diluted with ether, vacuum filtered into an Erlenmeyer flask, and hydrolyzed with saturated ammonium chloride solution. Excess magnesium solid is also hydrolyzed with saturated ammonium chloride separately. The mixture is transferred to a separatory funnel. The water layer is removed, and the organic layer is washed three times with 3% sodium thiosulfate. Theorganic layer is dried over magnesium sulfate and filtered under vacuum. The solvent is evaporated to dryness under reduced pressure using a rotovap. The impure product is redissolved in ether and transferred to a 50-mL pear-shaped flask. The ether is removed under reduced pressure. Kugelrohr distillation is peformed to remove a dimer impurity of (C6F13CH2CH2CH2CH2C6F13) at 0.02 mm, 100-120°C for 5 hours. The residue is further purified by column filtration over silica under pressure with hexane. The solvent is evaporated under reduced pressure to leave 17.2 g of pure compound as a colorless oil.

The spectral properties of product of product 1 are as follows: 1H NMR (CDCl3) δ:1.31 [t, 6 H, J = 8.3, 2J(119Sn-H) = 53.4], 2.31 (m, 6 H), 7.41 (s, 5 H) ; 119Sn NMR (CDCl3) − 11.7 ppm; IR (thin film) cm−1: 3100, 2950, 1238, 1190, 1144, 655 ; MS (m/z) 1161 (M+ - Ph), 891 (M+ -CH2CH2C6F13).

The spectral properties of product 3 are as follows: 1H NMR (CDCl3) δ: 1.16 [t, 6 H, J = 8.1, 2J(119Sn-H) = 53.4], 2.35 (m, 6 H), 5.27 (s, 1 H) ; 119Sn NMR (CDCl3) − 84.5 (1J(119Sn-H) = 1835) ;−1: IR (thin film) cm 1842, 1197 ; MS (m/z)1161 (M+ - H), 813 (M+ - CH2CH2C6F13).

Thin layer chromatography was performed using silica plates and eluting with

hexane. Potassium permanganate was used to visualize the spots. The Rf values for products 1 and 3 were 0.38 and 0.37, respectively.